ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Sangjin Hong; Peter L Pedersen

doi:10.1128/MMBR.00016-08

. 2008 Dec;72(4):590–641. doi: 10.1128/MMBR.00016-08

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Sangjin Hong ¹, Peter L Pedersen ^1,^*

PMCID: PMC2593570 PMID: 19052322

Abstract

Summary: ATP synthase, a double-motor enzyme, plays various roles in the cell, participating not only in ATP synthesis but in ATP hydrolysis-dependent processes and in the regulation of a proton gradient across some membrane-dependent systems. Recent studies of ATP synthase as a potential molecular target for the treatment of some human diseases have displayed promising results, and this enzyme is now emerging as an attractive molecular target for the development of new therapies for a variety of diseases. Significantly, ATP synthase, because of its complex structure, is inhibited by a number of different inhibitors and provides diverse possibilities in the development of new ATP synthase-directed agents. In this review, we classify over 250 natural and synthetic inhibitors of ATP synthase reported to date and present their inhibitory sites and their known or proposed modes of action. The rich source of ATP synthase inhibitors and their known or purported sites of action presented in this review should provide valuable insights into their applications as potential scaffolds for new therapeutics for human and animal diseases as well as for the discovery of new pesticides and herbicides to help protect the world's food supply. Finally, as ATP synthase is now known to consist of two unique nanomotors involved in making ATP from ADP and P_i, the information provided in this review may greatly assist those investigators entering the emerging field of nanotechnology.

INTRODUCTION

ATP synthase (F₀F₁) is a multisubunit, membrane-associated protein complex that catalyzes the phosphorylation of ADP to ATP at the expense of a proton motive force generated by an electron transport chain in energy-transducing membranes (303, 387). In some organisms, it also works in the reverse direction by hydrolyzing ATP and generating an electrochemical proton gradient across a membrane to support locomotion or nutrient uptake. ATP synthase is present in all living organisms and is located in the membranes of mitochondria, bacteria, and chloroplast thylakoids as well as on the surfaces of various cell types, including endothelial cells (269, 270), keratinocytes (58), and adipocytes (206).

ATP synthase is an exceptionally complicated protein complex. It is divided into two sectors, a soluble globular F₁ catalytic sector and a membrane-bound F₀ proton-translocating sector (Fig. 1) (304, 305). Even the simplest form of ATP synthase, found in nonphotosynthetic eubacteria, contains eight different subunit types, while the chloroplast and photosynthetic bacterial ATP synthase each consists of nine different subunit types (42, 331). The ATP synthase from mitochondria is much more complicated and, excluding regulators, is reported to date to consist of 15 and 17 different subunit types in animals and yeasts (or fungi), respectively (305, 413).

FIG. 1. — Current view of the structure of mitochondrial ATP synthase from metazoans. F₁ is composed of α, β, γ, δ, and ɛ subunits, and F₀ consists of *a, b, c, d, e, f, g*, A6L, and OSCP. IF₁ is a regulatory protein. The coordinates of the subunits used in the structural model are 1E79 for the α, β, γ, δ, and ɛ subunits; 1ABV for the N-terminal domain of OSCP; 2CLY for F₆, d, and the hydrophilic part of the b subunit; 1GMJ for IF₁; and 1B9U for the transmembrane part of the b subunit. The ac₁₀ subcomplex was modeled using the coordinates of the a and c subunits from 1C17, and the other subunits in the model were constructed manually using Quanta. No positions are assigned to the factor B and the e subunit. Here and where indicated in the other figure legends, the coordinates of protein structures were obtained from the PDB.

ATP synthase is associated directly or indirectly with various human diseases. One form of Leigh syndrome, a neurodegenerative disease which causes a neuromuscular disorder with a 50% survival rate to 3 years of age, is the consequence of a severe impairment of ATP synthesis. This is due to a mutation in subunit a of ATP synthase (99). The neuropathy, ataxia, retinitis pigmentosa syndrome and the familial bilateral striatal necrosis are also caused by the dysfunction of ATP synthase due to mutations within the same subunit (93, 396). In Batten's disease, a lysosomal storage disease also known as neuronal ceroid lipofuscinoses or Kufs' disease, the subunit c of ATP synthase has been found as a predominant storage protein (298, 299). In addition, in Alzheimer's disease or presenile dementia, which is a progressive and degenerative disease that attacks the brain, a deficiency of ATP synthase has been observed in mitochondria (357). A low expression of the ATP synthase β subunit and the cytosolic accumulation of the α subunit are detected in Alzheimer's disease, and the intraneuronal cytosolic accumulation of the α subunit is implicated in the neurodegenerative process (73, 208, 367). Moreover, the ATP synthase on the cell surface of endothelial cells has been reported to have an important role in the angiogenesis process required for tumor growth (269-271, 422). Additionally, the ATP synthase F₆ subunit circulating in the blood has been recognized to be involved in the increase of blood pressure (293, 294). Finally, the β subunit of ATP synthase has been identified as a target protein for innate antitumor cytotoxicity mediated by natural killer and interleukin 2-activated killer cells (91).

ATP synthase has also been demonstrated and suggested as a good molecular target for drugs in the treatment of various diseases and the regulation of energy metabolism (16, 38, 72, 193, 202, 367). One of the drugs developed for the treatment of tuberculosis, R207910, was shown to be active against a number of drug-resistant strains of Mycobacterium tuberculosis and to eradicate M. tuberculosis infection rapidly and effectively (15, 313, 340). The drug has been revealed to block the synthesis of ATP by targeting subunit c of ATP synthase. Another drug, Bz-423, which was developed for therapy of the autoimmune disorder systemic lupus erythematosus, kills pathogenic lymphocytes selectively by inducing apoptosis in lymphoid cells (41). Significantly, Bz-423 has been found to inhibit the mitochondrial ATP synthase by binding to the subunit known as oligomycin sensitivity-conferring protein (OSCP) (193). In addition, the inhibition of nonmitochondrial ATP synthase resulted in the inhibition of cytosolic lipid droplet accumulation, suggesting ATP synthase as a molecular target for antiobesity drugs (16). Finally, the inhibition of ATP synthase has been suggested for an antiangiogenic therapeutic strategy to block tumor angiogenesis (17, 59, 269-271, 422). Here, the reaction of ATP synthase inhibitors with the nonmitochondrial ATP synthase of endothelial cells has been shown to inhibit markedly the migration and proliferation of endothelial cells with little effect on intracellular ATP (17).

The aim of this review is to provide insight and encouragement into the development of new ATP synthase-directed agents. We have meticulously categorized most of the natural and synthetic inhibitors of ATP synthase reported to date in accordance with physical/chemical characteristics of the inhibitors and have summarized the current knowledge of the modes of action of these inhibitors. The information provided in this review should prove to be an invaluable resource, not only for obtaining information about the interactions of known effectors, primarily inhibitors of ATP synthase, but for generating new ideas for the development of numerous additional ATP synthase-directed agents that can be used (i) in the treatment of human and animal diseases, (ii) in agriculture as pesticides or herbicides, and (iii) in the developing field of nanotechnology to understand the mechanics of nanomotor function.

PEPTIDE INHIBITORS

α-Helical Basic Peptide Inhibitors

The α-helical basic peptide inhibitors bind to F₁ and inhibit ATPase activity (Table 1). Inhibitors in this group include α-helical structures containing basic residues, which appear to be crucial for their inhibitory activities. The α-helical basic peptide inhibitors include the bacterial/chloroplast ɛ subunit, melittin, the presequence of yeast cytochrome oxidase subunit IV (WT and its synthetic derivatives), and possibly the inhibitor protein (IF₁) (Fig. 2A).

TABLE 1.

α-Helical basic peptide inhibitors

Name	Amino acid sequence (species)^a	Source	Inhibitory potency (reference)
Bacterial/chloroplast ɛ subunit	MTLNLCVLTPNRSIWNSEVKEIILSTNSGQIGVLPNHAPTATAVDIGILRIRLNDQWLTLALMGGFARIGNNEITILVNDAERGSDIDPQEAQQTLEIAEANLRKAEGKRQKIEANLALRRARTRVEASNTISS (spinach)	Natural regulatory peptide	1-3 ɛ mol/mol^c CF₁(-ɛ)^b (spinach Ca²⁺-ATPase) (332); ∼0.73 μg/μg^c (spinach CF₁-Ca²⁺-ATPase) (284); ∼15 nM^c (EF₁-ATPase) (372); 100 nM^c (EF₁-ATPase, rotation rate of 60-nm beads) (282); 10 nM^d (EF₁-ATPase) (386); 2.1 nM^e (Thermosynecoccus ascicula F₁, αβγ complex) (212); 94% inhibition at 10 ɛ mol/mol CF₁(-ɛ) (spinach Ca²⁺-ATPase) (289)
IF₁	MAVTALAARTWLGVWGVRTMQARGFGSDQSENVDRGAGSIREAGGAFGKREQAEEERYFRAQSREQLAALKKHHEEEIVHHKKEIERLQKEIERHKQKIKMLKHDD (human)	Natural regulatory peptide	0.25 μM^c (bovine heart MF₁-ATPase) (143); 1.2 μM^c at 21°C and 0.84 μM at 37°C (bovine heart MF₁-ATPase) (446); 300 μg/mg protein^c (T. pyriformis SMP-ATPase) (404); 34 μg/mg protein^c (C. asciculate SMP-ATPase) (439); 0.24 μM^d (rat liver MF₁-ATPase) (229)
Melittin	GIGAVLKVLTTGLPALISWIKRKRQQ-NH₂	Apis mellifera (honey bee)	5 μM^c (bovine heart MF₁-ATPase) (52); 12 μM^c (bovine heart MF₁-ATPase) (143)
WT^f	MLSLRQSIRFFKPATRTLCSSRYLL-NH₂	Subunit IV of yeast cytochrome c oxidase	16 μM^c (bovine heart MF₁-ATPase) (52)
Δ11,12	MLSLRQSIRFPATRTLCSSRYLL-NH₂	Synthetic	29 μM^c (bovine heart MF₁-ATPase) (52)
Syn-A2	MLSRLSLRLLSRLSLRLLSRYLL-NH₂	Synthetic	42 nM^c (bovine heart MF₁-ATPase) (52); 290 nM^c (bovine heart MF₁-ATPase) (143); 1.7 μM^c (Bacillus PS3 F_1-ATPase) (143)
Syn-C	MLSSLLRLRSLSLLRLRLSRYLL-NH₂	Synthetic	58 nM^c (bovine heart MF₁-ATPase) (52); 160 nM (bovine heart MF₁-ATPase) (143); 1.6 μM^c (Bacillus PS3 F_1-ATPase) (143)

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Where a species is indicated, sequences vary with species.

CF₁ without ɛ subunit.

I₅₀.

K_i.

K_d.

Leader sequence of subunit IV of yeast cytochrome c oxidase.

The bacterial/chloroplast ɛ subunit, composed of ∼120 to 140 amino acid residues, is an endogenous inhibitory subunit in F₁, and inhibits ATPase activities of isolated and membrane-bound bacterial F₁ (BF₁) and chloroplast F₁ (CF₁) (198, 284, 332, 372, 386). The inhibition is reversible and noncompetitive with substrates (372, 386). It has no inhibitory effect on ATP synthesis and is required in the chloroplast ATP synthase for ATP synthesis in the light (289, 389, 402). The inhibition of F₁-ATPase by the ɛ subunit is controlled by the electrochemical gradient and ADP/ATP balance (389), and the C-terminal α-helical domain is responsible for its inhibitory activity (168, 212, 289). At high proton motive forces and low ATP concentrations, the C-terminal α-helical domain of the ɛ subunit performs large conformational changes from the hairpin conformation to a “lifted-up” extended conformation, shifting its position ∼70 Å to interact with the α₃β₃ hexagon ring (389, 402). In the “lifted-up” extended conformation, the C-terminal helix lies close to the β-DELSEED motif of the β subunit, and the direct electrostatic interaction between the β-DELSEED motif and the basic residues in the C-terminal domain of the ɛ subunit leads to the inhibition of ATP hydrolysis (168).

IF₁ is a natural regulatory peptide of 56 to 87 residues found in mitochondria (Fig. 2A). It binds to F₁ with a 1:1 stoichiometric ratio and inhibits the ATP hydrolysis of mitochondrial ATP synthase without affecting ATP synthesis. The inhibition is reversible and noncompetitive, and the binding of IF₁ to F₁ requires the presence of ATP (178, 228, 229, 409). IF₁ is more potent against the whole membrane-bound ATP synthase (F₀F₁-ATPase) complex than isolated F₁ (144, 409, 411). IF₁ inhibits the ATPase activity of mitochondrial ATP synthase and has no ATPase inhibitory effect against BF₁ (143). The yeast IF₁ can cross-react with animal F₁, whereas the potato IF₁ shows no inhibitory effect against animal F₁ (60, 319). IF₁ proteins from animals are considerably (18 to 31 residues) longer than those from plants and fungi (176). In a study of truncated bovine IF₁ for inhibitory activity, the minimal inhibitory sequence was shown to localize within residues 14 to 47 (411). The adjoining residues 10 to 13 and 48 to 56 are considered to play a stabilizing role. In the crystal structure of F₁ with IF₁, the N-terminal domain of IF₁ is bound at the interface between α_DP and β_DP subunits and also has contacts with β_TP386, α_E355, and the γ subunit (61). It has been suggested that the inhibitory mode of action of IF₁ could be similar to that of the bacterial ɛ subunit (260, 402). IF₁ is considered to play its inhibitory role by impeding the closure of the α_DP-β_DP catalytic interface to prevent the hydrolysis of bound ATP (61, 141). Cross-linking and intrinsic phosphorescence decay studies implicate IF₁ as being functionally associated with the mitochondrial ɛ subunit (260, 373). Both proteins are in close proximity in the crystal structure of the F₁-IF₁ complex (141).

Melittin, which is a 26-residue peptide known as the principal active component of bee venom and which has a powerful anti-inflammatory effect, inhibits the ATPase activity of F₁ (52, 143). The 25-residue presequence of yeast cytochrome oxidase subunit IV (WT) and its synthetic derivatives, Syn-A2, Syn-C, and Δ11,12, also inhibit ATP hydrolysis by F₁ (52, 143). Melittin, WT, Syn-A2, and Syn-C (and possibly Δ11,12) form basic and amphiphilic α-helical structures (191, 337, 338, 393). Melittin, Syn-A2, and Syn-C have been suggested to bind to F₁ at the same site as IF₁ (143), and WT and Δ11,12, which are derivatives of Syn-A2 and Syn-C, are considered to also play similar inhibitory roles. Syn-A2 and Syn-C are very effective inhibitors among amphiphilic peptide inhibitors, showing 50% inhibitory (I₅₀) values of about 40 to 50 nM for inhibition of bovine F₁-ATPase activity (52). Syn-A2 inhibits the ATPase activity of bovine F₁ noncompetitively in a parabolic manner, whereas Syn-C exhibits mixed inhibition and melittin shows noncompetitive hyperbolic inhibition (52).

Angiostatin and Enterostatin

Angiostatin is a 57-kDa N-terminal fragment of a larger protein, plasmin, which is also a fragment of plasminogen. Angiostatin has a triangular structure with three to five contiguous kringle domains, and it acts as a natural angiogenesis inhibitor (Fig. 2B) (1). It binds to the α and β subunits of ATP synthase and inhibits its ATP hydrolysis (269, 270). In an experiment with bovine F₁ and human angiostatin, the angiostatin bound strongly to F₁ and completely inhibited ATPase activity (269). Angiostatin was also found to inhibit ATP generation by the nonmitochondrial ATP synthase located on endothelial cells that comprise the human umbilical vein, with 1 μM angiostatin inhibiting about 81% of the ATP synthesis activity (270). However, no ATP synthesis by plasma membrane ATP synthase was reported in human vascular endothelial cells (325), and the inhibition of ATP synthesis of nonmitochondrial ATP synthase by ATP synthase-specific inhibitors is still controversial.

Enterostatin is a pentapeptide released from procolipase during dietary fat digestion (Fig. 2B). Enterostatin binds to the ATP synthase β subunit and inhibits ATP synthesis (38, 39, 301). Binding of enterostatin to the mitochondrial ATP synthase in insulinoma cells leads to an ∼31% decrease of ATP production accompanied by an increase in thermogenesis and oxygen consumption (38). The binding of enterostatin to F₁ is inhibited by β-casomorphin, a peptide derived from the digestion of β-casein in milk (38, 39, 301).

Tentoxin and Its Derivatives

The properties and inhibitory potencies of tentoxin and its analogs are summarized in Table 2. Tentoxin is a natural cyclic tetrapeptide produced by phytopathogenic fungi, Alternaria species (19, 257, 342). In aqueous solution, tentoxin exists as four interconverting conformations in different proportions (51, 37, 8, and 4%) resulting from a “conformational peptide flip” (318). At low concentrations, tentoxin acts as an uncompetitive inhibitor of the ATPase activity of CF₁ derived from certain sensitive plant species but not of homologous CF₁s from chloroplasts of some other plant species. Also, tentoxin does not inhibit the ATPase activity of F₁s derived from bacteria or mitochondria (19, 378, 380). Tentoxin also inhibits ATP synthesis in chloroplasts from the sensitive species. In contrast to the above, tentoxin at high concentrations strongly stimulates ATPase activity of CF₁ (379) and partially reactivates the proton transport-coupled activity of the membrane-bound CF₀F₁ (369). Based on labeling studies, tentoxin-susceptible CF₁ is considered to contain a high-affinity inhibitory binding site and one or two low-affinity stimulatory binding sites (69, 265, 317, 350). The binding of tentoxin to a low-affinity binding site releases the inhibitory effect caused by binding of tentoxin to the high-affinity binding site and reactivates the enzyme. The binding of a tentoxin molecule to the third site with very low affinity results in overactivation (265). In the crystal structure of the CF₁-tentoxin complex, a tentoxin molecule is bound at the high-affinity binding site located in a cleft at an αβ subunit interface. Here, it blocks the contact between αArg-297 and βAsp-83 (153, 155), restrains the movements of these residues, and also restrains conformational changes at the catalytic interface. This may arrest the catalytic αβ interface in the closed conformation and thereby hinder its transformation into the open conformation (153, 155).

TABLE 2.

Tentoxin and tentoxin analogs

Name or abbreviation	Sequence	Molecular formula	Inhibitory potency (reference)
Tentoxin	Cyclo-(l-N-methyl-Ala¹-l-Leu²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₂H₃₀N₄O₄	∼0.6 mol/mol^a (spinach CF₁-ATPase) (179); 50 nM^a (spinach CF₁(-ɛ)-ATPase) (69); 0.4-0.6 μM^a (lettuce chloroplasts, photophosphorylation) (380); 10 nM^b (spinach CF₁(-ɛ)-ATPase) (350); 30-60 μM^b (60°C, TF₁-ATPase) (351); 8-10 nM^c (spinach CF₁(-ɛ)-ATPase) (350, 351)
MeSer¹-TTX	Cyclo-(l-N-methyl-Ser¹-l-Leu²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₂H₃₀N₄O₅	50 nM^a (spinach CF₁(-ɛ)-ATPase) (69); 0.5 μM^a with 2 min incubation and 0.1 μM^a with 30 min incubation in the dark (spinach thylakoids, ATP synthesis) (316); 15 nM^c (spinach CF₁(-ɛ)-ATPase) (351)
Ala¹-TTX	Cyclo-(l-Ala¹-l-Leu²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₁H₂₈N₄O₄	34 nM^c (spinach CF₁(-ɛ)-ATPase) (351)
Sar¹-TTX	Cyclo-(l-N-methyl-Gly¹-l-Leu²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₁H₂₈N₄O₄	45 nM^c (spinach CF₁(-ɛ)-ATPase) (351)
Gly¹-TTX	Cyclo-(l-Gly¹-l-Leu²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₀H₂₆N₄O₄	34 nM^c (spinach CF₁(-ɛ)-ATPase) (351)
MeSer(Bn)¹-TTX	Cyclo-(l-N-methyl-Ser(Bn)¹-l-Leu²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₉H₃₆N₄O₅	0.5 μM^a (spinach CF₁(-ɛ)-ATPase) (69); 0.5 μM^c (spinach CF₁(-ɛ)-ATPase) (351)
MeGlu¹-TTX	Cyclo-(l-N-methyl-Glu¹-l-Leu²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₄H₃₂N₄O₆	5 μM^a (spinach CF₁(-ɛ)-ATPase) (69)
MeGlu(tBu)¹-TTX	Cyclo-(l-N-methyl-Glu(tBu)¹-l-Leu²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₈H₄₁N₄O₆	2 μM^a (spinach CF₁(-ɛ)-ATPase) (69); 1.5 μM^c (spinach CF₁(-ɛ)-ATPase) (351)
Lys²-TTX	Cyclo-(l-N-methyl-Ala¹-l-Lys²-N-methyl-Δ^ZPhe³-Gly⁴)	C₂₂H₃₁N₅O₄	3 μM^a (spinach CF₁(-ɛ)-ATPase); 2 μM^c (spinach CF₁(-ɛ)-ATPase) (351)
Lys(Z)²-TTX	Cyclo-(l-N-methyl-Ala¹-l-Lys(Z)²-N-methyl-Δ^ZPhe³-Gly⁴)	C₃₀H₃₇N₅O₆	1 μM^a (spinach CF₁(-ɛ)-ATPase) (69); 0.75 μM^c (spinach CF₁(-ɛ)-ATPase) (351)
MeΔTyr³-TTX	Cyclo-(l-N-methyl-Ala¹-l-Leu²-N-methyl-Δ^ZTyr³-Gly⁴)	C₂₂H₃₀N₄O₅	0.05 μM^a (spinach CF₁(-ɛ)-ATPase) (69); 12 nM^c (spinach CF₁(-ɛ)-ATPase) (351)
Tyr(Me)³-TTX	Cyclo-(l-N-methyl-Ala¹-l-Leu²-N-methyl-Δ^ZTyr(Me)³-Gly⁴)	C₂₃H₃₂N₄O₅	0.05 μM^a (spinach CF₁(-ɛ)-ATPase) (69); 10 nM^c (spinach CF₁(-ɛ)-ATPase) (351)
ΔPhe³-TTX	Cyclo-(l-N-methyl-Ala¹-l-Leu²-Δ^ZPhe³-Gly⁴)	C₂₁H₂₈N₄O₄	0.8 μM^c (spinach CF₁(-ɛ)-ATPase) (351)
Dihydro-TTX	Cyclo-(l-N-methyl-Ala¹-l-Leu²-N-methyl-Phe³-Gly⁴)	C₂₂H₃₂N₄O₄	0.5 μM^c (spinach CF₁(-ɛ)-ATPase) (351)
Iso³-TTX	Cyclo-(l-N-methyl-Ala¹-l-Leu²-N-methyl-Δ^EPhe³-Gly⁴)	C₂₂H₃₀N₄O₄	8.7 μM^c (spinach CF₁(-ɛ)-ATPase) (351)

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I₅₀.

K_i.

K_d.

MeSer¹-TTX, Ala¹-TTX, Sar¹-TTX, Gly¹-TTX, MeSer(Bn)¹-TTX, MeGlu¹-TTX, MeGlu(tBu)¹-TTX, Lys²-TTX, Lys(Z)²-TTX, MeΔTyr³-TTX, MeΔTyr(Me)³-TTX, ΔPhe³-TTX, dihydro-TTX, and Iso³-TTX are synthetic analogs of tentoxin in which an amino acid residue is mutated at the residue number indicated (316, 351) (Fig. 2C). MeSer¹-TTX appears to inhibit isolated CF₁ and the membrane-bound enzyme (CF₀CF₁) in thylakoids and proteoliposomes the same way and with the same efficiency as tentoxin. However, MeSer¹-TTX exhibits much weaker reactivation of CF₁ than tentoxin at high concentrations (69). On the other hand, MeΔTyr(Me)³-TTX shows similar activities as tentoxin in both inhibitory and stimulatory potencies (69). MeSer(Bn)¹-TTX, MeGlu¹-TTX, Glu(tBu)¹-TTX, Lys²-TTX, and MeSer¹-TTX analogs exhibit inhibitory activities with lower affinities but show no stimulatory effects (69).

Leucinostatins and Efrapeptins

The leucinostatins (A to D, H, and K) are nonapeptide antibiotics produced by Paecilomyces (Fig. 2D and Table 3). Leucinostatin A is produced by Paecilomyces lilacinus, P. marquandii, and P. abruptus (434), leucinostatin B by P. lilacinus, and P. marquandii (266), leucinostatin C by P. lilacinus (259), leucinostatin D by P. lilacinus and P. marquandii (259, 339), and leucinostatin H and K by P. marquandii (259, 339). Leucinostatins adopt an α-helical conformation, and contains three Aib residues and some uncommon amino acid residues (71). Different types of leucinostatin differ in the kinds of amino acid at position 2 (Dec or Leu) and in the substitution pattern at the terminal nitrogen atom [-N(CH₃)₂, -NHCH₃, -NH₂, or -NO(CH₃)₂]. Leucinostatins bind to the F₀ part of ATP synthases (127, 404, 439) and inhibit oxidative phosphorylation in mitochondria and photophosphorylation in chloroplasts (224, 242, 328). Leucinostatins have no inhibitory activity on isolated F₁-ATPase (127, 439).

TABLE 3.

Leucinostatins and efrapeptins

Name	Molecular formula	Source	Synonyms	Inhibitory potency (reference)
Leucinostatin	A, C₆₂H₁₁₁N₁₁O₁₃; B, C₆₁H₁₀₉N₁₁O₁₃; C, C₆₀H₁₀₇N₁₁O₁₃; D, C₅₆H₁₀₁N₁₁O₁₁; H, C₅₇H₁₀₃N₁₁O₁₂; K, C₆₂H₁₁₁N₁₁O₁₄	A, P. lilacinus, P. marquandii, and P. abruptus; B, P. lilacinus and P. marquandii; C, P. lilacinus; D, P. lilacinus and P. marquandii; H and K, P. marquandii	A, A20668, paecilotoxin A, CC-1014; B, paecilotoxin B; C, paecilotoxin C; D, paecilotoxin D; H, paecilotoxin H; K, paecilotoxin K	11 μg/mg protein^a (Crithidia asciculate SMP-ATPase) (439); 2 μg inhibitor/ml^a (spinach chloroplast, photophosphorylation) (242); 0.1-0.4 μg/mg protein (rat liver mitochondria, ATPase) (328)
Efrapeptin	C, C₈₀H₁₃₇N₁₈O₁₆⁺; D, C₈₁H₁₃₉N₁₈O₁₆⁺; E, C₈₂H₁₄₁N₁₈O₁₆⁺; F, C₈₂H₁₄₁N₁₈O₁₆⁺; G, C₈₃H₁₄₃N₁₈O₁₆⁺	Tolypocladium species	Efrastatin, A23871	0.56 mol/mol F₁^a (bovine heart MF₁-ATPase) (83); 70 ng/ml^a (C. asciculate MF₁-ATPase) (173); 0.3 μM^a (human umbilical vein endothelial cell, nonmitochondrial ATP synthase, ATP synthesis) (17); 0.5 μg/ml^a (R. rubrum chromatophores, photophosphorylation) (241); 0.05-0.5 μg of inhibitor/mg protein^a (T. pyriformis SMP-ATPase) (404); 21.5 μM^b (EF₁-ATPase) (436); 10 nM^c (bovine heart MF₁-ATPase) (83); complete inhibition at 2.4 mol inhibitor/mol enzyme (bovine heart SMP-ATPase and ATP synthesis) (83)

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I₅₀.

K_i.

K_d.

Efrapeptins are a group of lipophilic peptide antibiotics (efrapeptins C to G) produced by Tolypocladium species (Fig. 2D and Table 3). Efrapeptin inhibits both ATP hydrolysis and ATP synthesis reactions of the ATP synthase from mitochondria, chloroplasts, and photosynthetic bacteria by binding at the F₁ catalytic domain (2, 164, 173, 224, 232, 241, 242). Efrapeptin inhibits the ATP synthase from some, but not all, nonphotosynthetic bacteria, including thermophilic Bacillus strain PS3 (343, 436). The mode of inhibition by efrapeptin during ATP synthesis is competitive with ADP and phosphate (83). Efrapeptin also binds to the nonmitochondrial ATP synthase of endothelial cells and inhibits extracellular ATP synthesis (17). In the crystal structure of the F₁-ATPase-efrapeptin complex, a single efrapeptin molecule is bound in the large central cavity of F₁ lined with β_E, α_E, α_TP, and the α-helical structure of the γ subunit. The binding of efrapeptin is stabilized predominantly by hydrophobic interactions between efrapeptin and the residues in the cavity and also by two potential intermolecular hydrogen bonds (2). Efrapeptin is believed to inhibit the ATP synthase by preventing the β_E subunit from converting into a nucleotide binding conformation.

POLYPHENOLIC PHYTOCHEMICALS, ESTROGENS, AND STRUCTURALLY RELATED COMPOUNDS

Phytochemicals are naturally occurring bioactive nonnutrient compounds derived from plants. They possess chemopreventive or chemotherapeutic effects associated with reduced risk of various diseases, including cancer, and they bind to multiple molecular targets in the body (30, 286, 395). Phytochemicals are categorized into various groups, and among these are the polyphenolic phytochemicals. Some of the polyphenolic phytochemicals, many of which are phytoestrogens, bind to the ATP synthase and inhibit its ATPase activity. (Fig. 3) (143, 448, 449). The effects of polyphenolic phytochemicals on the ATPase activity of ATP synthase are additive, and the phenolic structures that comprise the polyphenolic phytochemicals play an important role in their inhibitory potencies (448). Two or more phenolic structures appear to be required, and the position of hydroxy groups seems to affect significantly the inhibitory effectiveness of polyphenolic phytochemicals on the ATP synthase (448).

FIG. 3. — Structures of polyphenolic phytochemicals, estrogens, and structurally related compounds. (A) Stilbenes. SITS, 4-Acetamido-4′-isothiocyanostilbene 2,2′-disulfonate; DIDS, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid. (B) Flavones and isoflavones. (C) Other polyphenolic phytochemicals. ECG, epicatechin gallate; EGCG, epigallocatechin gallate. (D) Steroidal estradiols and estrogen metabolites.

Some endogenous and synthetic estrogens also target ATP synthase. Endogenous steroidal estradiols and estrogen metabolites and synthetic nonsteroidal stilbene estrogens bind to mitochondrial ATP synthase and inhibit its ATPase activity (450, 451).

Stilbenes

Stilbenes consist of two phenolic rings linked by a spacer containing a double bond (Fig. 3A). Stilbene phytoalexins, resveratrol, and piceatannol are natural phytochemicals found in grapevine organs such as berries, leaves, canes, and roots. They inhibit the ATPase activity of mitochondrial ATP synthase by targeting the F₁ catalytic headpiece (Table 4) (325, 448, 449). The mode of inhibition by resveratrol is mixed (448). In contrast to the above, resveratrol and piceatannol show no inhibition of ATPase activity of F₁ from thermophilic Bacillus strain PS3 (TF₁) (143). Resveratrol and piceatannol bind to a hydrophobic pocket between the hydrophobic tip in the C-terminal region of the γ subunit and the hydrophobic inside of an annulus provided by the β_TP subunit (142). The binding of these inhibitors, stabilized by hydrophobic interactions and hydrogen bonds, is believed to block the rotation of the γ subunit, inhibiting both the hydrolysis and synthesis of ATP. Resveratrol and piceatannol are bound to a single binding site in F₁, and there are no equivalent sites between the γ subunit and either the β_DP or β_E subunit.

TABLE 4.

Stilbenes

Name or abbreviation	Molecular formula	Source	Other names	Inhibitory potency, I₅₀ (reference)
Resveratrol	C₁₄H₁₂O₃	Grapes and red wine	3,4′,5-Stilbenetriol; 3,4′,5-trihydroxystilbene	27.7 μM (rat brain SMP, ATP synthesis) (448); 14 μM (rat liver MF₁-ATPase) (449); 19 μM (rat brain M F₀F_1-ATPase) (448); 6.4 μM (bovine heart MF₁-ATPase) (143); 2 μM (human umbilical vein endothelial cell, nonmitochondrial ATP synthase, ATP synthesis) (17)
Piceatannol	C₁₄H₁₂O₄	Seeds of Euphorbia lagascae	3,5,3′,4′-Tetrahydroxystilbene; 3-hydroxyresveratol	8-9 μM (rat brain MF₀F₁ ATPase) (448, 449); 4 μM (rat liver MF₁-ATPase) (449); 6.1 μM (bovine heart MF_1-ATPase) (143); 1.5 μM (human umbilical vein endothelial cell, nonmitochondrial ATP synthase, ATP synthesis) (143); ∼70% inhibition at 10 μM (bovine heart MF₁-ATPase) (325)
DES	C₁₈H₂₀O₂	Synthetic	Diethylstilbestrol; (E)-4,4′-(1,2-diethyl-1,2-ethenediyl)bisphenol; 4,4′-dihydroxydiethylstilbene; (E)-3,4-bis(4-hydroxyphenyl)-3-ascic; Acnestrol; Antigestil; Comestrol; Cyren; Desma; Dibestrol; Distilbene; Estrobene; Pabestrol; Stilbetin; Vagestrol	10 μM (rat liver MF₀F_1-ATPase) (252); 10-25 μM (rat brain MF₀F₁-ATPase) (451)
SITS	C₁₇H₁₄N₂O₇S₃	Synthetic	4-Acetamido-4′-isothiocyanostilbene 2,2′-disulfonate	∼1.3 μM (V. parahaemolyticus F₀F₁-ATPase) (290); 95% inhibition at 25 μM (V. parahaemolyticus F₁-ATPase) (344)
DIDS	C₁₆H₁₀N₂O₆S₄	Synthetic	4, 4′-d-Isothiocyanatostilbene-2,2′-disulfonic acid; diisothiocyanatostilbene-2,2-disulfonic acid	20.9 μM (rat liver MF₁ATPase) (40)

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Diethylstilbestrol (DES) is a synthetic nonsteroidal estrogen. DES targets F₀ and inhibits both ATPase and ATP-dependent proton translocation activities of both membrane-bound and isolated F₀F₁ from mitochondria (252, 451). DES inhibits membrane-bound F₀F₁ with half-maximal and maximal inhibitory effects at about 10 and 60 μM, respectively (252). For the isolated F₀F₁, the concentration for 50% inhibition is 10 μM, and maximal inhibition of ATPase activity is about 90%. In contrast, DES has little effect on the ATPase activity of the F₁ moiety, exhibiting only ∼20% inhibition at 60 μM. The binding site of DES is considered to be structurally distinct from other types of F₀ inhibitors, as DES provides no protection against the inhibition of the F₀F₁ complex by N,N′-dicyclohexylcarbodiimide (DCCD), which is protected by oligomycin, venturicidin, and tricyclohexyltin. The combination of DES and DCCD produces a synergic inhibitory effect at low concentrations (<20 μM).

4-Acetamido-4′-isothiocyanostilbene 2,2′-disulfonate and 4,4′-di-isothiocyanatostilbene-2,2′-disulfonic acid are structurally very analogous and have been known as anion exchanger inhibitors. They also bind to ATP synthase and inhibit its catalytic activity. 4-Acetamido-4′-isothiocyanostilbene 2,2′-disulfonate strongly inhibits the ATPase activity of both F₁ and F₀F₁ from Vibrio parahaemolyticus (290, 344). 4,4′-Di-isothiocyanatostilbene-2,2′-disulfonic acid also inhibits both the hydrolysis and synthesis of ATP in submitochondrial particles (SMP) and also ATP hydrolysis of isolated F₁ from rat liver mitochondria (40).

Flavones and Isoflavones

Flavones and isoflavones are flavonoid-related polyphenolic compounds. Flavones and isoflavones differ in the position of a phenyl group on the 4H-1-benzopyr-4-one skeleton. Flavones are produced in various plants, whereas isoflavones are produced almost exclusively by beans. The flavones, quercetin, kaempferol, morin, and apigenin inhibit ATP hydrolysis (Fig. 3B). Specifically, quercetin inhibits the ATPase activities of mitochondrial F₁ (MF₁) and F₀F₁ (223, 448, 449) and also these activities in spinach chloroplasts (96), Escherichia coli (130), and Clostridium thermoaceticum (190). However, quercetin inhibits neither the ATPase activity of TF₁ (343), a thermophilic bacterial ATP synthase, nor the ATP synthetic activity of mitochondrial ATP synthase (F₀F₁) (223). In contrast, quercetin has a stimulatory effect on photophosphorylation (218). Kaempferol and morin have inhibitory potencies similar to that of quercetin on the ATPase activity of mitochondrial F₀F₁, while apigenin, in which the 3-hydroxyl group in the chromone moiety is absent, shows about half the inhibitory potency (Table 5) (448).

TABLE 5.

Flavones and isoflavones

Name	Molecular formula	Source	Other names	Inhibitory potency (reference)
Quercetin	C₁₅H₁₀O₇	Various plants	3,3′,4′,5,7-Pentahydroxyflavone; natural yellow 10; meletin; flavin meletin; quercetol; Xanthaurine	5 kmol/mol^a (232), 85 μM^a (343) (bovine heart MF₁-ATPase); 180 μM^a (bovine heart SMP-ATPase) (343); 50 μM^a (rat brain F₀F_1-ATPase) (448); 3 μM^a (rat liver F₁-ATPase) (449); 2 kmol/mol^a (spinach CF₁-ATPase) (232); 2.6 μg/mg protein^a (C. asciculate SMP-ATPase) (439); 0.2 mM^b (pig heart MF₁-ATPase) (100); 27 μM^c (bovine heart MF₁-ATPase) (232); 46% inhibition at 5 μM (C. thermoaceticum membrane-bound F₀F₁-ATPase) (190)
Kaempferol	C₁₅H₁₀O₆	Delphinium, witch-hazel, grapefruit, and other plant sources	Kempferol; campherol; indigo yellow; nimbecetin; pelargidenolon; populnetin; rhamnolutein; 3,4′,5,7-tetrahydroxyflavone; trifolitin	55 μM^a (rat brain MF₀F₁-ATPase) (448)
Morin	C₁₅H₁₀O₇	Various plants	2′,3,4′,5,7-Pentahydroxyflavone; 2′,4′,5,7-tetrahydroxyflavan-3-ol; 3,5,7,2′,4′-pentahydroxyflavonol; al-morin; aurantica; calico yellow; osage orange	60 μM^a (rat brain MF₀F₁-ATPase) (448)
Apigenin	C₁₅H₁₀O₅	Parsley, artichoke, basil, celery and other plants	4′,5,7-Trihydroxyflavaone; 2-(p-hydroxyphenyl)-5,7-dihydroxychromone; apigenol; chamomile; spigenin	105 μM^a (rat brain MF₀F₁-ATPase (448)
Genistein	C₁₅H₁₀O₅	Soybean	4′,5,7-Trihydroxyisoflavone; genisteol; genisterin; prunetol; sophoricol; differenol A	55 μM^a (rat brain MF₀F₁-ATPase) (448); 10% inhibition at 50 μM (rat liver F₁-ATPase) (449)
Biochanin A	C₁₆H₁₂O₅	Soybean	Biochanin; 4′-methylgenistein; 5,7-dihydroxy-4′-methoxyisoflavone; CCRIS 5449; 5,7-dihydroxy-4′-methoxyisoflavone	65 μM^a (rat brain MF₀F₁-ATPase) (448)
Daidzein	C₁₅H₁₀O₄	Soybean	4′,7-Dihydroxyisoflavone; daidzeol; 7-hydroxy-3-(4-hydroxyphenyl)-4-benzopyrone	127 μM^a (rat brain MF₀F₁-ATPase) (448)

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I₅₀.

K_i.

K_d.

Genistein, biochanin A, and daidzein are isoflavone phytoalexins found in soybeans. Genistein inhibits noncompetitively both the ATP hydrolysis and ATP synthesis activities of mitochondrial ATP synthase, most likely by targeting F₀ (448, 449). Biochanin A inhibits the ATPase activity of mitochondrial F₀F₁ with an inhibitory potency similar to that of genistein. Compared to genistein and biochanin, daidzein contains only one hydroxyl group in the 4-chromone moiety and shows about half the inhibitory potency (448).

Other Polyphenolic Phytochemicals

Catechins are flavonoid compounds called flavan 3-ols. They are abundant in green tea, which includes four main catechins, epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate. Among the catechins, epicatechin gallate and epigallocatechin gallate are inhibitors of the ATP hydrolysis activity of ATP synthase (Fig. 3C) (448). Epigallocatechin gallate, in which one more hydroxyl group is attached in the catechol moiety of epicatechin gallate, shows about three times higher potency than epicatechin gallate in the inhibition of ATPase activity of mitochondrial F₀F₁.

Grape seed proanthocyanidin extract, curcumin, an active ingredient of the Indian curry spice, and phloretin from apples inhibit the ATPase activity of mitochondrial F₀F₁. Theaflavin, a phytochemical from tea, and tannic acid, anionic polymers from the bark of trees, also exhibit inhibitory effects on the ATPase activity of mitochondrial F₀F₁ (Table 6) (448).

TABLE 6.

Other polyphenolic phytochemicals

Name or abbreviation	Molecular formula	Source	Other names	Inhibitory potency, I₅₀ (reference)
ECG	C₂₂H₁₈O₁₀	Green tea	(−)Epicatechin gallate; epicatechin-3-gallate; epicatechin-3-galloyl ester	45 μM (rat brain MF₀F₁-ATPase) (448)
EGCG	C₂₂H₁₈O₁₁	Green tea	(−)-Epigallocatechin gallate; (−)-epigallocatechin gallate; (−)-epigallocatechin-3-O-gallate; CCRIS 3729; tea catechin	17 μM (rat brain MF₀F₁-ATPase) (448)
GSPE	C₃₁H₂₈O₁₂	Grape seed	Grape seed proanthocyanidin extract; polyhydroxyflavan-3-ol	30 μg of inhibitor/ml (rat brain F₀F₁-ATPase) (448)
Curcumin	C₂₁H₂₀O₆	Curcuma longa	Natural yellow 3; 1,7-bis(4-ascicul-3-methoxyphenyl)-1,6-heptadiene-3,5-dione	40 μM (rat brain MF₀F₁ ATPase) (448)
Phloretin	C₁₅H₁₄O₅	Mainly from apples	Phloretol; 2′,4′,6′-trihydroxy-3-(p-hydroxyphenyl)propiophenone; dihydronaringenin; β-(p-hydroxyphenyl)-2,4,6-trihydroxypropiophenone	40% inhibition at 70 μM (rat brain MF₀F₁-ATPase) (448)
Theaflavin	C₂₉H₂₄O₁₂	Tea	1,8-Bis((2R,3R)-3,5,7-trihydroxy-2H-1-benzopyran-2-yl)-3,4,6-trihydroxy-5H-benzocyclohepten-5-one	20 μg of inhibitor/ml (rat brain F₀F₁-ATPase) (448)
Tannic acid	A mixture of related compounds (mainly glucose esters of gallic acid)	Bark of trees	Gallotannic acid; gallotannin; glycerite; tannin	5 μg of inhibitor/ml (rat brain F₀F₁-ATPase) (448)

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Steroidal Estradiols and Estrogen Metabolites

Endogenous steroidal estradiols and estrogen metabolites have inhibitory effects on mitochondrial ATP synthase (Fig. 3D and Table 7) (451). Two catecholestrogens, 4-hydroxyestradiol and 2-hydroxyestradiol, inhibit the ATPase activity of the mitochondrial ATP synthase, and the 4-hydroxyestradiol is about twofold more effective than the 2-hydroxyestradiol. 17β-Estradiol and 17α-estradiol inhibit the ATPase activity of solubilized brain mitochondrial fractions by 7 and 25% at 14 and 42 μM, respectively. Two micoestrogens, α-zearalenol and β-zearalenol, also inhibit mitochondrial F₀F₁-ATPase activity. The I₅₀ value of α-zearalenol is about 50 μM, and the inhibitory potency of α-zearalenol is about three- to fourfold stronger than that of β-zearalenol. The mechanism of inhibition by the steroidal estradiols and estrogen metabolites is not defined clearly, but the ATP synthase OSCP subunit has been identified as an estradiol binding protein, and it has been suggested that the inhibition is mediated by the binding of estrogens to OSCP (450).

TABLE 7.

Steroidal estradiols and estrogen metabolites

Name	Molecular formula	Source	Other names	Inhibitory potency, I₅₀ (reference)
4-Hydroxyestradiol	C₁₈H₂₄O₃	Natural estrogen	4-Hydroxyestradiol-17β; 4-hydroxy-17-β−estradiol; estra-1,3,5(10)-triene-3,4,17-β-triol	55 μM (rat brain MF₀F₁-ATPase) (451)
2-Hydroxyestradiol	C₁₈H₂₄O₃	Natural estrogen	(17β)-Estra-1,3,5(10)-triene-2,3,17-triol; estra-1,3,5(10)-triene-2,3,17-β-triol	110 μM (rat brain MF₀F₁-ATPase) (451)
17-α-Estradiol	C₁₈H₂₄O₂	Natural estrogen	1,3,5-Estratriene-3,17-α-diol; 3,17-dihydroxyestratriene; 3,17-α-dihydroxyoestra-1,3,5(10)-triene; epiestradial; epiestradiol; estra-1,3,5(10)-triene-3,17α-diol; oestra-1,3,5(10)-triene-3,17α-diol; estradiol-17-α; α-estradiol	25% inhibition at 42 μM (rat brain MF₀F₁-ATPase) (451)
17-β-Estradiol	C₁₈H₂₄O₂	Natural estrogen	1,3,5-Estratriene-3,17-β-diol; 17-β-estra-1,3,5(10)-triene-3,17-diol; 17-β-OH-estradiol; 17-β-OH-estradiol; 17-β-oestra-1,3,5(10)-triene-3,17-diol; 17β-oestra-1,3,5(10)-triene-3,17-diol; 3,17-epidihydroxyestratriene; 3,17-epidihydroxyoestratriene; 3,17-β-dihydroxy-1,3,5(10)-oestratriene; 3,17-β-estradiol; 3,17-β−estradiol; Aerodiol; Aquadiol	7% inhibition at 14 μM (rat brain MF₀F₁-ATPase) (451)
α-Zearalenol	C₁₈H₂₄O₅	Natural mycoestrogen	(4S,8R,12E)-8,16,18-Trihydroxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-12,15,17,19-tetraen-2-one; trans-zearalenol	50 μM (rat brain MF₀F₁-ATPase) (451)
β-Zearalanol	C₁₈H₂₄O₅	Natural mycoestrogen	(8S,12E)-8,16,18-Trihydroxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-12,15,17,19-tetraen-2-one	150-200 μM (rat brain MF₀F₁-ATPase) (451)

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POLYKETIDE INHIBITORS

Polyketides are polymers of two-carbon ketide units synthesized by polyketide synthases. Macrolides belong to the polyketide class and contain a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached (Fig. 4). Some natural macrolides, apoptolidin, cytovaricin, oligomycin, ossamycin, and venturicidin are elaborated by Nocardiopsis spp. and various strains of Streptomyces and are known as potent inhibitors of ATP synthase (Table 8) (205, 207, 225, 330, 358, 359). The binding sites of the macrolide inhibitors are located within the F₀ part of the complex.

FIG. 4. — Structures of polyketide inhibitors.

TABLE 8.

Polyketide inhibitors

Name	Molecular formula	Source	Other names	Inhibitory potency (reference)
Oligomycin	A, C₄₅H₇₄O₁₁; B, C₄₅H₇₂O₁₂; C, C₄₅H₇₄O₁₀; D, C₄₄H₇₂O₁₁; E, C₄₅H₇₂O₁₃; F, C₄₆H₇₆O₁₁	A, B, and C, Streptomyces diastratochroogenes; D, Streptomyces griseus, Streptomyces aureofaciens, Streptomyces rutgersensis	D, Rutamycin, 26-demethyl-oligomycin A, A272	152 μg inhibitor/mg protein^a (E. coli membrane vesicle, pH gradient formation) (311); 7.1 μg inhibitor/mg protein^a (C. asciculate SMP-ATPase) (439); 2.0-3.0 μg inhibitor/mg protein^a (S. cerevisiae SMP-ATPase) (150, 151); A, 0.3 μM^a (human NCI-60 cell lines, F₀F₁-ATPase) (348); 15 ng inhibitor/mg protein^b (N. crassa SMP-ATPase) (112); 0.21 μM^b (bovine heart MF₀F₁-ATPase) (85); 95% inhibition at 0.4 μg inhibitor/mg protein (bovine heart SMP-ATPase) (140); D, 75% inhibition at 0.5 μg/ml (rat liver SMP-ATPase) (423)
Peliomycin	C₄₆H₇₆O₁₄	Various strains of Streptomyces		4.5 μg inhibitor/mg protein^a (S. cerevisiae SMP-ATPase) (150)
Venturicidin	A, C₄₁H₅₇NO₁₁; B, C₄₀H₆₄NO₁₀; X, C₃₄H₅₄O₇	Streptomyces aureofaciens, Streptomyces griseolus, Streptomyces halstedii, Streptomyces xanthophaeus, Streptomyces hygroscopicus	X, botrycidin	9 μg inhibitor/mg protein^a (E. coli pH gradient formation by membrane vesicle) (311); 11 μg inhibitor/mg protein^a (E. coli membrane-bound ATPase) (311); 0.13 μg inhibitor/mg protein^a (150); 0.06-0.18^a (A and B) and 11.0^a (X) μg inhibitor/mg protein (S. cerevisiae SMP-ATPase) (151); 5-11 μg inhibitor/mg protein^a (T. pyriformis) (404); 3.0 μg/mg protein^a (C. asciculate SMP-ATPase) (439); 0.5 μM^a (spinach thylakoids, photophosphorylation) (447); 0.5 μM^a (spinach thylakoids, ATPase) (447)^a
Ossamycin	C₅₀H₈₇NO₁₄	S. hygroscopicus subsp. ossamyceticus		1.3 μg of inhibitor/mg protein^a (S. cerevisiae SMP-ATPase) (150); 46 μg of inhibitor/mg protein^a (E. coli pH gradient formation by membrane vesicle) (311); 8 μM^a (human NCI-60 cell lines, F₀F₁-ATPase) (348)
Apoptolidin	C₅₈H₉₆O₂₁	Nocardiopsis sp.		4-5 μM^b (S. cerevisiae membrane-bound F₀F₁-ATPase) (349); 18 μM^a (human NCI-60 cell lines, F₀F₁-ATPase) (348)
Cytovaricin	C₄₈H₈₂O₁₅	Streptomyces sp. strain H-230	H-230	1 μM^a (human NCI-60 cell lines, F₀F₁-ATPase) (348); 0.4 μM^b (S. cerevisiae membrane-bound F₀F₁-ATPase) (349)

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I₅₀.

K_i.

Oligomycins are a closely related group of 26-membered macrolides with both lactone moieties and double bonds. Oligomycins are produced in various strains of Streptomyces. They include six different types, A, B, C, D, E, and F, based on the R groups attached to the macrolide ring and sugar. Oligomycin D is also named rutamycin. Other specific oligomycins include peliomycin and botrycidin; the latter is known also as venturicidin X. Oligomycin inhibits ATP synthases from mitochondria and the chromatophores of photosynthetic bacteria (85, 150, 151, 253, 311, 347, 360). However, it has no or only a weak effect on photophosphorylation activity in chloroplasts and on membrane-bound ATPase activity of nonphotosynthetic bacteria (22, 36, 118, 285, 311, 376). Mutagenesis studies that cause resistance to oligomycin in yeast implicate a target site residing at the interface of subunits a and c, with an involvement of both Gly23 and Glu59 of the N- and C-terminal transmembrane helices of subunit c, respectively (97, 192, 280). Yeast Glu59 of subunit c is equivalent to E. coli Asp61, located in the middle of the membrane, and is believed to be involved in proton translocation that drives ATP synthesis.

Peliomycin, produced from various strains of Streptomyces (323, 358), is cytotoxic to mammalian cells, with limited antimicrobial and antifungal activities. The inhibitory properties of peliomycin on ATP synthesis by oxidative phosphorylation in mitochondria mimic those of rutamycin (423).

Venturicidin consists of three different types, A, B, and X, where venturicidin X is an aglycone of venturicidin A or B (401). It binds to subunit c of the ATP synthase and inhibits both proton translocation and membrane-bound ATPase activities from bacteria, chloroplasts, and mitochondria (62, 251, 311, 423, 447). The region conferring venturicidin resistance or hypersensitivity in ATP synthase is located in the middle of the membrane, and most of this region overlaps with that for oligomycin resistance (123, 131, 280).

Ossamycin is a 24-membered macrolide produced in Streptomyces hygroscopicus subsp. ossamyceticus (209, 359). Ossamycin inhibits both the ATPase and oxidative phosphorylation activities of mitochondrial ATP synthase (150, 423). It has no direct effect on E. coli F₁ (EF₁) or F₀, but it does inhibit ATP-driven proton transport by uncoupling ATP hydrolysis from proton transport (311). The binding site of ossamycin in mitochondrial ATP synthase lies close to the boundaries of regions that cause oligomycin and venturicidin resistance in subunit c. This site contains residues Leu53 to Leu57 (yeast sequence) in the C-terminal transmembrane helix (131).

Apoptolidin and cytovaricin are 20- and 26-membered macrolides found in Nocardiopsis spp. and Streptomyces sp. strain H-230, respectively. Both apoptolidin and cytovaricin inhibit membrane-bound mitochondrial ATP synthase. The precise binding sites of apoptolidin and cytovaricin are not yet defined. However, they are believed to be located at regions where oligomycin and ossamycin bind, as the chemical backbones of these inhibitors are structurally similar to those of oligomycin and ossamycin (349).

ORGANOTIN COMPOUNDS AND STRUCTURAL RELATIVES

Organotin compounds are organic compounds that contain tin. They are classified as R₄Sn, R₃SnX, R₂SnX₂, and RSnX₃. Among these, R₃SnX organotin compounds have been used as biocides and pesticides and are known to inhibit ATP synthase (Fig. 5) (148-150, 190, 252, 403-405, 418, 437). Some R₄Sn organotin compounds, such as tributyltin 3-hydroxyflavone, also inhibit ATP synthase (405). The organotin compounds inhibit both ATP hydrolysis and ATP synthesis catalyzed by the membrane-bound and isolated F₀F₁ complex. However, they have no effect on the ATPase activity of isolated F₁ (Table 9). Organotin compounds react noncovalently with the ATP synthase, and the inhibitory effect of the compounds is reversed by mono- and dithiols such as dithiothreitol and mercaptoethanol (437). The sites of action of organotin compounds are located in the ion channel within subunit a. Here, they are believed to inhibit ATP synthase by competing with Na⁺ or H⁺ for the same binding site (418). Diorganotin-3-hydroxyflavone complexes such as dibutyltin 3-hydroxyflavone bromide and diphenyltin 3-hydroxyflavone chloride show a marked fluorescence enhancement on binding to mitochondrial ATP synthase (405).

FIG. 5. — Structures of organotin compounds and structural relatives.

TABLE 9.

Organotin compounds and structural relatives

Name	Molecular formula	Other names	Inhibitory potency (reference)
Tributyltin chloride	C₁₂H₂₇ClSn	TBT-Cl; tributylchlorostannane; chlorotributyltin; tri-n-butyltin chloride; monochlorotributyltin; tri-n-butylchlorotin; tributylstannyl chloride	200 nM^b (E. coli and I. tartaricus F₀F₁-ATPase) (418); 47% inhibition at 1 μM and 87% inhibition at 5 μM (C. thermoaceticum membrane-bound F₀F₁-ATPase) (190); 80% inhibition at 1 μM (TF₀F₁-ATPase) (403)
Tricyclohexyltin hydroxide	C₁₈H₃₄OSn	Cyhexatin; tricyclohexylhydroxytin; hydroxytricyclohexylstannane; tricyclohexylhydroxystannane; tricyclohexylstannanol; Plictran; tricyclohexylstannium hydroxide	92.9% inhibition at 37 μM (rat liver MF₀F₁-ATPase) (252)
Triethyltin sulfate	C₁₂H₃₀O₄SSn₂	Triethylstannium hydrogen sulfate; bis(triethyltin) sulfate; triethylhydroxytin sulfate	0.13 μg of inhibitor/mg protein^a (S. cerevisiae SMP-ATPase) (150, 151); 3-7 μg of inhibitor/mg protein^a (T. pyriformis SMP-ATPase) (404); 1.2 μg/mg protein^a (C. asciculate SMP-ATPase) (439)
Triphenyltin chloride	C₁₈H₁₅ClSn	Chlorotriphenylstannane; chlorotriphenyltin; triphenylchlorotin	<10 μM^a (bovine heart SMP-ATPase) (437)
Dimethyltin 3-hydroxyflavone chloride	C₁₇H₁₅ClO₃Sn		12-13 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Diethyltin 3-hydroxyflavone chloride	C₁₉H₁₉ClO₃Sn		1.5 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Dibutyltin 3-hydroxyflavone bromide	C₂₃H₂₇BrO₃Sn		0.7-0.9 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Dioctyltin 3-hydroxyflavone chloride	C₃₁H₄₃ClO₃Sn		12-13 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Diphenyltin 3-hydroxyflavone chloride	C₂₇H₁₉ClO₃Sn		1.5 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Diethyltin 3,5,7,2′,4′-pentahydroxy flavone chloride	C₁₉H₁₉ClO₇Sn		5-6 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Dibutyltin 3,5,7,2′,4′-pentahydroxy flavone bromide	C₂₃H₂₇BrO₇Sn		0.6-0.8 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Diphenyltin 3,5,7,2′,4′-pentahydroxy flavone chloride	C₂₇H₁₉ClO₇Sn		3.5-4 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Tributyltin 3-hydroxyflavone	C₂₇H₃₆O₃Sn		1.5-2 nmol inhibitor/mg protein^a (rat liver SMP-ATPase) (405)
Triethyllead	C₆H₁₅ClPb	Triethylplumbane	16-17 μM^a (rat liver SMP-ATPase) (275)

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I₅₀.

K_i.

POLYENIC α-PYRONE DERIVATIVES

α-Pyrone (or 2-pyrone) is a six-membered cyclic unsaturated ester. Its derivatives are widely distributed in nature, and some α-pyrone-containing mycotoxins, such as aurovertin, citreoviridin, and asteltoxin, inhibit ATP synthase by targeting F₁ (Fig. 6).

FIG. 6. — Structures of polyenic α-pyrone derivatives.

Aurovertin is an antibiotic from Calcarisporium arbuscula. Five different types of aurovertins (A to E) have been reported (Table 10). Aurovertin inhibits the ATPase activity of F₁ from mitochondria and mesophilic bacteria (108, 189), whereas it has no inhibitory effect on thermophilic TF₁ (196, 343). It binds to the ATP synthase β subunit and inhibits its ATPase activity uncompetitively (108, 189). There are two or three binding sites for aurovertin in F₁ in the presence of ADP: one high-affinity site (K_d [dissociation constant] of 0.2 to 1 μM) and the others (one or two) of lower affinity (K_d of 3 to 6 μM) (188, 416). In contrast, two high-affinity sites are observed in the presence of ATP (188). In the crystal structure of one F₁-aurovertin complex (410), two aurovertin B molecules are bound at two equivalent sites within the β_TP and β_E subunits. These sites are located in a cleft between the nucleotide binding and C-terminal domains of the subunits and do not overlap with the nucleotide binding sites. In β_TP, the pyrone ring of aurovertin interacts with α-Glu399 of α_TP. However, in β_E the pyrone ring has no equivalent interaction with α_E, as the aurovertin bound in β_E is too far from α_E. The interactions between aurovertin and amino acids are mainly hydrophobic. In β_DP, the interface between α_DP and β_DP is tightly packed, making the aurovertin binding pocket inaccessible (410). In the binding of aurovertin to F₁, β-Arg398 (E. coli sequence) appears to play an important role, as mutations in this residue confer aurovertin resistance (230, 231, 424). In bacteria that are naturally resistant to aurovertin, the β-Arg398 residue is replaced with other amino acid residues (172, 343). Aurovertin is believed to inhibit F₁ by preventing catalytic interface closure involved in the cyclic interconversion of catalytic sites (410, 430). In addition, aurovertin increases the affinity of F₁ for phosphate (307). Aurovertin fluoresces weakly at 470 nm, and this is enhanced by 50- to 60-fold when aurovertin binds to F₁ (74, 136, 232). The fluorescence increase is considered to be due to the limited mobility of aurovertin at its binding site and has been used to monitor inhibition of F₁-ATPase activity (74, 136).

TABLE 10.

Polyenic α-pyrone derivatives

Name	Molecular formula	Source	Inhibitory potency (reference)
Aurovertin	A, C₂₇H₃₄O₉; B, C₂₅H₃₂O₈; C, C₂₄H₃₀O₈; D, C₂₅H₃₂O₉; E, C₂₃H₃₀O₇	C. arbuscula	9.2 μmol/mg protein^a and 25 μM^c (aurovertin A, bovine heart MF_1-ATPase) (232); 2 μM^a (aurovertin B, EF₁-ATPase) (353); 17-30 nmol/mg protein^a and 0.1 μM^c (aurovertin B, bovine heart MF₁-ATPase) (232); 2 nmol/mg protein^a and 0.6 μM^c (aurovertin C, bovine heart SMP) (232); 0.9 μM^a (aurovertin D, EF₁-ATPase) (353); 1 μM^a (aurovertin D, EF₁-ATPase) (436); 9-20 nmol/mg protein^a and 60 nM^c (aurovertin D, bovine heart MF₁-ATPase) (232); 1.6 μmol/mg protein^a and 22 μM^c (aurovertin E, bovine heart SMP) (232); 80 nM^a (rat liver MF1-ATPase) (108); 66% inhibition at 10 μM (bovine heart MF₁-ATPase) (325)
Citreoviridin	A, C₂₃H₃₀O₆; B, unknown; C, C₂₃H₃₀O₆; D, C₂₄H₃₂O₆	A, Penicillium citreoviride, Penicillium toxicarium, Penicillium ochrosalmoneum, Aspergillus terreus; B, A. terreus; C, A. terreus; D, A. terreus	60 μM^a (EF₁-ATPase) (353); 1.11 μmol/mg protein^a (bovine heart MF₁-ATPase) (232); 2 μM^b (S. cerevisiae MF₁-ATPase) (136); 4.23 μM^b (354) (bovine heart MF₁-ATPase); 2.82 μM^b (354), 6.1 μM^b (354) (bovine heart SMP-ATPase); 3.1 μM^c (232), 4.1 μM^c (354) (bovine heart MF₁-ATPase); 60 μM^c (EF₁-ATPase) (353)
Asteltoxin	C₂₃H₃₀O₇	A. stellatus Curzi, E. variecolor	10 μM^a (EF₁-ATPase) (352); ∼450 nM^a (state 3 respiration of rat liver mitochondria) (200); 8 μM^c (EF₁-ATPase) (352)

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K_i.

K_d.

Aurovertin B has been tested for the treatment of breast cancer cells as an anticancer agent and has shown strong inhibition of the proliferation of breast cancer cell lines, whereas it showed little influence on normal cells (180). Aurovertin B induced apoptosis of cancer cells and arrested their cell cycles in G₀/G₁ phase.

Citreoviridin, produced by some molds of the genera Penicillium and Aspergillus, inhibits the ATPase activities of F₁ from bacteria and mitochondria by binding to the ATP synthase β subunit (136, 353) (Table 10). However, ATP synthases from some species are resistant (404, 439). In sensitive species, citreoviridin acts as an uncompetitive inhibitor of ATP hydrolysis by soluble and membrane-bound ATP synthase and as a noncompetitive inhibitor of ATP synthesis by the membrane-bound ATP synthase enzyme (354). The binding of citreoviridin to F₁ or its isolated β subunit is noncompetitive with respect to aurovertin (136). Although the binding site of citreoviridin within the β subunit is not clarified, it has been suggested that citreoviridin and aurovertin interact at separate sites (136). Citreoviridin fluoresces weakly at 530 nm when irradiated at 380 nm. However, unlike aurovertin, enhancement is not observed when bound to F₁ (233). Light converts citreoviridin to its stereoisomer, isocitreoviridin, which has no effect on either ATP hydrolysis or ATP synthesis catalyzed by ATP synthase (354).

Asteltoxin is made in Aspergillus stellatus Curzi and Emericella variecolor. It contains a unique 2,8-dioxabicyclooctane ring and inhibits both BF₁ and MF₁ with a stoichiometry of 1:1 in the presence of ADP (Table 10) (200, 352). As asteltoxin fails to inhibit aurovertin-resistant mutants, it is believed to bind to the same site as aurovertin (352). Asteltoxin binding to F₁ shows an enhancement of fluorescence (emission maximum, 470 nm; excitation maximum, 385 nm). The ADP-stimulatory effect and the Mg²⁺-quenching effect on the fluorescence enhancement of asteltoxin binding are similar to those observed for aurovertin. However, the stimulatory effect on phosphate binding to F₁ observed with aurovertin is not observed with asteltoxin (352).

CATIONIC INHIBITORS

Amphiphilic Cationic Dyes

Amphiphilic cationic dyes containing a basic amine group and a lipophilic portion (Fig. 7A) inhibit the ATPase activities of both F₁ and F₀F₁. Most exhibit a stronger inhibitory effect on the ATPase activity of F₀F₁ than on that of F₁ (Table 11).

TABLE 11.

Amphiphilic cationic dyes

Name or abbreviation	Molecular formula	Other names	Inhibitory potency (reference)
Rhodamine B	C₂₈H₃₁ClN₂O₃	N-(9-(2-Carboxyphenyl)-6-(diethylamino)-3H-xanthen-3-ylidene)-N-ethylethanaminium chloride; rheonine B; rhodamine O; rhodamine S	475 μM^a (bovine heart MF₁-ATPase) (52); 125 μM^a (bovine heart MF₀F₁-ATPase) (52)
Rhodamine 123	C₂₁H₁₇ClN₂O₃	3,6-Diamino-9-(2-(methoxycarbonyl)phenyl)xanthylium chloride; RH 123	270 μM^a (bovine heart MF₁-ATPase) (52); 141 μM^a (bovine heart MF₀F₁-ATPase) (52); 580 μM^a (EF₀F₁-ATPase) (268); 177 μM^b (rat liver MF₁-ATPase) (113)
Rhodamine 6G	C₂₈H₃₁ClN₂O₃	Basic rhodamine yellow; rhodamine J	10 μM^a (bovine heart MF₁-ATPase) (52); 27 μM^a (bovine heart MF₁-ATPase) (143); 2 μM^a (bovine heart MF₀F₁-ATPase) (52); 34 μM^a (EF₀F₁-ATPase) (268); 2.4 μM^b (S. cerevisiae MF₁-ATPase) (433); 1.95 μM^b (S. cerevisiae MF₀F₁-ATPase) (433); 1.91 μM^b (S. cerevisiae SMP-ATPase) (433)
Rosaniline	C₂₀H₂₀ClN₃	Magenta base; 4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-2-methylbenzenamine	15 μM^a (bovine heart MF₁-ATPase) (52); 16 μM^a (bovine heart MF₀F₁-ATPase) (52)
Malachite green	C₂₃H₂₅N₂Cl	Aniline green; benzal green; Victoria green; (4-(4-dimethylaminobenzhydriylidene)cyclo-hexa-2,5-dienylidene)dimethylammonium chloride	14 μM^a (bovine heart MF₁-ATPase) (52); 7 μM^a (bovine heart MF₀F₁-ATPase) (52)
Brilliant green	C₂₇H₃₃N₂.HO₄S	Basic green 1; (4-(4-(diethylamino)benzhydrylene)cyclohexa-2,5-dien-1-ylidene)diethylammonium hydrogen sulfate	27 μM^a (EF₀F₁-ATPase) (268)
Quinacrine	C₂₃H₃₀ClN₃O	2-Methoxy-6-chloro-9-diethylaminopentylaminoacridine; 3-chloro-7-methoxy-9-(1-methyl-4-diethylaminobutylamino)acridine; mepacrine	580 μM^a (EF₀F₁-ATPase) (268); 580 μM^a (bovine heart MF₁-ATPase) (220); 440 μM^b (bovine heart MF₁-ATPase) (220)
Quinacrine mustard	C₂₃H₂₈Cl₃N₃O	Quinacrine mustard dihydrochloride; 2-methoxy-6-chloro-9-(3-(ethyl-2-chloroethyl)aminopropylamino)acridine dihydrochloride; 9-[4-(bis(2-chloroethyl)amino)-1-methylbutylamino]-6-chloro-2-methoxyacridine dihydrochloride	5.3 μM^a (EF₀F₁-ATPase) (268); 27 μM^c (bovine heart MF₁-ATPase) (53)
Acridine orange	C₁₇H₁₉N₃Cl	3,6-Acridinediamine, N,N,N′,N′-tetramethyl-, monohydrochloride; 3,6-bis(dimethylamino)acridine hydrochloride; rhoduline orange	180 μM^a (bovine heart MF₁-ATPase) (52); 1 μM^a (bovine heart MF₀F₁-ATPase) (52); 68 μM^a (EF₀F₁-ATPase) (268)
Coriphosphine	C₁₆H₁₇N₃.HCl	Coriphosphine O; coriphosphine OX; 3-amino-6-(dimethylamino)-2-methylacridine monohydrochloride	480 μM^a (bovine heart MF₁-ATPase) (52); 16 μM^a (bovine heart MF₀F₁-ATPase) (52)
Pyronin Y	C₁₇H₁₉ClN₂O	Pyronine; pyronin G	1.65 mM^a (bovine heart MF₁-ATPase) (52); 10 μM^a (bovine heart MF₀F₁-ATPase) (52); 70 μM^a (EF₀F₁-ATPase) (268)
Dequalinium	C₃₀H₄₀N₄	1,1′-(1,10-Decanediyl)bis(4-amino-2-methyl-quinolinium	8 μM^a (52), 12 μM^a (452), 46 μM^a (143) (bovine heart MF₁-ATPase); 24 μM^a (EF₀F₁-ATPase) (268); 50 μM^a (TF₁-ATPase, photoinactivation) (296);19 mM (Bacillus PS3 ATPase, αβγ complex) (143); 4 μM^b (spinach CF₁, Ca²⁺-ATPase) (329); 12.5 μM^c (TF₁-ATPase) (296); 12.5 μM^c (bovine heart MF₁-ATPase) (452)
Safranin O	C₂₀H₁₉ClN₄	Basic red 2; 3,7-diamino-2,8-dimethyl-5-phenylphenazinium chloride; safranine T	1.14 mM^a (bovine heart MF₁-ATPase) (52); 175 μM^a (bovine heart MF₀F₁-ATPase) (52); 330 μM^a (EF₀F₁-ATPase) (268)
Nile blue A	C₂₀H₂₀N₃OCl	Nile blue; Nile blue AX; 5-amino-9-(diethylamino)benzo(a)phenoxazine-7-ium chloride	>2,000 μM^a (bovine heart MF₁-ATPase) (52); 16 μM^a (bovine heart MF₀F₁) (52)
EtBr	C₂₁H₂₀BrN₃	Ethidium bromide; homidium bromide; AI3-62997; 2,7-diamino-10-ethyl-9-phenylphenanthridinium bromide	220 μM^a (S. cerevisiae MF₁-ATPase) (82); 250 μM^a (Trypanosoma cruzi F₀F₁-ATPase) (66); 279 μM^b (S. cerevisiae MF₁-ATPase) (433); 256 μM^b (S. cerevisiae MF₀F₁-ATPase) (433); 263.6^b μM (S. cerevisiae SMP-ATPase) (433)

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K_i.

K_d.

Rhodamines are a group of fluorone dyes made by fusing an amino derivative of phenol with phthalic anhydride, and they include rhodamine B, rhodamine 123, and rhodamine 6G. Rhodamine B and rhodamine 123 inhibit the ATPase activity of MF₁ from bovine heart in a parabolic, noncompetitive manner, whereas inhibition by rhodamine 6G is mixed (433). In contrast, rhodamine 6G acts as an uncompetitive inhibitor of MF₁ and as a noncompetitive inhibitor for isolated and membrane-bound ATP synthase F₀F₁ from yeast (433). Rhodamine B and rhodamine 123 are considered to bind F₁ at more than one binding sites, while rhodamine 6G at high concentrations is believed to bind at least two binding sites (52). The precise location of rhodamine 6G binding sites in the three-dimensional structure of F₁ has yet to be identified (143).

Rosaniline, malachite green, and brilliant green are closely related in structure. Rosaniline and malachite green inhibit MF₁ in a parabolic mixed fashion, indicating at least two binding sites at high concentrations (52).

Quinacrine inhibits reversibly the ATPase activities of EF₁ and bovine MF₁ with a similar inhibitory potency (220, 268). This agent inhibits the ATP hydrolysis activity of F₁ competitively when Mg²⁺ is at a constant concentration and ATP at a variable concentrations (220, 268). Quinacrine mustard is a quinacrine derivative in which a diethyl group attached to the tertiary amino group is replaced by a bischloroethyl groups. The quinacrine mustard binds to F₁ and alkylates β subunits. The inhibition of the ATPase activity of F₁ by quinacrine mustard is irreversible (220) and is due, at least in part, to modification of one or more of the carboxylic acid side chains in the β subunit DELSEED region and possibly also to modification of unspecified amino acid side chains between residues β302 and 356 in the bovine sequence (53). The rate of inactivation of MF₁ and TF₁ by quinacrine mustard is inhibited by ATP, whereas the rate of inactivation of EF₁ is stimulated by ATP (54).

Acridine orange and coriphosphine are acridine derivatives that inhibit the ATPase activity of MF₁ in a mixed fashion (52). Pyronin Y, a xanthene derivative, inhibits the ATPase activities of F₀F₁ from mitochondria and E. coli (52, 268). Here, the inhibitory effect on the mitochondrial ATPase is more potent for F₀F₁ (>100-fold) than for F₁ (52).

Dequalinium is a quinoline derivative that inhibits the ATPase activities of F₁ from both mitochondria and bacteria (52, 268, 296, 329, 452). Dequalinium inhibits chloroplast Ca²⁺-ATPase, whereas it stimulates chloroplast Mg²⁺-ATPase (329). The inhibition of ATPase activity by dequalinium is reversible, hyperbolic, and noncompetitive for MF₁ and TF₁ in the dark (52, 268, 296, 329, 452). A long lag is observed in the inhibition of TF₁ by dequalinium that is not observed for the inhibition of MF₁ (296). Dequalinium, upon illumination at 350 nm, inactivates F₁-ATPase with pseudo-first-order kinetics (296, 329, 452, 454). This is accompanied by derivatization of βPhe420 in TF₁ (296), βMet183 in CF₁ (329), and αPhe403, αPhe406, and a side chain within residues 440 to 459 of the β subunit in bovine heart MF₁ (454).

Safranin O inhibits the ATPase activities of membrane-bound F₀F₁ from both bovine heart mitochondria and E. coli (52, 268). Safranin O also inhibits soluble MF₁ with weaker inhibitory potency (52). Nile blue A inhibits the ATPase activity of membrane-bound F₀F₁ from mitochondria, whereas it has no inhibitory effect on isolated F₁ (52). Ethidium bromide inhibits noncompetitively ATP hydrolysis by both MF₁ and F₀F₁ from Saccharomyces cerevisiae (82, 433), with similar inhibitory potencies (66, 82).

TALAs and Related Compounds

Tertiary amine local anesthetics (TALAs) are composed of an aromatic portion, an intermediate chain, and a terminal amine group (Fig. 7B) (370). The intermediate chain contains either an ester (tetracaine and procaine) or an amide (dibucaine and lidocaine) group. In procainamide, the ester group in procaine is replaced with an amide. Chlorpromazine and trifluoroperazine are cationic phenothiazine derivatives. The TALAs are known to inhibit primarily sodium influx through sodium-specific ion channels in the neuronal cell membrane. However, they can also bind to ATP synthases from mitochondria and some bacteria and can inhibit ATP hydrolysis activity (Table 12) (76, 406).

TABLE 12.

Tertiary amine local anesthetics and related compounds

Name	Molecular formula	Other names	Inhibitory potency, I₅₀ (reference)
Tetracaine	C₁₅H₂₄N₂O₂	Dicaine; 2-(dimethylamino)ethyl p-(butylamino)benzoate; dimethylaminoethyl p-butyl-aminobenzoate; p-butylaminobenzoyl-2-dimethylaminoethanol	0.7-0.83 mM (76), 1.1 mM (406), 1.95 mM (343) (bovine heart MF₁-ATPase); 1.4 mM (76), 1.79 mM (343) (bovine heart SMP-ATPase)
Dibucaine	C₂₀H₂₉N₃O₂	2-Butoxy-N-(2-(diethylamino)ethyl) cinchoninamide; 2-butoxy-N-(2-DEAE) quinoline-4-carboxamide; cincainum; cinchocaine; Dermacaine; dibucainum; Nupercaine; Percamine; Sovcaine; α-butyloxycinchonic acid-γ-diethylethylenediamine	0.19-0.5 mM (bovine heart MF₁-ATPase) (76); 0.26 mM (bovine heart SMP-ATPase) (76); 29% inhibition at 1 mM (M. phlei F₁-ATPase) (4); 55.7% inhibition at 1 mM (M. phlei membrane-bound ATPase) (4)
Procaine	C₁₃H₂₀N₂O₂	2-DEAE-4-aminobenzoate; DEAE p-aminobenzoate; p-aminobenzoyldiethylaminoethanol; procain; Spinocaine	1.8 mM (343), 15-17 mM (76) (bovine heart MF₁-ATPase); 8.4 mM (343), 9.5 mM (76) (bovine heart SMP-ATPase)
Lidocaine	C₁₄H₂₂N₂O	2-(Diethylamino)-N-(2,6-imethylphenyl) acetamide; cappicaine; Duncaine; Esracaine; Isicaine; Lidocaine; Maricaine; xycaine; Xylocaine	12-16 mM (76), 18.2 mM (343) (bovine heart MF₁-ATPase); 10 mM (76), 22 mM (343) (bovine heart SMP-ATPase)
Chlorpromazine	C₁₇H₁₉N₂SCl	2-Chloro-10-(3-(dimethylamino)propyl) phenothiazine; Aminazin; Aminazine; Chlor-Promanyl; Chlorderazin; Chlorpromados; Contomin; Elmarin; Esmind; Fenactil; Largactil; Megaphen; Novomazina; Proma; Phenactyl; Promactil; Propaphenin; Prozil; Psychozine; Sanopron; Thorazine; Torazina; Wintermin	50 μM(54), 60 μM (343), 50-150 μM (221) (bovine heart MF₁-ATPase); 26 μM (76), 450 μM (343) (bovine heart SMP-ATPase); 150 μM (EF₁-ATPase) (54); 30.8-56.0 μM (bovine heart MF₀F₁-ATPase) (87); 6.5-12 μM (bovine heart MF₀F₁, photoinactivation) (87)
Trifluoperazine	C₂₁H₂₄F₃N₃S	10-(3-(4-Methyl-1-piperazinyl)propyl)-2-(trifluoromethyl)phenothiazine; trifluoromethylperazine	17.2-30.5 μM (bovine heart MF₀F₁-ATPase) (87); 3.0-5.5 μM (bovine heart MF₀F₁, photoinactivation) (87)
Procainamide	C₁₃H₂₁N₃O	4-Amino-N-(2-(diethylamino)ethyl)benzamide	17-35 mM (76), 33 mM (343) (bovine heart MF₁-ATPase); 31 mM (bovine heart SMP-ATPase) (76)
Propranolol	C₁₆H₂₁NO₂	1-((1-Methylethyl)amino)-3-(1-naphthalenyloxy)-2-propanol	210 μM (343), 0.87-1.4 mM (76) (bovine heart MF₁-ATPase); 310 μM at 37°C and 880 μM at 60°C (TF₁-ATPase) (343); 660 μM (343), 840 μM (76) (bovine heart SMP-ATPase)

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TALAs inhibit both membrane-bound and soluble MF₁. Inhibition of MF₁ is reversible, and the concentration ranges for inhibition are near those for blocking nerve conduction (76). The hydrophobicity of TALAs seems to determine their relative affinities for F₁, as the inhibitory potencies are directly correlated with the octanol/water partition coefficient (76). Among the TALAs, procainamide shows activation of the ATPase activity of F₁ at low concentrations prior to its inhibition of F₁ at high concentrations. This is not observed with other TALAs (76). The mechanism of the inhibitory action of TALAs on MF₁ is still controversial, with one view implicating the induction of the structural dissociation of the multisubunit structure of F₁ (76) and a second view the interaction with the catalytic sites of F₁ (221).

In contrast to the case for the mitochondrial ATP synthase, the TALAs inhibit bacterial ATP synthases selectively. For example, they exhibit no inhibition of F₁ from the thermophilic bacterium PS3 under the conditions tested (343). However, tetracaine and dibucaine do inhibit the ATPase activity of the membrane-bound ATP synthase from the bacterium Mycobacterium phlei (4), whereas procaine and lidocaine show no inhibitory effects. In addition, tetracaine and dibucaine show no or partial inhibition of the ATPase activity of soluble F₁, in contrast to full inhibition of the ATPase activity of the membrane-bound ATP synthase. Upon inhibition (uncompetitive) of the membrane-bound ATP synthase from M. phlei by tetracaine and dibucaine, proton conductivity is markedly inhibited. Tetracaine and DCCD are not mutually exclusive in binding to the ATP synthase from M. phlei, and they appear to bind to separate binding sites within the proton-translocating “F₀” region (4).

Chlorpromazine and trifluoroperazine interact with various subunit types of F₁ and F₀. Both bind to membrane-bound subunits more readily than to soluble subunits, with trifluoroperazine binding to hydrophobic subunits more extensively than chlorpromazine (88). The binding sites of chlorpromazine and trifluoroperazine are not identical and mutually nonexclusive (87, 88). Upon photoactivation with UV light, the phenothiazine moiety of chlorpromazine and trifluoroperazine forms covalent bonds with the ATP synthase, leading to its irreversible inhibition. In other studies, chlorpromazine has been shown to protect MF₁ and EF₁ against both cold-induced dissociation and inactivation by DCCD (54). This agent is believed to cause inhibition by interacting with the catalytic site at position βGlu188 (bovine sequence). However, in other studies, chlorpromazine has been shown to stimulate the ATPase activity of TF₁ both at 37°C and at low concentrations (below 0.6 mM) at 23°C. It shows no inhibition up to 1.2 mM at 37°C or 60°C (54).

Propranolol is a nonselective beta blocker for the treatment of hypertension. It is not a TALA and has no ester or amide group in the intermediate chain. However, it is structurally analogous to TALAs. The main action of propanolol is to block the action of epinephrine on both β1- and β2-adrenergic receptors, but it also targets ATP synthase. Propranolol inhibits the mitochondrial ATPase activities of both membrane-bound ATP synthase and isolated F₁ (76, 343). It also inhibits TF₁ at both 37°C and 60°C with nearly the same effective concentrations as that for inhibition of membrane-bound mitochondrial ATP synthase (76, 343).

Other Organic Cations

Alkylguanidines (Fig. 7C) that possess an alkyl chain of more than six carbons inhibit the ATPase activities of both membrane-bound and isolated MF₁ (92, 300). The inhibition by octylguanidine, an alkylguanidine, is fully reversible, and the octylguanidine prevents cold-induced dissociation of F₁ (92).

1-Dansylamido-3-dimethypropylamine compounds are dansylated organic cationic inhibitors (Fig. 7C). They inhibit both ATP hydrolysis and ATP synthesis at similar concentrations (116). The 1-dansylamido-3-dimethypropylamine compounds inhibit the ATPase activities of both isolated and membrane-bound F₁ and exhibit more potent inhibitory effect on the membrane-bound F₁ than the isolated enzyme. The 1-dansylamido-3-dimethypropylamine compounds with longer alkyl groups (decyl and hexadecyl) have stronger inhibitory activity than those with short groups (propyl and hexyl) (Table 13). The binding site(s) of these compounds is not clarified but is considered to be located on the β subunit (116).

TABLE 13.

Other organic cations

Name or abbreviation	Molecular formula	Other names	Inhibitory potency (reference)
Octyl guanidine	C₉H₂₁N₃		300 μM^a (bovine heart SMP- and MF₁-ATPase) (92); 330 μM^a (rat liver SMP-ATPase) (300)
1-Dansyl amido-3-dimethypropylamine compounds	C₂₀H₃₂N₃O₂S (n = 2) C₂₃H₃₈N₃O₂S (n = 5) C₂₇H₄₆N₃O₂S (n = 9) C₃₃H₅₈N₃O₂S (n = 15)		1.4 mM^a (n = 2), 0.4 mM^a (n = 5), 7.9 μM^a and 4.4 μM^b (n = 9), and 3.4 μM^a (n = 15) (bovine heart SMP-ATPase) (116)
Cetyltrimethylammonium	C₁₉H₄₂N	Cetrimonium; cetrimonum; cetyltrimethylammonium; hexadecyltrimethylammonium; trimethylhexadecylammonium	80 μM^b (bovine heart MF₁-ATPase) (31)
Spermine	C₇H₁₉N₃	4-Azaoctamethylenediamine	Inhibitory effect at 1-2 mM range (185); ∼55% inhibition at 2 mM with 2 mM Mg²⁺ (rat liver MF₁-ATPase) (185)
Spermidine	C₁₀H₂₆N₄	1,4-Bis(aminopropyl) butanediamine; diaminopropyltetramethylenediamine	Inhibitory effect at 2.5-5 mM range (rat liver MF_1-ATPase) (185)
Bathophenan throline-metal (Ru²⁺, Ni²⁺, Fe²⁺) chelate	C₂₄H₁₆N₂, 3C₂₄H₁₆N₂·Ru, 3C₂₄H₁₆N₂·Ni, 3C₂₄H₁₆N₂·Fe	1,10-Bathophenanthroline; 4,7-diphenyl-1,10-phenanthroline; bathophenanthroline ruthenium(II); Ru-Tdpa; tris(4,7-diphenyl-1,10-phenanthroline)ruthenium (II); 4,7-diphenyl-1,10-phenanthroline-ferrous chelate; BPh₃Fe²⁺	For BPh, almost complete inhibition at 5 μM (bovine heart MF1) (315); for BPh₃·Fe²⁺, 30 nmol/mg protein^b (N. crassa SMP-ATPase) (112); 100% inhibition at 0.67 μM (bovine heart MF₁-ATPase) (63)
DPBP-ferrous chelate	3C₂₂H₁₆N₂·Fe	4,4-Diphenyl-2,2-bipyridine	85% inhibition at 0.67 μM and 99% inhibition at 3.33 μM (bovine heart MF₁-ATPase) (63)
PDT-ferrous chelate	3C₂₀H₁₄N₄·Fe	3-(2-Pyridyl)-5,6-diphenyl-1,2,4-triazine	73% inhibition at 0.67 μM and 95% inhibition at 3.33 μM (bovine heart MF₁-ATPase) (63)
Atrazine	C₈H₁₄ClN₅	6-Chloro-N-ethyl-N′-(propan-2-yl)-1,3,5-triazine-2,4-diamine
Atrazine amino derivative	C₇H₁₃ClN₆	N-(Aminomethyl)-6-chloro-N′-(propan-2-yl)-1,3,5-triazine-2,4-diamine

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I₅₀.

K_i.

Cetyltrimethylammonium inhibits the ATPase activities of soluble and membrane-bound F₁ in a noncompetitive manner (31). The inhibition is reversible and can be reversed by dilution. The inhibition of membrane-bound F₁ shows a more complex pattern than that of isolated F₁ with a sigmoidal dependence on the concentration of cetyltrimethylammonium. Also, cetyltrimethylammonium potentiates inhibition of membrane-bound ATP synthase by oligomycin, and vice versa. It lowers the K_i of the ATP synthase for oligomycin by about 1 order of magnitude. The inhibitory effect by cetyltrimethylammonium is believed to be due to an interaction of negatively charged residues buried in a hydrophobic environment of F₁.

Spermine and spermidine are polyamines distributed widely in nature. Both activate the ATPase activity of membrane-bound ATP synthase at low physiological concentrations (312, 374) and inhibit it at high concentrations (185). Spermine and spermidine also inhibit the ATPase activity of isolated F₁. Inhibition by spermine (1 to 2 mM range) is much greater than that by spermidine (2.5 to 5 mM range) and is uncompetitive with variable concentrations of ATP in the presence of Mg²⁺ but competitive when both ATP and Mg²⁺ concentrations are variable. Spermine and spermidine bind to ATP, an event that is inhibited by Mg²⁺. In fact, the inhibition of the ATPase activities of membrane-bound and isolated F₁ by polyamines is considered to be due to their direct binding to ATP. In contrast to their ATPase-inhibitory actions, spermine and spermidine stimulate catalysis in SMP of both succinate-dependent ATP synthesis and P_i-ATP exchange (185).

Octahedral bathophenanthroline (BPh₃)-metal chelates inhibit MF₁ in an uncoupler-reversible fashion (63-65, 315). They bind to the ATP synthase β subunit and form a complex with a stoichiometic ratio of 3 mol BPh₃-Me²⁺/mol F₁. Full inhibition is observed with 0.67 μM of BPh₃-Fe²⁺ for MF₁ from bovine heart (63). BPh₃-Fe²⁺ competes with aurovertin for binding to the β subunit. The inhibition is relieved by addition of uncouplers of oxidative phosphorylation via a process that involves direct interaction of the uncouplers with the inhibitory chelates. In fact, inhibitor-uncoupler adducts are believed to be formed (63). BPh₃-Ni²⁺ and BPh₃-Ru²⁺ are equally efficient inhibitors in the uncoupler-reversible inhibition of MF₁ (63, 65). Moreover, BPh₃-Fe²⁺ protects F₁ from cold-induced dissociation and light-induced inactivation by Rose bengal in an uncoupler-reversible manner (64). The related chelates 4,4-diphenyl-2,2-bipyridine and 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine with Fe²⁺ also inhibit MF₁, but with weaker inhibitory potencies than BPh₃-metal chelates (63).

Atrazine is a globally used triazine herbicide that inhibits photosynthetic electron transport by binding the plastoquinone binding protein in photosystem II (382). Atrazine also targets ATP synthase from sperm and mitochondria, inhibiting the ATP synthesis activity of ATP synthase (170). The amino derivative of atrazine in which a terminal methyl group is replaced with an amino group is more potent in inhibition of ATP synthesis.

SUBSTRATES AND SUBSTRATE ANALOGS

Phosphate Analogs

Arsenate mimics the γ-phosphate of ATP. It inhibits ATP synthesis at the active site of ATP synthase by competing with phosphate (Fig. 8 and Table 14) (81, 264, 307). Arsenate blocks the P_i↔ H₂O exchange and also the ATP↔ P_i exchange catalyzed by the ATP synthase (201) and is a more effective inhibitor when the concentration of phosphate is low (307). Thus, at 40 μM phosphate, 4.6 mM arsenate inhibits phosphate binding to bovine heart MF₁ by 84%.

TABLE 14.

Phosphate analogs

Name or abbreviation	Molecular formula	Inhibitory potency (reference)
Arsenate	AsO₄	84% inhibition at 4.6 mM at low conc of phosphate (40 μM) (bovine heart MF₁-ATPase) (307)
Aluminum fluoride	AlF₃ and AlF₄⁻	10 μM^a of AlCl₃ in the presence of 5 mM NaF and 100 μM ADP (bovine heart MF₁-ATPase) (243)
Beryllium fluoride	BeF⁺, BeF₂, and BeF₃⁻	10 μM^a of BeCl₂ in the presence of 5 mM NaF and 100 μM ADP (bovine heart MF₁-ATPase) (243); 20 μM^a of BeCl₂ in the presence of 2.5 mM NaF with 80 μM ADP with 50 mM Cl⁻ (45 min incubation), 20 mM SO₄²⁻ (14 min incubation), or 20 mM SO₃⁻ (2 min incubation) (bovine heart MF₁-ATPase) (187)
Scandium fluoride	ScF_x	60 μM^a and 95% inhibition at 0.3 mM in the presence of 2.5 mM MgSO4, 1 mM ADP, and 10 mM NaF (279)
Vanadate	VO₄³⁻ and VO₃⁻	VO₄³⁻, 50% inhibition in ∼45 min and ∼80% inhibition in ∼2 h at 200 μM in the presence of 200 μM each of MgCl₂ and ADP (rat liver MF₁-ATPase) (210); VO₃⁻, 30% inhibition at 300 μM (V. parahaemolyticus F₁-ATPase) (344)
Magnesium fluoride	MgF_x	50% inhibition at 1mM NaADP, 1 mM NaF, and 11-12 mM MgCl₂ with 5-12 h preincubation (EF₁-ATPase) (5)
Sulfite	SO₃²⁻	3.5 mM^a and maximal 70% at 10 mM (P. denitrificans F₀F₁, ATP synthesis) (295)
Thiophosphate	SPO₃³⁻	K_m, 1.5 μM in the presence of 1 mM from 4.5 μM in the absence (pea SMP-ATP synthesis) (254)
Azide	N₃⁻	∼10⁻⁵ M^b (bovine heart MF₁-ATPase) (412); ∼25 μM^b (EF₁-ATPase) (287); 71% inhibition at 1 mM (V. parahaemolyticus F₁-ATPase) (344); >90% inhibition at 0.5 mM (EF₁-ATPase) (287); 55% inhibition at 500 μM (C. thermoaceticum F₁-ATPase) (190)
ANPP	C₆H₄N₄O₆P	25 μM^a (spinach CF₁-ATPase, photoinactivation) (321); 60 μM^b in the dark (bovine heart MF₁-ATPase) (227)

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I₅₀.

K_i.

The phosphate analogs aluminum fluoride and beryllium fluoride also bind to the catalytic sites of ATP synthase by mimicking the γ-phosphate of ATP (48, 107, 195, 243, 256). The inhibition by these fluorides of aluminum and beryllium involves ADP, Mg²⁺, and the fluoride ion (F⁻). In fact, no inhibition occurs without fluoride. Inhibition also occurs when IDP, GDP, or CDP replaces ADP (187, 243). Aluminum fluoride and beryllium fluoride inhibit F₁ to the same extent via a “quasi-irreversible” process (243). The inhibitory species recognized by F₁ are AlF₃ and AlF₄⁻ for aluminum fluoride (48, 256) and BeF⁺, BeF₂, and BeF₃⁻ for beryllium fluoride (187, 195). In crystals of F₁ grown with ADP and one of the inhibitors (AlF₄⁻ or BeF₃⁻), two catalytic sites are occupied, one in the β_TP subunit and the other in the β_DP subunit (195, 256). Only one catalytic site, β_DP, is occupied with aluminum fluoride (AlF₃) in the crystal grown in the presence of ADP, adenylyl imidodiphosphate (AMP-PNP), and the inhibitor. No bound aluminum fluoride or beryllium fluoride is found in the α and β_E subunits. Three basic residues located in the vicinity of the γ-phosphate site, βLys162, βArg189, and αArg373, are involved in coordination of the inhibitors and are considered to provide charge stabilization (256).

Scandium fluoride (ScF_x) binds to F₁ of ATP synthase and inhibits its ATPase activity (279). ScF_x forms a tight-binding inhibitory ternary complex with MgADP at the catalytic sites, and the MgADP·ScF_x complex acts as a transition state analog. The inhibition by ScF_x is Mg²⁺ dependent, and ADP is also required for strong inhibition. The inhibition is reversible, and the ATPase activity is slowly regained in a single exponential reactivation process.

Two vanadate species, VO₄³⁻ and VO₃⁻, inhibit F₁-ATPase (77, 210, 211, 344). Orthovanadate (VO₄³⁻) binds to the catalytic sites and forms a transition-like state MgADP·V_i-F₁ complex in the presence of ADP and Mg²⁺. The inhibition of rat liver MF₁ by orthovanadate is reversible, with a restoration of original activity to a level close to 90% (210, 211), whereas EF₁ is resistant to orthovanadate (6). In the presence of UV and O₂, the cleavage of the β subunit from rat liver MF₁ occurs at position Ala158 in the P-loop (210, 211). In the crystal structure of F₁ with vanadate from the same source, one vanadate ion is found in each catalytic site of the β subunit (77). The vanadate in this transition-like state is located in a charged pocket surrounded by βLys162, βGlu188, βArg189, and βArg260 and is complexed with ADP and Mg²⁺. Moreover, the vanadate is positioned closer to P-loop βAla158 than is phosphate in the F₁-ADP,P_i ground state structure. It has been proposed that the positioning of βAla158 closer to the γ-phosphate of ATP in the transition state may help facilitate the dehydration of ADP and P_i (to give water) and therefore facilitate ATP synthesis (77).

Magnesium fluoride inhibits F₁ by acting also as an apparent transition state analog in combination with MgADP (5). Like vanadate, it mimics the γ-phosphate of ATP in the transition state. The inhibition is slow and reversible and requires ADP.

Sulfite is known as an effective activator of F₁-ATPase. However, it can also play a role as an inhibitor of the reversal of ATP synthase as a mixed-type inhibitor in the presence of ADP and phosphate (Fig. 8 and Table 14). The sulfite diminishes the rate of ATP synthesis of Paracoccus denitrificans with an I₅₀ of 3.5 mM (295). The mechanism of sulfite inhibition is uncertain, but it has been suggested that the action of inhibitory ADP is involved in the binding of nucleotides to noncatalytic sites (249), and the binding of sulfite to the noncatalytic sites increases the K_i for inhibitory ADP (295, 327).

Thiophosphate is a group of compounds in which a phosphorus atom is bonded to one or more sulfur and zero or more oxygen atoms, and it is found in a number of insecticides. A thiophosphate, SPO₃³⁻, has been shown to inhibit ATP synthesis in mitochondria (254, 363). It inhibits the P_i↔ ATP exchange in SMP from bovine heart mitochondria competitively and also inhibits ATP synthesis noncompetitively with respect to ADP without a change in K_m for ADP (363). In contrast, in pea SMP, thiophosphate decreases the K_m of the enzyme for ADP (254).

Azide inhibits the ATPase activity of F₁ from mitochondria, bacteria, and chloroplasts (25, 46, 126, 274, 278, 287, 391, 412). Azide has no inhibitory effect on ATP synthesis (25). The inhibition by azide is noncompetitive (287, 391) and occurs only in the presence of ADP and ATP (274). The binding of inhibitory azide requires prior binding of both ADP and Mg²⁺ (160, 278). Azide binds to the catalytic site in β_DP of F₁ and resides adjacent to the β-phosphate of ADP, mimicking the nonbridging oxygen atom of the γ-phosphate (46). The binding of azide in the β_DP catalytic site is very tight, and the azide is closely associated via hydrogen bonds with βLys162 in the P-loop and αArg373 (46). The inhibition is dependent on ATP concentration (274) and is reversed by addition of phosphate, possibly by competing for the azide binding site (262, 274).

Azido-2-nitrophenyl phosphate (ANPP) is a photoaffinity phosphate analog in which the 4-azido-2-nitrophenyl group is attached to phosphate (Fig. 8 and Table 14). ANPP inhibits F₁ as a competitive inhibitor in the dark by specifically targeting γ-phosphate binding sites within the nucleotide binding pockets on the β subunit of isolated F₁ or on both α and β subunits of membrane-bound F₀F₁ (154, 227). However, upon photoirradiation with visible light, ANPP inactivates the enzyme by binding covalently to these subunits. This occurs most frequently on βTyr 311, together with βIle304 and βGln308 in MF₁, and on the analogous βTyr 328, together with βVal329 and βPro330 in CF₁ (133, 258). Phosphate added before photoirradiation protects the photoinactivation by ANPP. The stoichiometry for full photoinactivation of F₁ is approximately 1 mol of ANPP/mol of CF₁ (321).

Divalent Metal Ions

Divalent metal ions are usually activators of F₁, but in their free form, they can also function as inhibitors at high concentrations (47, 98, 174, 278, 291, 365). Free Mg²⁺ acts as a linear competitive inhibitor (98, 365). The inhibition of CF₁ by free Mg²⁺ requires the presence of a tightly bound ADP at the catalytic site (160, 278). The K_i values are variable, and CF₁ and BF₁ are about 2 orders of magnitude more sensitive to the inhibition by free Mg²⁺ than is MF₁. Free Mn²⁺ and Ca²⁺ ions also inhibit F₁-ATPase in a competitive manner and are more effective than free Mg²⁺ in inhibition of CF₁ (Table 15) (174).

TABLE 15.

Divalent metal ions

Name	Inhibitory potency (reference)
Inhibitory free Mg²⁺	2.8 mM^a (P. blakesleeanus MF₁-ATPase) (98); 3 mM^a (ox heart MF₁-ATPase) (365); 20 μM^a (lettuce CF₁-ATPase) (174); 7 μM^a (R. rubrum F₁-ATPase) (291); 10-15 μM^b and 4 μM^b (spinach CF₁-ATPase) (278)
Inhibitory free Mn²⁺	5 μM^a (lettuce CF₁-ATPase) (174)
Inhibitory free Ca²⁺	5-7 μM^a (lettuce CF₁-ATPase) (174)

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K_i.

K_d.

Purine Nucleotides and Nucleotide Analogs

Excess free ATP is also an inhibitor of ATP synthase (Tables 16 and 17 and Fig. 9A) (98, 291, 365). Inhibition of ATPase activity of F₁ by free ATP can be competitive (in the photosynthetic bacterium Rhodospirillum rubrum [291], biphasic (in Phycomyces blakesleeanus [98], or second order/parabolic (in ox heart mitochondria (365).

TABLE 16.

Properties of purine nucleotides and nucleotide analogs

Name or abbreviation	Molecular formula	Source	Other names
Excess free ATP	C₁₀H₁₆N₅O₁₃P₃	Natural	Adenosine triphosphate; adenosine 5′-triphosphate
ADP	C₁₀H₁₅N₅O₁₀P₂	Natural	Adenosine diphosphate; adenosine 5′-diphosphate
GTP	C₁₀H₁₆N₅O₁₄P₃	Natural	Guanosine triphosphate; guanosine 5′-triphosphate
FTP	C₁₀H₁₆N₅O₁₃P₃	Synthetic	Formycin triphosphate; formycin 5′-triphosphate; formycin A 5′-triphosphate
TNP-ATP	C₁₆H₁₇N₈O₁₉P₃	Synthetic; fluorescent	2′,3′-O-(2,4,6-Trinitrophenyl) adenosine 5′-triphosphate
TNP-ADP	C₁₆H₁₅N₈O₁₆P₂	Synthetic; fluorescent	2′,3′-O-(2,4,6-Trinitrophenyl) adenosine 5′-triphosphate
TNP-Ado	C₁₆H₁₃N₈O₁₀	Synthetic; fluorescent	(2′,3′)-O-(2,4,6-Trinitrocyclohexadienylidine)adenosine
Lin-benzo-ADP	C₁₄H₁₇N₅O₁₀P₂	Synthetic; fluorescent	Linear-benzoadenosine diphosphate
AP₄A	C₂₀H₂₈N₁₀O₁₉P₄	Natural extracellular mediator	Diadenosine tetraphosphate; 5′,5′′′-diadenosine tetraphosphate
AP₅A	C₂₀H₁₄N₁₀O₂₂P₅	Natural extracellular mediator	Diadenosine pentaphosphate
AP₆A	C₂₀H₃₀N₁₀O₂₅P₆	Natural extracellular mediator	Diadenosine hexaphosphate; diadenosine 5′,5′′′′-P1,P6-hexaphosphate
AMP-PNP	C₁₀H₁₇N₆O₁₂P₃	Synthetic	Adenylyl imidodiphosphate; p[NH]ppA; γ-imino-ATP
GMP-PNP	C₁₀H₁₇N₆O₁₃P₃	Synthetic	5′-Guanylyl imidodiphosphate; p[NH]ppG
IMP-PNP	C₁₀H₁₆N₅O₁₃P₃	Synthetic	Inosine-5′-[(β,γ)-imido]triphosphate
AMP(CH₂)P	C₁₁H₁₇N₅O₉P₂	Synthetic	Adenosine 5′-methylenediphosphate; adenosine-5′-(α,β-methylene)-diphosphate; α,β-methylene ADP
RhATP	C₁₀H₂₃N₅O₁₆P₃Rh (tridentate RhATP)	Synthetic	Bidentate RhATP, bidentate tetraaquarhodium-adenosine 5′-triphosphate [Rh(H₂O)₄ATP]; tridentate RhATP, tridentate triaquarhodium-adenosine 5′-triphosphate [Rh(H₂O)₃ATP]
CrATP or Cr(NH₃)₄ATP	C₁₀H₂₆CrN₅O₁₇P₃ (bidentate CrATP)	Synthetic	Monodentate CrATP, monodentate pentaaquachromium-adenosine 5′-triphosphate [Cr(H₂O)₅ATP]; monodentate Cr(NH₃)₄ATP, Monodentate tetraaminemonoaquachromium-adenosine 5′-triphosphate [Cr(NH₃)₄(H₂O)ATP]; bidentate CrATP, bidentate tetraaquachromium-adenosine 5′-triphosphate [Cr(H₂O)₄ATP]; bidentate Cr(NH₃)₄ATP, bidentate tetraaminechromium-adenosine 5′-triphosphate; bidentate Cr(NH₃)₂ATP, bidentate biaminebiaquachromium-adenosine 5′-triphosphate [Cr(NH₃)₂(H₂O)₂ATP]
Co(NH₃)₄ATP	C₁₀H₃₄CoN₉O₁₃P₃	Synthetic	Bidentate tetraaminecobalt-adenosine 5′-triphosphate; bidentate cobalt(III)tetraamine-adenosine 5′-triphosphate
3′-O-Acetyl-ATP	C₁₆H₁₇N₈O₁₉P₃	Synthetic	Acetyl adenosine triphosphate
3′-O-Acetyl-ADP	C₁₆H₁₆N₈O₁₆P₂	Synthetic	Acetyl adenosine diphosphate
3′-O-Caproyl-ADP	C₁₆H₂₅N₅O₁₁P₂	Synthetic	Caproyl adenosine diphosphate
3′-O-Enanthyl-ADP	C₁₇H₂₇N₅O₁₁P₂	Synthetic	Enanthyl adenosine diphosphate
3′-O-Caprylyl-ADP	C₁₈H₂₉N₅O₁₁P₂	Synthetic	Caprylyl adenosine diphosphate
F-ADP/DMAN-ADP	C₂₃H₂₃N₆O₁₁P₂	Synthetic; fluorescent	3′-O-[1-(5-Dimethylamino)-naphthoyl]adenosine diphosphate; 3′-O-(5-dimethylaminonaphthoyl-1)-adenosine diphosphate
F-ATP	C₂₃H₂₅N₆O₁₄P₃	Synthetic; fluorescent	3′-O-[1-(5-Dimethylamino)-naphthoyl]adenosine triphosphate; 3′-O-(5-dimethylaminonaphthoyl-1)-adenosine triphosphate
3′-O-(1-Naphthoyl)-ADP/N-ADP	C₂₁H₂₁N₅O₁₁P₂	Synthetic; fluorescent	3′-O-(Naphthoyl-1)adenosine diphosphate; 3-NP-ADP
3′-O-(1-Naphthoyl)-ATP	C₂₁H₂₂N₅O₁₄P₃	Synthetic; fluorescent	3′-O-(Naphthoyl-1)adenosine triphosphate
3′-O-(2-Naphthoyl)-ADP	C₂₁H₂₂N₅O₁₄P₃	Synthetic	3′-O-(2-Naphthoyl)-adenosine 5′-diphosphate
BzATP	C₂₄H₂₄N₅O₁₅P₃	Synthetic; photoreactive	3′-O-(4-Benzoyl) benzoyl ATP; 3′-O-(4-benzoyl)benzoyladenosine 5′-triphosphate
BzADP	C₂₄H₂₃N₅O₁₂P₂	Synthetic; photoreactive	3′-O-(4-Benzoyl) benzoyl ADP; 3′-O-(4-benzoyl)benzoyladenosine 5′-diphosphate
t-Butylacetyl-ADP	C₁₆H₂₅N₅O₁₁P₂	Synthetic	tert-Butylacetyl-adenosine 5′-diphosphate
3′-O-Phenylacetyl-ADP	C₁₈H₂₁N₅O₁₁P₂	Synthetic	3′-O-Phenylacetyl-adenosine 5′-diphosphate
3′-O-Phenylbutyryl-ADP	C₂₀H₂₅N₅O₁₁P₂	Synthetic	3′-O-Phenylbutyryl-adenosine 5′-diphosphate
3′-O-Benzoyl-ADP	C₁₇H₁₉N₅O₁₁P₂	Synthetic	3′-O-Benzoyl-ADP
3′-O-[N-(2-Nitrophenyl)-γ-aminobutyryl]-ADP	C₂₀H₂₅N₇O₁₃P₂	Synthetic	3′-O-[N-2-Nitrophenyl-γ-aminobutyryl]-adenosine 5′-diphosphate
3′-O-[N-(4-Nitrophenyl)-γ−aminobutyryl]-ADP	C₂₀H₂₅N₇O₁₃P₂	Synthetic	3′-O-[N-(4-Nitrophenyl)-γ-aminobutyryl]-adenosine 5′-diphosphate
3′-O-(1-Naphthylacetyl)-ADP	C₂₂H₂₃N₅O₁₁P₂	Synthetic	3′-O-(1-Naphthylacetyl)-adenosine 5′-diphosphate
3′-O-(2-Naphthyl acetyl)-ADP	C₂₂H₂₃N₅O₁₁P₂	Synthetic	3′-O-(2-Naphthylacetyl)-adenosine 5′-diphosphate
3′-O-(1-Anthranoyl)-ADP	C₂₅H₂₃N₅O₁₁P₂	Synthetic	3′-O-(1-Anthranoyl)-adenosine 5′-diphosphate
3′-O-(9-Anthranoyl)-ADP	C₂₅H₂₃N₅O₁₁P₂	Synthetic	3′-O-(9-Anthranoyl)-adenosine 5′-diphosphate
FSBI	C₁₇H₁₅FN₄O₈S	Synthetic	5′-p-Fluorosulfonylbenzoylinosine; 5′-4-Fsbi
FSBA	C₁₇H₁₆FN₅O₇S	Synthetic	5′-p-Fluorosulfonylbenzoyladenosine; 5′-(4-(fluorosulfonyl)benzoyl)adenosine; 5-Fsba
FSBɛA	C₁₉H₁₆FN₅O₇S	Synthetic	5′-p-Fluorosulfonylbenzoylethenoadenosine; 5′-(4-fluorosulfonylbenzoyl)-1,N(6)-ethenoadenosine; FSB epsilon A; Fsbn-ethenoadenosine
AP₂-PL	C₁₈H₂₂N₆O₁₂P₂	Synthetic	Adenosine diphosphopyridoxal; PLP-AMP; ADP-pyridoxal; pyridoxal 5′-diphospho-5′-adenosine; 5′-adenosine-5′-diphosphopyridoxal
AP₃-PL	C₁₈H₂₃N₆O₁₅P₃	Synthetic	Adenosine triphosphopyridoxal; adenosine 5′-(tetrahydrogen triphosphate), mono((4-formyl-5-hydroxy-6-methyl-3-pyridinyl)methyl) ester
AP₄-PL	C₁₈H₂₄N₆O₁₈P₄	Synthetic	Adenosine tetraphosphopyridoxal; adenosine tetraphosphate pyridoxal
oATP	C₁₀H₁₄N₅O₁₃P₃	Synthetic	2′,3′-Dialdehyde of ATP; dial-ATP
oADP	C₁₀H₁₃N₅O₁₀P₂	Synthetic	2′,3′-Dialdehyde of ADP
oAMP	C₁₀H₁₂N₅O₇P	Synthetic	2′,3′-Dialdehyde of AMP
Cibacron blue	C₂₉H₁₇N₇O₁₁S₃Cl	Synthetic; protein synthesis inhibitor
BzAF	C₃₄H₂₁NO₇	Synthetic; photoreactive	4-Benzoyl(benzoyl)-1-amidofluorescein

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TABLE 17.

Inhibitory potencies of purine nucleotides and nucleotide analogs

Name or abbreviation	Inhibitory potency (reference)
Excess free ATP	1 Mg²⁺/8-10 ATP^a (R. rubrum F₁-ATPase) (291); 1 mM^b (R. rubrum F₁-ATPase) (291); 5% inhibition at 12 mM (P. blakesleeanus F₁-ATPase) (98)
ADP	15-17 μM^b (bovine heart MF₁-ATPase) (272, 362); 8.6-9 μM^b (rat liver SMP-ATPase) (263, 272)
GTP	5-10 μM^a for 15 min (spinach CF₁-ATPase) (159)
FTP	5-10 μM^a for 15 min (spinach CF₁-ATPase) (159)
TNP-ATP	100 nM^a (bovine heart MF₁-ATPase) (277); 5.5 nM^b (157), 25 nM^b (214) (bovine heart MF₁-ATPase); 21 nM^b (bovine heart SMP-ATPase) (157); noncatalytic sites 0.2 μM^c and catalytic sites < 0.001, 0.023, 1.39 μM^c (EF₁-ATPase) (429)
TNP-ADP	15-20 nM^a (bovine heart MF₁-ATPase) (277); 8 nM^b (214), 10 nM^b (157) (bovine heart MF₁-ATPase); 1.3 μM^b (bovine heart SMP-ATP synthesis) (157); noncatalytic sites 6.5 μM^c and catalytic sites 0.008, 1.3, 1.3 μM^c (EF₁-ATPase) (429)
TNP-Ado	33 μM^b (bovine heart MF₁-ATPase) (214)
Lin-benzo-ADP	16 μM^b (bovine heart MF₁-ATPase) (199); 0.2 μM^c (EF₁-ATPase) (424); <10 nM^c and 1-2 μM^c (bovine heart MF₁-ATPase) (428)
AP₄A	18 μM^a (bovine heart MF₁-ATPase) (417)
AP₅A	∼60% inhibition at 520 μM in 10 min (bovine heart MF₁-ATPase) (417); no inhibition up to 100 μM (bovine heart MF₁-ATPase) (325)
AP₆A	∼80% inhibition at 520 μM in 80 min (bovine heart MF₁-ATPase) (417)
AMP-PNP	0.5 μM^b (37), 0.33 μM^b (306), 0.32 μM^b (361), 14 nM^b (84) (bovine heart MF₁-ATPase); 0.16 μM^b (bovine heart SMP-ATPase) (306); 0.92 μM^b (255), 0.3 μM^b (361) (rat liver MF₁-ATPase); 1.3 μM^b (rat liver SMP-ATPase) (255); 0.6^b (EF₁-ATPase) (436)
GMP-PNP	12.3 μM^b (bovine heart MF₁-ATPase) (37); 300 μM^b (rat liver MF₁-ATPase) (361)
IMP-PNP	105 μM^b with bicarbonate (bovine heart MF₁-ATPase) (362)
AMP(CH₂)P	K_m, 2.8 μM in the presence of 1 mM inhibitor from 0.85 μM in its absence (pea SMP-ATP synthesis) (254)
RhATP	Bi- and tridentate RhATP, 300 μM^b (bovine heart MF₁-ATPase) (383)
CrATP or Cr(NH₃)₄ATP	Monodentate CrATP, 78 μM^b (bovine heart MF₁-ATPase) (383); monodentate Cr(NH₃)₄ATP, 500 μM^b (bovine heart MF₁-ATPase) (383); bidentate CrATP, 1 mM^b (bovine heart MF₁-ATPase) (383) and 170 μM^b (S. cerevisiae MF₁-ATPase) (432); bidentate Cr(NH₃)₄ATP, 100 μM^b (bovine heart MF₁-ATPase) (383); tridentate CrATP, 150 μM^b (S. cerevisiae MF₁-ATPase) (432)
Co(NH₃)₄ATP	Bidentate Co(NH₃)₄ATP, 400 μM^b (bovine heart MF₁-ATPase) (384)
3′-O-Acetyl-ATP	400 nM^b (bovine heart MF₁-ATPase) (394)
3′-O-Acetyl-ADP	55.3-85 μM^a (bovine heart SMP, oxidative phosphorylation) (355, 356)
3′-O-Caproyl-ADP	1.7 μM^a (bovine heart SMP-oxidative phosphorylation) (355)
3′-O-Enanthyl-ADP	2.7 μM^a (bovine heart SMP-oxidative phosphorylation) (355)
3′-O-Caprylyl-ADP	1.7 μM^a (bovine heart SMP-oxidative phosphorylation) (355)
DMAN-ADP/F-ADP	0.25 μM^a (bovine heart SMP-oxidative phosphorylation) (356); 40 nM^b (bovine heart SMP-oxidative phosphorylation) (356); 9.8 μM^b (bovine heart SMP-uncoupled ATPase) (356); 50 nM^c (bovine heart MF₁-ATPase) (397)
F-ATP	2.1 μM^a (bovine heart SMP-oxidative phosphorylation) (356); 0.3 μM^b (bovine heart SMP, oxidative phosphorylation) (356); 12-27 μM^b (bovine heart SMP-uncoupled ATPase) (356)
3′-O-(1-Naphthoyl)-ADP/N-ADP	300-350 nM^a (bovine heart SMP-oxidative phosphorylation) (355, 356); 4.6 μM^b (bovine MF₁-ATPase) (240); 9 μM^b (bovine heart SMP-ATPase) (240); 48 nM^b (bovine heart SMP-oxidative phosphorylation) (355); 20-50 nM^c (bovine MF₁-ATPase) (397)
3′-O-(1-Naphthoyl)-ATP	2.0 μM^a (bovine heart SMP-oxidative phosphorylation) (356)
3′-O-(2-Naphthoyl)-ADP	5.0 μM^a (bovine heart SMP-oxidative phosphorylation) (356)
BzATP	0.85 μM^b (bovine heart MF₁-ATPase) (3); ∼6 μM^b (TF₁-ATPase) (8); 1.6 μM^c (bovine heart MF_1-ATPase) (3)
BzADP	0.72 μM^b (bovine heart MF₁-ATPase) (3)
t-butylacetyl-ADP	1.5 μM^a (bovine heart SMP-oxidative phosphorylation) (355)
3′-O-Phenylacetyl-ADP	3.2-3.6 μM^a (bovine heart SMP-oxidative phosphorylation) (355, 356)
3′-O-Phenylbutyryl-ADP	1.3-4.6 μM^a (bovine heart SMP-oxidative phosphorylation) (355, 356); 0.2 μM^b (bovine heart SMP-oxidative phosphorylation) (355)
3′-O-Benzoyl-ADP	6.0 μM^a (bovine heart SMP-oxidative phosphorylation) (355, 356)
3′-O-[N-(2-Nitrophenyl)-γ− aminobutyryl]-ADP	0.55 μM^a (bovine heart SMP-oxidative phosphorylation) (356)
3′-O-[N-(4-Nitrophenyl)-γ− aminobutyryl]-ADP	0.76 μM^a (bovine heart SMP-oxidative phosphorylation) (356)
3′-O-(1-Naphthylacetyl)-ADP	0.8 μM^a (bovine heart SMP-oxidative phosphorylation) (356)
3′-O-(2-Naphthylacetyl)-ADP	0.8 μM^a (bovine heart SMP-oxidative phosphorylation) (356)
3′-O-(1-Anthranoyl)-ADP	0.56 μM^a (bovine heart SMP-oxidative phosphorylation) (356)
3′-O-(9-Anthranoyl)-ADP	5.9 μM^a (bovine heart SMP-oxidative phosphorylation) (355, 356, 397); 1.1 μM^b (bovine heart SMP-oxidative phosphorylation) (355)
FSBI	0.5 mM^c for reversible binding (bovine heart MF₁-ATPase) (49)
FSBA	45% (1 h) and 65% (2 h) inhibition at 0.8 mM (bovine heart SMP-ATPase) (51); 0.23 mM^c for reversible binding (pig heart MF₁-ATPase) (101)
FSBεA	250 μM^c (bovine heart MF₁-ATPase) (414)
AP₂-PL	∼150 μM^c (α subunit of EF₁-ATPase) (326); 30% inhibition at 50 μM (EF₁-ATPase) (288)
AP₃-PL	18 μM^a (EF₁-ATPase) (288); 2.5 μM^a with Mg²⁺ and 10 μM^a without Mg²⁺ (EF₁-ATPase) (184)
AP₄-PL	18 μM^a (EF₁-ATPase) (288)
oATP	10 mM^b (M. phlei F₁-ATPase) (219); 1.05 mol/mol of ATPase^a (ox heart MF₁-ATPase) (239); 40% inhibition at 1 mol/mol ATPase without ADP and 60 min incubation (ox heart MF₁-ATPase) (239)
oADP	80 μM^c (bovine heart MF₁-ATPase) (217)
oAMP	90% inhibition at 3 mM (bovine heart MF₁-ATPase) (95)
Cibacron blue	600 μM^a (rat liver MF₁-ATPase) (28)
BzAF	50 μM^b in the dark (bovine heart MF₁-ATPase) (297); 58 μM^c (bovine heart MF₁-ATPase) (297)

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I₅₀.

K_i.

K_d.

FIG. 9. — Structures of purine nucleotides and nucleotide analogs. (A) Nucleotides and nucleotide analogs. (B) Azidonucleotides.

ADP is a substrate for F₁, but preincubation of F₁ with ADP and Mg²⁺ induces hysteretic inhibition (32, 102, 261). The inhibition arises when medium Mg²⁺ combines with F₁ to which ADP is bound to only a single catalytic site in the absence of bound P_i. The onset of the inhibition is rather slow (seconds to minutes). The Mg²⁺ADP-induced inhibition can be slowly and partially reversed by addition of ATP in the absence of Mg²⁺ (272), and the recovery of ATPase activity requires the binding of ATP at a noncatalytic site. The recovery is promoted by anions such as bicarbonate and sulfite (272, 412). The inhibition can arise from the medium ADP, but ADP produced at the catalytic site by ATP hydrolysis can also start Mg²⁺ADP-induced inhibition. F₁ from chloroplasts is more readily inhibited than F₁ from mitochondria, whereas EF₁ is not susceptible to Mg²⁺ADP-induced inhibition under conditions where Mg²⁺ is not in huge excess (6, 106). The Mg²⁺ADP-induced inhibition of F₁ also occurs in the intact ATP synthase with no or low proton motive force. However, sufficient proton motive force can drive the ATP synthase to remove the inhibitory Mg²⁺ADP without altering net ATP synthesis (47).

GTP and formycin 5′-triphosphate (FTP) bind to empty noncatalytic sites on CF₁ in the presence of Mg²⁺ and inhibit its ATPase activity (159). Binding of GTP or FTP to two sites causes more inhibition than binding to one site, and the GTP has stronger inhibitory potency than FTP. With GTP or FTP bound at two noncatalytic sites, the GTP inhibits the ATPase activity about 90%, and the FTP about 80%. After a 15-min incubation period, about 50% maximal inhibition is achieved with 5 to 10 μM GTP or FTP for spinach CF₁-ATPase.

2′,3′-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP) and TNP-ADP are ribose-modified chromophoric and fluorescent analogs of ATP and ADP in which a trinitrophenyl group is attached to the 2′ and 3′ hydroxyls of ribose (Fig. 9A). These compounds have been used widely for various assays of ATP binding to proteins. Both compounds are potent inhibitors of F₁ with high affinity, and the TNP-ATP is hydrolyzable by F₁ from mitochondria, chloroplasts, and bacteria (157, 219, 273, 368, 429). The inhibition of ATP hydrolysis by TNP-ATP or TNP-ADP has been reported to be competitive (157) or biphasic (277). These nucleotide analogs bind to both catalytic and noncatalytic sites of F₁. Their binding is noncooperative at the three noncatalytic sites and cooperative at the three catalytic sites (429).

2-Azido-TNP-ATP, a 2-azido derivative of TNP-ATP, inhibits F₁ catalyzed ATP hydrolysis biphasically (Fig. 9B and Table 18) (276). Bicarbonate decreases the degree of inhibition by 2-azido-TNP-ATP. The K_m and V_max for 2-azido-TNP-ATP hydrolysis are similar to those for TNP-ATP hydrolysis. Upon UV illumination of the F₁-ATPase complex with the bound 2-azido-TNP-ATP, it is incorporated into the complex covalently and inactivates the F₁-ATPase irreversibly.

TABLE 18.

Azidonucleotides

Name	Molecular formula	Other names	Inhibitory potency (reference)
8-Azido-ATP	C₁₀H₁₅N₈O₁₃P₃	8-Azidoadenosine 5′-triphosphate	1 mM^b (bovine heart SMP, phosphorylation) (371); 1 mM^b (bovine heart SMP-ATPase) (371); 88% inhibition at 1.7 mM (bovine heart MF₁-ATPase) (419); complete inhibition at 2 inhibitor bound mol/mol F₁ (bovine heart MF₁-ATPase) (110, 420)
8-Azido-ADP	C₁₀H₁₄N₈O₁₀P₂	8-Azidoadenosine 5′-diphosphate	86% inhibition at 1.7 mM (bovine heart MF₁-ATPase) (419); full inhibition at 1.9-2 mol bound inhibitor/mol F₁ (134, 419)
2-Azido-ATP	C₁₀H₁₅N₈O₁₃P₃	2-Azidoadenosine 5′-triphosphate	52% inhibition at 1.8 (0.8 covalent) inhibitor mol/mol F₁ (EF₁-ATPase) (425); complete inhibition at 0.92 inhibitor bound mol/mol F₁ (bovine heart MF₁-ATPase) (408)
2-Azido-ADP	C₁₀H₁₄N₈O₁₀P₂	2-Azidoadenosine 5′-diphosphate; 1-azidoadenosine-3′,5′-bisphosphate	5 μM^c in the dark (bovine heart MF₁-ATPase) (45); full inhibition at 1.9-2 mol bound inhibitor/mol F₁ (45, 134)
2-Azido-TNP-ATP	C₁₇H₂₀N₁₁O₁₈P₃	2-N₃-TNP-ATP
ANA-ADP	C₂₁H₁₇N₈O₁₁P₂	3′-O-[5-Azidonaphthoyl]-ADP	11 μM^b in the dark (bovine heart MF₁-ATPase) (240); total inactivation at 2 mol/mol F₁ (bovine heart MF₁-ATPase) (240)
8-Azido-FSBA	C₁₇H₁₅FN₈O₇S	5′-p′-Fluorosulfonylbenzoyl-8-azidoadenosine; 8-N₃-FSBA	0.47 mM^c in the dark (bovine heart MF₁-ATPase) (453)
2-Azido-AMP-PNP	C₁₀H₁₅N₉O₁₂P₃	2-Azidoadenyl-5′-yl imidodiphosphate	4 μM^b (bovine heart MF₁-ATPase) (109)
8-Azido-AMP-PNP	C₁₀H₁₅N₉O₁₂P₃	8-Azidoadenyl-5′-yl imidodiphosphate	460 μM^b (bovine heart MF₁-ATPase) (109)
NAP₄-ADP	C₂₀H₂₄N₁₀O₁₃P₂	N-4-Azido-2-nitrophenyl-γ−aminobutyryl-ADP	2.0 μM^a (bovine heart SMP-oxidative phosphorylation) (355); 0.6 mM^b in the dark (bovine heart MF₁-ATPase) (244); 0.5 μM^b (bovine heart SMP-oxidative phosphorylation) (355)
NAP₄-AMP-PNP	C₂₀H₂₃N₁₁O₁₅P₃	Nap₄-PPNHP; NAP₄-AdoPP[NH]P; N-4-azido-2-nitrophenyl γ−aminobutyryl-5-adenylyl imidodiphosphate; N-4-Azido-2-nitrophenyl-γ-aminobutyryl-AdoPP[NH]P	3 μM^c in the dark (bovine heart MF₁-ATPase) (247)
NAP₃-ATP	C₁₉H₂₃N₁₀O₁₆P₃	3′-O-{3-[N-(4-Azido-2-nitrophenyl) amino]propionyl}adenosine 5′-triphosphate; arylazido aminopropionyl ATP	43% maximum inhibition at 36 μM with 15 min photoreaction (bovine heart MF₁-ATPase) (341)
NAP₃-ADP	C₁₉H₂₂N₁₀O₁₃P₂	3′-O-[3-[N-(Azido-2-nitrophenyl) amino]propionyl]adenosine 5′-diphosphate; arylazido-β-alanyl-ADP; arylazido aminopropionyl ADP	80% inhibition at 50 μM in the dark (pig heart MF₁-ATPase) (117)
NAB-ATP	C₁₇H₁₈N₉O₁₆P₃	3′(2′)-O-(2-Nitro-4-azidobenzoyl)adenosine 5′-triphosphate	K_m of 0.85 mM, maximal 40-45% modification (bovine heart MF₁-ATPase) (216)
NAB-GTP	C₁₇H₁₈N₉O₁₇P₃	3′(2′)-O-(2-Nitro-4-azidobenzoyl)guanosine 5′-triphosphate	Maximal 40-45% modification (bovine heart MF₁-ATPase) (216)
ANP-ADP	C₁₉H₂₇N₉O₁₃P₂	3′-O-[3-(4-Azido-2-nitrophenyl)propionyl]-ADP	1.3 μM^a (bovine heart SMP-oxidative phosphorylation) (355); 50 μM^b (bovine heart MF₁-ATPase) (426); 0.2 μM^b (bovine heart SMP-oxidative phosphorylation) (355, 426); full inhibition at 3 mol/mol F₁ (bovine heart MF₁-ATPase) (426)

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I₅₀.

K_i.

K_d.

Linear-benzoadenosine diphosphate (lin-benzo-ADP) is a fluorescent adenine-modified ADP analog in which the adenine ring is laterally extended by the insertion of a benzene ring between the pyrimidine and imidazole ring (Fig. 9A) (199, 428). Lin-benzo-ADP binds to all six nucleotide binding sites. The affinities for lin-benzo-ADP to three α subunits and one β subunit of MF₁ from bovine heart are low (K_d = 1 to 2 μM), whereas the affinities for the other two β subunits are very high (K_d <10 nM) (428). Inhibition by lin-benzo-ADP is competitive and has complex kinetics of inhibition. Lin-benzo-ADP is fluorescent, and its fluorescence spectrum is extensively quenched by adding F₁. As expected, this fluorescence quenching is reversed by adding ADP (199).

5′,5′-Diadenosine oligophosphates (AP_xA) are compounds which have a chain of phosphoryl groups linking two adenosine moieties. The AP_xA that have a long chain of phosphoryl groups (AP₄A, AP₅A, and AP₆A) has been shown to inhibit the ATP hydrolysis activity of MF₁, whereas compounds that have a shorter chain (AP₂A and AP₃A) showed stimulatory effects (417). The inhibition by AP₄A, AP₅A, and AP₆A required the presence of at least one vacant noncatalytic site, and the maximal level of inhibition was 80%. AP₄A was the most potent, and its stoichiometry for maximal inhibition was near 1 mol/mol of F₁. In contrast, a contradictory result has also been reported in the inhibition of the same enzyme by AP₅A, and no inhibition was observed up to 100 μM (325).

AMP-PNP is a nonhydrolyzable ATP analog in which the terminal bridge oxygen of the triphosphate moiety is replaced by an NH group (444). AMP-PNP has been used widely in kinetic studies of F₁ and has been found to be a potent competitive inhibitor in ATPase assays of either the soluble or membrane-bound enzyme from bovine heart (37, 147, 306, 361) However, AMP-PNP is reported to be noncompetitive in ATPase assays with membrane-bound rat liver F₁ (361). The K_i values reported are variable (14 nM to 0.5 μM) (37, 84, 255, 306, 361). AMP-PNP has no effect on the ATP synthesis activity of ATP synthase, although it is a potent inhibitor of F₁-catalyzed ATP hydrolysis (302, 306). It binds to both catalytic and noncatalytic sites, and when it is bound to the latter sites, it induces hysteretic inhibition to the same extent as ADP (34, 37).

Guanylyl imidodiphosphate (GMP-PNP) and inosine-5′-[(β,γ)-imido]triphosphate (IMP-PNP) are analogs of GTP and ITP, respectively, in which the bridge oxygen atom between the β and γ phosphorus atoms is replaced by an NH group. The inhibition by GMP-PNP versus GTP and ITP is competitive (361), whereas inhibition versus ATP is competitive (37) or mixed (361). Unlike AMP-PNP, GMP-PNP shows no induction of hysteretic inhibition (34). IMP-PNP inhibits ITP hydrolysis potently, whereas it inhibits ATP hydrolysis only at low concentrations of ATP below 100 μM (362). At high concentrations of ATP, IMP-PNP stimulates the rate of ATP hydrolysis. In contrast, the stimulation of ATP hydrolysis by IMP-PNP is not seen in the presence of bicarbonate, and IMP-PNP inhibits ATP hydrolysis competitively.

Adenosine 5′-methylenediphosphate is an analog of ADP in which the bridge oxygen atom between the α and β phosphorus atoms is replaced by a CH₂ group. Adenosine 5′-methylenediphosphate inhibits ATP synthesis competitively with respect to ADP (254, 363) and inhibits P_i↔ ATP exchange uncompetitively (363).

Exchange-inert metal-nucleotide complexes are stable, inert octahedral complexes of Cr(III), Co(III), or Rh(III) with ATP and ADP (383). The exchange-inert metal-nucleotide complexes inhibit ATP synthase by binding to F₁ (44, 158, 383, 384, 432). Chromium complexes of ATP and ADP, i.e., α,β-CrADP, β,γ-CrATP, and α,β,γ-CrATP, are competitive inhibitors of MF₁ with respect to MgATP (383, 432). β,γ-CrATP and α,β,γ-CrATP inhibit F₁ by binding at the catalytic site and α,β-CrATP by binding at a regulatory site (432). The binding sites show no significant selectivity for the steric arrangement of the chromium complexes. β,γ-CrATP and α,β,γ-CrATP bind to the catalytic site with the same affinity, although they have different steric arrangements of the chromium (β,γ-CrATP with monocyclic coordination at the metal ion and α,β,γ-CrATP with bicyclic coordination). Two diastereomers of α,β-CrADP (Λ and Δ isomers) also exert similar inhibitory effects (432). Monodentate Cr(NH₃)₄ATP, bidentate/tridentate RhATP, bidentate Cr(NH₃)₄ATP, and bidentate Co(NH₃)₄ATP are mixed noncompetitive inhibitors of F₁ (44, 158, 383, 384). All the amine and aqua exchange-inert metal-nucleotide complexes are mutually exclusive during ATP hydrolysis and appear to bind the same site(s) (383).

3′-acetyl ATP and 3′-acetyl ADP are monoacetylated adenine nucleotides in which an acetyl group is attached to the 3′ hydroxyl group of ribose. 3′-Acetyl ATP and 3′-acetyl ADP inhibit the ATPase activity of MF₁ in a competitive fashion with ATP and ADP, respectively (355, 394). They bind to catalytic sites, but no reactions occur; i.e., the 3′-acetyl ADP is not phosphorylated, and the 3′-acetyl ATP is not hydrolyzed (355).

3′-O-[1-(5-dimethylamino)-naphthoyl]ADP (F-ADP or DMAN-ADP) and 3′-O-(1-naphthoyl)ADP (N-ADP) are fluorescent analogs of ADP in which 5-dimethyl amino-naphthoyl and naphthoyl groups are attached to the 3′ hydroxyls of ribose, respectively (356, 397, 427). Both inhibitors are potent competitive inhibitors of both ATP hydrolysis and ATP synthesis and exhibit a much stronger inhibition of ATP synthesis than of ATP hydrolysis (356, 397). F-ADP binds to three sites in bovine heart MF₁ with K_d values of 50 nM for all sites, whereas the N-ADP binds to two sites with K_d values of 20 to 50 nM (397). F-ADP binds approximately 10 times more strongly than F-ATP (3′-O-[1-(5-dimethylamino)-naphthoyl]ATP), whereas F-AMP (3′-O-[1-(5-dimethylamino)-naphthoyl]AMP) is not inhibitory (356). ANA-ADP (3′-O-[5-azidonaphthoyl]-ADP) is a photoreactive analog of N-ADP (Fig. 9B and Table 18). It binds to the same site as N-ADP but with a lower affinity, i.e., about 2.5 times lower than the K_i of N-ADP for bovine heart MF₁. Upon illumination, ANA-ADP rapidly photoinactivates F₁ (240).

3′-O-(4-Benzoyl)benzoyladenosine 5′-triphosphate (BzATP) and BzADP are ribose-modified photoactivatable analogs of ATP and ADP in which a photoreactive (4-benzoyl)benzoyl group is attached to the 3′ hydroxyls of ribose (Fig. 9A) (435). BzATP binds to the ATP synthase β subunits both isolated and complexed but binds only to isolated α subunits (33). BzATP and BzADP bind to the catalytic site as competitive and reversible inhibitors in the absence of illumination. However, under actinic illumination, BzATP and BzADP inactivate F₁ irreversibly by covalently modifying the catalytic site (3, 8, 435).

Other 3′-O-substituted adenine nucleotides include 3′-O-phenylacetyl-ADP, 3′-O-phenylbutyryl-ADP, 3′-O-benzoyl-ADP, 3′-O-[N-(2-nitrophenyl)-γ-aminobutyryl]-ADP, 3′-O-[N-(4-nitrophenyl)-γ-aminobutyryl]-ADP, 3′-O-naphthoyl-(1)-ADP, 3′-O-naphthoyl-(1)-ATP, 3′-O-naphthoyl-(2)-ADP, 3′-O-naphthyl-(1)-acetyl-ADP, 3′-O-naphthyl-(2)-acetyl-ADP, 3′-O-5-dimethylaminonaphthoyl-(1)-ADP, 3′-O-5-dimethylaminonaphthoyl-(1)-ATP, 3′-O-anthranoyl-(1)-ADP, and 3′-O-anthranoyl-(9)-ADP (356). These inhibitors inhibit oxidative phosphorylation in bovine heart SMP with K_i values in the range of 0.3 to 5.9 μM (Table 17).

The fluorosulfonylbenzoyl nucleotides 5′-p-fluorosulfonylbenzoylinosine (FSBI), 5′-p-fluorosulfonylbenzoyladenosine (FSBA), and 5′-p-fluorosulfonylbenzoylethenoadenosine (FSBɛA) bind to F₁ and inactivate the enzyme by modifying amino acid side chains of α and/or β subunits. FSBI binds to the β subunit reversibly and reacts covalently with a Tyr residue. The inactivation follows pseudo-first-order kinetics, and the residues modified are βTyr345 in bovine heart MF₁ (49, 57) and βTyr364 in F₁ from thermophilic bacterium PS3 (50). The modification of a Tyr residue in a single β subunit is sufficient to inactivate F₁ completely (49).

FSBA binds reversibly to a single binding site on the β subunit of MF₁ (101). This inactivates F₁ irreversibly by forming a covalent bond via a process that follows pseudo-first-order kinetics (51, 101). The modified residues are αTyr244, αTyr300, and either βTyr368 or βHis427 (51, 56, 114, 407). The complete inactivation of F₁-ATPase by FSBA requires the modification of all three copies of the β subunits, in contrast to that by FSBI (49). 8-azido-FSBA (5′-p-fluorosulfonylbenzoyl-8-azidoadenosine) binds to MF₁ in the absence of light and inhibits ATPase activity. Upon illumination of the dark-inactivated F₁, 8-azido-FSBA induces in high yield cross-linking between βHis427 and βTyr345 within the same β subunit (453).

FSBɛA binds to αTyr244 of MF₁, inactivating ATPase activity with pseudo-first-order kinetics (152, 414). Maximal inactivation is achieved when FSBɛA modifies αTyr244 in one or two copies of the subunit. Inactivation of F₁ by both FSBA and FSBɛA is stimulated by high concentrations of phosphate, whereas inactivation by FSBI is not greatly affected. Prior modification of F₁ with FSBA completely prevents modification of αTyr244 by FSBɛA, while prior inactivation with FSBI allows considerable modification.

Adenosine oligophospho-pyridoxal compounds (AP_xPL) contain a chain of phosphoryl groups linking adenosine and pyridoxal moieties. Adenosine triphospho-pyridoxal (AP₃-PL) binds to the catalytic sites of EF₁ and inhibits hydrolytic activity by modifying α and β subunits. The stoichiometric ratio of binding of AP₃-PL for complete inactivation of F₁ is about 1 mol of AP₃-PL per 1 mol F₁ (288). Addition of Mg²⁺ increases the inhibitory potencies of AP₃-PL and also causes a change in the ratio of modification of α and β subunits by AP₃-PL from 4:1 in the absence of Mg²⁺ to 1:3 in its presence (184). The residues modified by AP₃-PL are αLys201, βLys155, and βLys201 (184, 281, 390). Adenosine tetraphospho-pyridoxal (AP₄-PL) binds to EF₁ with the same concentration for half-maximal inactivation as AP₃-PL and shows essentially the same absorption spectrum and binding kinetics (288). Adenosine diphospho-pyridoxal (AP₂-PL or PLP-AMP) is a weak inhibitor compared to AP₃-PL (288). It binds to αLys201 in the isolated α subunit from E. coli with a maximal stoichiometry of approximately 1 mol/mol (K_d of ∼150 μM). It also impairs the reconstitution of α subunits with β and γ subunits.

The 2′,3′-dialdehydes of ATP, ADP, and AMP (oATP, oADP, and oAMP) are periodate-oxidized derivatives of ATP, ADP, and AMP in which the ribose ring is opened (Fig. 9A). In the presence of Mg²⁺, oATP is a substrate and acts as a competitive inhibitor of ATP hydrolysis. Prolonged incubation of the enzyme with oATP inactivates F₁-ATPase activity irreversibly with pseudo-first-order kinetics by modifying both α and β subunits (95, 219, 239). Similar inactivation kinetics are also observed with oADP, but the kinetics of inactivation are the same whether Mg²⁺ is present or absent (95). The type of subunits and stoichiometry for the binding of oADP to F₁ are somewhat controversial; the binding of oADP to both α and β subunits with a stoichiometry of 2 to 3 mol oADP/mol F₁ (95, 239) and the binding of oADP only to α subunits with a stoichiometry of 0.9 to 1 mol oADP/mol F₁ (217) both have been proposed. oAMP also inactivates F₁, while AMP is not a substrate for F₁. Finally, both oADP and oAMP inactivate F₁ more efficiently than does oATP (Table 17).

Cibacron blue and 4-benzoyl(benzoyl)-1-amidofluorescein (BzAF) are structural analogs of purine nucleotides. They bind to MF₁ and inhibit ATPase activity (28, 297). BzAF contains a benzophenone moiety on one side of the molecule that is excitable by irradiation at ∼340 to 366 nm, and the irradiation of BzaF leads to the covalent insertion of BzAF into F₁. BzAF also contains a fluorescein moiety on the other side of the molecule that fluoresces at >515 nm upon excitation at ∼460 to 490 nm. BzAF inhibits mitochondrial ATP synthase as a catalytic site-specific covalent modifying agent (297). Like BzATP, BzAF binds to F₁ competitively with respect to ATP in the absence of illumination and forms a covalent bond with F₁ upon actinic irradiation. The photoinactivation of F₁ by BzAF follows pseudo-first-order kinetics.

8-Azido-ATP and 8-azido-ADP are adenine-modified analogs of ATP and ADP in which an azido group is attached to the carbon 8 of adenine (Fig. 9B). 8-Azido-ATP is a substrate of F₁ and is hydrolyzed slowly by F₁ in the dark (420). The K_m for 8-azido-ATP is similar to that for ATP, but the V_max of hydrolysis with 8-azido-ATP is only 6% of that observed with ATP (bovine heart MF₁) (371). On irradiation at 350 to 360 nm, the 8-azido-ATP inactivates F₁-ATPase by binding covalently to F₁, where both α and β subunits are modified. About 2.5 to 3 times more 8-azido-ATP is bound to β than to α subunits in MF₁ (175, 371), whereas almost equal amounts are bound at these two subunits in CF₁ (421). The modified residues in the β subunit of bovine heart F₁ are Lys301, Ile304, and Tyr311 (175). F₁-ATPase activity is completely inhibited when 2 mol 8-azido-ATP binds per mol F₁. Moreover, Mg²⁺ is not required for the binding (420). Interestingly, 8-azido-ADP is phosphorylated by ATP synthase in SMP at a very low rate in the dark. The K_i for 8-azido-ADP is about 1 mM for mitochondrial F₀F₁ from bovine heart, whereas the K_i for ADP is ∼20 nM for MF₁ from the same source (371). Photolysis at 350 nm leads to the inactivation of ATP synthase, as the 8-azido-ADP preferentially binds to β subunits (133, 371). The ATPase activity of F₁ is completely inhibited at 2 mol of 8-azido-ADP bound per 1 mol F₁ (419). In the presence of fluoroaluminate, 8-azido-ADP modifies βTyr-345 (133).

2-Azido-ATP and -ADP are also adenine-modified analogs of ATP and ADP in which an azido group is attached to carbon 2 of adenine. 2-Azido-ADP photolabels β subunits exclusively upon photoirradiation, in contrast to 8-azido-ADP or -ATP, which modify both α and β subunits (86, 89, 419, 421). 2-Azido-ADP binds to F₁ with an affinity similar to the affinity of ADP (45), and upon irradiation it modifies βLeu342, βIle344, βTyr345, βPro346, or βTyr368 (bovine heart MF₁) (111, 132).

2- and 8-Azidoadenyl-5′-imidodiphosphate (2-azido-AMP-PNP and 8-azido-AMP-PNP) are derivatives of AMP-PNP. They bind to F₁ at what appear to be both catalytic and noncatalytic sites (109). Under nonphotolytic conditions, 2-azido-AMP-PNP has a much higher inhibitory potency (K_i = 4 μM) than 8-azido-AMP-PNP (K_i = 460 μM).

3′-Arylazido butyryl ADP (NAP₄-ADP) is a photoreactive derivative of ADP in which a photosensitive N-4-azido-2-nitrophenylaminobutyryl group is attached to the adenine ring of ADP (244). NAP₄-ADP is a competitive inhibitor with respect to ATP, with a K_i value of 0.6 mM (bovine heart MF₁). NAP₄-ADP is a moderate inhibitor in the dark. However, upon photoirradiation with visible light, it inactivates F₁ by binding covalently to both α and β subunits. NAP₄-AMP-PNP (or NAP₄-AdoPP[NH]P) is an analog of NAP₄-ATP containing an NH group that replaces oxygen at the position of the terminal bridge oxygen of the triphosphate chain. NAP₄-AMP-PNP binds to F₁ with high affinity, and upon illumination, it inactivates F₁ by covalently modifying α and β subunits (247). NAP₄-AMP-PNP preferentially modifies the α subunit(s) at low concentrations, whereas it modifies α and β subunits equally at high concentrations.

3′-O-[3-[N-(Azido-2-nitrophenyl)amino]propionyl]ATP (NAP₃-ATP) and NAP₃-ADP are analogs of ATP and ADP in which a photoreactive N-4-azido-2-nitrophenylaminopropionyl group is attached to the adenine ring. NAP₃-ATP acts as a substrate in the dark and shows photodependent inhibition associated with covalent modification of F₁ upon illumination (117, 341). In contrast, NAP₃-ADP, just like ADP, induces hysteretic inhibition of soluble F₁ and membrane-bound F₁, with the latter being more sensitive (117). The kinetics of inhibition is biphasic. Preincubation of MF₁ from pig heart with NAP₃-ADP in the dark inhibits ATPase activity about 80%, a value that is increased to 87% upon photoirradiation (117).

3′(2′)-O-(2-Nitro-4-azidobenzoyl)ATP (NAB-ATP) and NAB-GTP are 3′(2′)-O-(2-nitro-4-azidobenzoyl)-derivatives of ATP and GTP in which a 2-nitro-4-azidobenzoyl group is attached to the 2′ hydroxyls of ribose. NAB-ATP binds to the catalytic site of F₁ and is hydrolyzed to NAB-ADP and inorganic phosphate (216). After hydrolysis, NAB-ADP remains bound to F₁, whereas phosphate is dissociated. The F₁·NAD-ADP complex is inactive, but in the presence of ATP, the bound NAB-ADP is released, resulting in the reactivation of ATPase activity. Illumination (300 to 380 nm) of F₁ inhibited with NAB-ADP leads to its covalent binding to the enzyme. NAB-GTP has an inhibitory activity similar to that of NAB-ATP.

3′-O-[3-(4-Azido-2-nitrophenyl)propionyl]-ADP (ANP-ADP) is a photoreactive analog of ADP in which a 4-azido-2-nitrophenyl propionyl group is attached to the 3′ hydroxyls of ribose (Fig. 9B). ANP-ADP binds to nucleotide binding sites on F₁, inhibiting both ATP hydrolysis and ATP synthesis (355, 426). Inhibition of F₁ by ANP-ADP is competitive with ADP in the dark, but upon illumination, ANP-ADP inactivates F₁ by covalently modifying α and β subunits. The stoichiometry for complete photoinactivation of F₁ is 3 mol of ANP-ADP/mol of F₁. The inhibition of F₁ by the photolabeling is reversed by mild alkaline treatment due to the hydrolysis of the 3′-ester bond and release of the ADP moiety of the inhibitor (426).

AMINO ACID MODIFIERS

Amino Group Modifiers

Phenylglyoxal and butanedione are dicarbonylic Arg residue modifiers. They inactivate both membrane-bound and isolated F₁ (Fig. 10A and Table 19) (43, 128, 129, 162, 248, 375, 381, 385). Inactivation by these agents follows pseudo-first-order kinetics (67, 128, 129, 248). Although the rate of inactivation is decreased in the presence of ADP and ATP (67, 128, 398), it is not significantly influenced by the presence of phosphate (398). Phenylglyoxal and butanedione also inhibit ATP↔ P_i exchange activity (43, 128, 162, 248, 385). Only one molecule of reagent per F₁ active site is required for inactivation, with the binding site(s) believed to be located at or near this active site (128, 248).

TABLE 19.

Amino group modifiers

Name or abbreviation	Molecular formula	Other names	Inhibitory potency, I₅₀ (reference)
Phenylglyoxal	C₈H₆O₂	Benzoylcarboxaldehyde; phenylglyoxal; benzoylformaldehyde; phenylethanedione; α-oxobenzeneacetaldehyde	25% inhibition at 2.7 μmol/mg protein (bovine heart SMP-ATPase) (162); 47.5% inhibition at 3 mM (E. coli F₀F₁-ATPase after F₀ modification) (381); 33.5% inhibition at 20 mM (E. coli F₀-liposome proton uptake) (381)
Butanedione	C₄H₆O₂	Diacetyl; dimethyl glyoxal; 2,3-butanedione; dimethyl diketone; butadione	0.63 μmol/mg protein and ∼100% inhibition at 1.7 μmol/mg protein (bovine heart SMP-ATPase) (162)
FDNB	C₆H₃FN₂O₄	1-Fluoro-2,4-dinitrobenzene; dinitrofluorobenzene; 2,4-DNFB; 2,4-dinitro-1-fluorobenzene; 2,4-dinitrofluorobenzene; fluoro-1,3-dinitrobenzene; Sanger's reagent	96% inhibition at about four 2,4-dinitrophenyl labels (bovine heart MF₁-ATPase) (194)
Dansyl chloride	C₁₂H₁₂ClNO₂S	5-(Dimethylamino)-naphthalene-1-sulfonyl chloride; 1-chlorosulfonyl-5-dimethylaminonaphthalene; 1-dimethylaminonaphthalene-5-sulfonyl chloride; dansyl; DNS chloride

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1-Fluoro-2,4-dinitrobenzene is a Lys residue modifier that inhibits the hydrolytic activity of MF₁ (11, 194, 250, 399). It modifies Lys162 (bovine sequence) in the P loop, the same residue to which the nitrobenzene (NBD) group migrates at pH 9 (194). Inhibition of ATPase activity follows first-order kinetics (399), with about four 2,4-dinitrophenyl labels required for 96% inhibition (194). Inhibition is reversed nearly 50% by dithiothreitol (11) and is protected effectively by ATP or P_i and slightly by ADP (399).

Dansyl chloride is an acyl chloride of 5-dimethylamino-1-naphthalenesulfonic acid. It modifies reactive amino groups of proteins. Dansyl chloride binds to MF₁ and inhibits both ATP synthesis and membrane-bound ATPase activity to approximately the same extent (250).

Carboxyl Group Modifiers

Carbodiimides are compounds containing a N=C=C functional group. Some inhibit ATP synthase by modifying carboxyl residues residing within F₁, F₀, or both (Fig. 10B). DCCD and N-(2,2,6,6-tetramethylpeperidyl-1-oxyl)-N-(cyclohexyl)carbo-diimide (NCCD) are lipid-soluble carbodiimides. DCCD binds to both F₁ and F₀ of ATP synthases from mitochondria and some bacteria (137, 204, 400, 441) (Table 20). F₁ from some bacteria, such as Helicobacter pylori, are insensitive to DCCD (36). DCCD reacts covalently with DCCD-sensitive F₁ via a Glu residue in the β subunit. In F₁ from E. coli, βGlu192 binds DCCD, while in bovine MF₁, βGlu199, corresponding to E. coli βGlu192, is modified. In F₁ from thermophilic Bacillus, βGlu181 (E. coli sequence) rather than βGlu192 is modified (137, 400, 441). Incorporation of 1 mol of DCCD into 1 mol of F₁ results in 95% inhibition of the ATPase activity of EF₁, and 2 mol of DCCD/mol F₁ leads to complete inhibition (400). In the crystal structure of the F₁-DCCD complex from bovine heart mitochondria, one molecule of DCCD is bound per F₁ (137). In this structure, the βGlu199 of β_DP located at the interface between β_DP and α_DP is modified. The covalently modified DCCD (dicyclohexyl-N-acylurea) is bound in a hydrophobic cleft with one face exposed to the solvent. Residues βVal164, βMet167, βVal420 and βPhe424 contribute to the binding of DCCD, and the steric hindrance involved is believed to inhibit F₁ by blocking a conformational change from β_DP to β_E.

TABLE 20.

Carboxyl group modifiers

Name or abbreviaion	Molecular formula	Other names	Inhibitory potency (reference)
DCCD	C₁₃H₂₂N₂	1,3-Dicyclohexylcarbodiimide; N,N′-dicyclohexylcarbodiimide; bis(cyclohexyl)carbodiimide; carbodicyclohexylimide; N,N′-methanetetraylbiscyclo-hexaamine	1.2 μg of inhibitor/mg protein^a (S. cerevisiae SMP-ATPase) (150); 1-5 μg of inhibitor/mg protein^a (T. pyriformis SMP-ATPase) (404); 200 μM^a in less than 5 min and at ∼40 μM^a in 30 min (R. rubrum F₁-ATPase) (204); 1.9 μg/mg protein^a (C. fasciculata SMP-ATPase) (439); 95% inhibition with 1 mol DCCD/mol F₁ (EF₁-ATPase) (400); maximal 70-80% inhibition at 30 μM (membrane-bound EF₀F₁-ATPase) (171); 47% inhibition at 5 μM (C. thermoaceticum membrane-bound F₀F₁-ATPase) (190); 97% inhibition with 2 mol inhibitor bound/mol F₁ (bovine heart MF₁-ATPase) (250); maximal inhibition at 1 mol inhibitor/mol F₀ (bovine heart SMP-ATPase) (140); maximal inhibition at 2 mol inhibitor/mol F₀ (bovine heart H⁺-translocation) (140); maximal inhibition at 1 mol inhibitor/mol F₀ (E. coli membrane H⁺-translocation) (171)
NCCD	C₁₆H₂₈N₃O	N-(2,2,6,6-Tetramethylpeperidyl-1-oxyl)-N(cyclohexyl)carbodiimide; N-(2,2,6,6-tetramethyl-1-oxypiperid-4-yl)-N′-cyclohexylcarbodiimide	0.65 nmol/mg protein^a (bovine heart SMP-ATPase) (24); 85% inhibition at 1 nmol NCCD/mg protein (bovine heart SMP-ATPase) (23)
CMCD	C₁₄H₂₈N₃O·C₇H₈O₃S	1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluenesulfonate; N-cyclohexyl-N′-2-morpholinoethyl-carbodiimide-methyl-4-toluolsulfonate	200 μM^b (bovine heart MF₁-ATPase) (186)
EDC	C₈H₁₇N₃	Ethyldimethylaminopropyl carbodiimide; 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide; (3-(dimethylamino) propyl)ethylcarbodiimide	95% inhibition at 13 mol of EDC/mol F₁ (EF₁-ATPase) (236)
EEDQ	C₁₄H₁₇NO₃	N-Ethoxycarboxyl-2-ethoxy-1,2-dihydroquinoline	200 μM^a in less than 5 min and at ∼40 μM^a in 30 min (R. rubrum F₁-ATPase) (204); 70% inhibition at 400-600 μM (bovine heart MF₁-ATPase) (250, 320); 75% inhibition at 400 μM (E. coli F₁-ATPase) (320)
Woodward's reagent K	C₁₁H₁₁NO₄S	2-Ethyl-5-phenylisoxazolium-3′-sulfonate; N-ethyl-5-phenylisoxazolium-3′-sulfonate	88% inhibition at 15 mM (E. coli F₀-liposome proton uptake) (162)

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I₅₀.

K_d.

DCCD, by binding F₀ (35), also inhibits F₀-mediated proton translocation and the ATPase activity of the coupled F₀F₁ complex. Here, DCCD is bound covalently to an essential carboxyl residue of subunit c at position 61 (E. coli sequence) (68, 122, 364). The stoichiometries for the maximal inhibition of function are 1 mol of DCCD/mol of F₀, i.e., modification of 1 subunit c/F₀ for inhibiting ATPase activity of ATP synthase and 2 mol of DCCD/mol F₀ for inhibiting proton translocation (140, 171, 213).

NCCD is a lipid-soluble spin-labeled inhibitor of ATP synthase that targets the F₀ of ATP synthase (23, 24). The binding site for NCCD is believed to be the same as that for DCCD, i.e., Asp61 of subunit c, as NCCD's binding to the ATP synthase is prevented by DCCD (24). Moreover, the mutant of Ala25 in subunit c, which is near Asp61, shows a greatly reduced inhibitory activity with NCCD (138).

1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate and ethyldimethylaminopropyl carbodiimide (EDC) are water-soluble carbodiimides that modify a carboxyl group(s) in F₁. 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate binds to F₁ reversibly and likely modifies carboxyl groups near the catalytic sites (186). EDC inhibits F₁ after modifying several carboxyl groups in β subunits. The inhibition by EDC is greatly reduced by Mg²⁺ (236). Incorporation of about 13 mol of EDC/mol F₁ (E. coli) leads to 95% inhibition of ATPase activity. Here, two-thirds of the bound EDC is bound to β subunits, where it modifies multiple sites in a short segment (residues 162 to 194) (E. coli sequence) (236). EDC also promotes formation of intersubunit cross-links between subunits β and ɛ. The residues involved are βGlu381 and likely ɛSer108 (90).

N-Ethoxycarboxyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) inhibits both MF₁ and BF₁ (Fig. 10B and Table 20) (204, 222, 250, 320, 322, 399). The inactivation by EEDQ is both pH and temperature dependent and also time and concentration dependent (204, 322). One mole of EEDQ binds to one mole of F₁. The inactivation follows pseudo-first-order kinetics until 90 to 95% inactivation occurs (322). Inhibitions by EEDQ and DCCD are additive, suggesting that the binding sites of EEDQ and DCCD are either the same (204, 222) or located close to each other (320).

Woodward's reagent K inhibits both F₁ and F₀ (204, 381). The chemical modification of the β subunit of F₁ from Rhodospirillum rubrum with this reagent results in loss of both phosphate and ATP binding capacities (203). However, ADP binding sites remain active. Chemical modification of F₀ from E. coli by Woodward's reagent K inhibits both proton translocation and total ATPase activity (381).

Cys and Tyr Residue Modifiers

4-Chloro-7-nitrobenzofurazan (NBD-Cl) is a fluorescent adenine analog that labels Tyr or Cys residues (Fig. 10C and Table 21). It inhibits both the synthetic and hydrolytic activities of ATP synthases from bacteria, chloroplasts, and mitochondria by modifying an essential residue (βTyr311, bovine sequence) at the catalytic site(s) of F₁ (12, 70, 119, 120, 245, 388, 415). Depending on the experimental conditions, other subunits, particularly the α subunit, are also modified by NBD-Cl (96, 121, 146, 283). In F₁ modified by NBD-Cl, the Tyr-O-NBD linkage is unstable at alkaline pH. The NBD group from βTyr311 migrates to βLys162 in the P-loop at pH 9 as a consequence of O-to-N migration (13, 14, 121). The resulting NBD-N-Lys derivative of F₁ is also catalytically inactive (14, 121). In a crystal structure of bovine MF₁ covalently modified by NBD-Cl, the NBD-Cl is found in only one of three β subunits, β_E (292). The βTyr311 residues in the β_TP and β_DP subunits are buried at the α-β subunit interfaces and are inaccessible to NBD-Cl. The NBD binding pocket is positioned in the central nucleotide binding domain with no hydrogen bonds between the NBD ring and the protein. NBD-Cl appears to inhibit F₁ by preventing β_E from undergoing a conformational change (292).

TABLE 21.

Cys/Tyr residue modifiers

Name or abbreviation	Molecular formula	Other names	Inhibitory potency, I₅₀ (reference)
NBD-Cl	C₆H₂ClN₃O₃	NBF-Cl; 7-chloro-4-nitrobenzofurazan; 4-chloro-7-nitrobenzofurazan; 7-chloro-4-nitrobenzofurazan; 4-chloro-7-nitro-2,1,3-benzoxadiazole; 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole; 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole	4.5 μg of inhibitor/mg protein (T. pyriformis SMP-ATPase) (404); 68% inhibition at 50 μM (C. thermoaceticum F₁-ATPase) (190); complete inhibition at 1 mol inhibitor bound/mol F₁ (bovine heart F₁-ATPase) (246); >90% inhibition at 1.4 mol inhibitor bound/mol F₁ (TF₁-ATPase) (415)
Tetranitromethane	CN₄O₈	Tetan	130 nmol/mg protein and ∼100% inhibition at 210 nmol/mg protein (bovine heart SMP-ATPase) (162); 2.5 mM (TF₀ vesicle, proton conduction) (375); almost complete inhibition at 8 mM (TF₀ vesicle, proton conduction) (375)
DFDNB	C₆H₂F₂N₂O₄	1,5-Difluoro-2,4-dinitrobenzene; 4,6-difluoro-1,3-dinitrobenzene	Complete inhibition at 3 mol inhibitor/mol F₁ (bovine heart MF₁-ATPase) (7)
NEM	C₆H₇N₁O₂	N-Ethylmaleimide; maleic acid N-ethylimide	∼0.6 mM (S. pombe MF₁-ATPase) (115); 74% inhibition at 1 mM (V. parahaemolyticus F₁-ATPase) (344)
Bismuth subcitrate	C₆H₈O₇Bi	CBS; colloidal bismuth subcitrate; tripotassium dicitratobismuthate	73 μM (H. pylori F₁-ATPase) (36)
Omeprazole^a	C₁₇H₁₉N₃O₃S	5-Methoxy-2-(((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl)benzimidazole; Audazol; Omepral	90 μM (without acid activation) and 43 μM (with acid activation) (H. pylori F₁-ATPase) (36)
DTNB	C₁₄H₈N₂O₈S₂	5,5′-Dithiobis(2-nitrobenzoic acid); dithionitrobenzoic acid; 2,2′-dinitro-5,5′-dithiodibenzoic acid; 3,3′-dithiobis(6-nitrobenzoic acid); dithiobisnitrobenzoic acid; Ellman's Reagent	39% inhibition at 0.4 mM and 46% inhibition at 1.3 mM (bovine heart MF₁-ATPase) (392)
PCMB	C₇H₅ClHgO₂	p-Chloromercuribenzoic acid; 4-carboxyphenylmercuric chloride; 4-chloromercuribenzoic acid	∼90% inhibition at 4.5 mM (bovine heart SMP-ATPase) (438)
PCMS	C₆H₅ClHgO₃S	p-Chloromercuribenzene sulfonate; 4-chloromercuribenzenesulfonate; PCMBS	6 mM (bovine heart SMP-ATPase) (438)
Mersalyl	C₁₃H₁₆HgNO₆.Na	O-((3-Hydroxymercuri-2-methoxypropyl)carbamoyl)phenoxy-acetic acid; (3-((2-(carboxymethoxy)benzoyl)amino)-2-methoxypropyl)hydroxymercury; mercuramide; mercusal; mersalyl acid	70% inhibition at 130 μM (bovine heart MF₀, proton conductivity) (445)
2,2′-Dithiobispyridine	C₁₀H₈N₂S₂	2,2′-Dithiodipyridine; 2,2′-dipyridyl disulfide; 2PDS; bis(2-pyridinyl) disulfide	55% inhibition at 1 mM (bovine heart MF₀, proton conductivity) (445)
N-(7-Dimethylamino-4-methyl-coumarinyl)-maleimide	C₁₆H₁₄N₂O₄	N-(4-Methyl-7-dimethylamino-3-coumarinyl)maleimide	60% inhibition at 400 μM (bovine heart MF₀, proton conductivity) (445)

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Omeprazole is converted to a cyclic sulfenamide with acid-activation.

Tetranitromethane and 1,5-difluoro-2,4-dinitrobenzene (DFDNB) modify Tyr residues. Tetranitromethane nitrates the Tyr residue of ATP synthase subunit c of the thermophilic bacterium PS3 and inhibits the proton conduction of TF₀ (375). In contrast, tetranitromethane inhibits neither proton translocation nor ATPase activity of E. coli ATP synthase (381). However, DFDNB does inhibit the ATPase activity of MF₁ (7, 55), with a molar ratio of 3 for complete inhibition. Here, inhibition is reversed by dithiothreitol. (7). Inactivation of F₁ by DFDNB is believed to be due to modification of either βTyr311 (55) or another Tyr residue (7).

Thiol group reagents, N-ethylmaleimide (NEM), bismuth subcitrate, omeprazole, 5,5′-dithiobis(2-nitrobenzoic acid), p-chloromercuribenzoate (PCMB), p-chloromercuribenzene sulfonate (PCMS), mersalyl, 2,2′-dithiobispyridine, and N-(7-dimethylamino-4-methyl-coumarinyl)-maleimide inhibit ATP synthase by modifying Cys residues. Specifically, NEM inhibits the ATPase activity of F₁s from fungi, some bacteria such as Vibrio parahaemolyticus, and some mitochondria, i.e., those from S. cerevisiae and Schizosaccharomyces pombe (115, 145, 344). The inactivation of F₁ by NEM in sensitive cases is irreversible and protected by nucleotides (115). In contrast, the F₁s from E. coli and bovine heart mitochondria are resistant to NEM (344, 366). NEM also binds various F₀ polypeptides, inhibiting proton conduction (445). For example, NEM inhibits mitochondrial F₀ from bovine heart while labeling 25-, 11-, and 9-kDa polypeptides (445).

Bismuth subcitrate and omeprazole are antiulcer drugs. They bind to sulfhydryl groups of F₁ and form stable complexes (36). They inhibit the ATPase activity of F₁ from Helicobacter pylori via a reaction that can be prevented and also reversed by mercaptan glutathione. At low pH, omeprazole is converted into a cyclic sulfonamide, and this form inhibits the ATPase activity of H. pylori F₁ more potently than the form without acid activation (I₅₀ = 43 μM when acid activated, compared to 90 μM without acid activation).

Regarding other sulfhydryl reactive agents, 5,5′-dithiobis(2-nitrobenzoic acid) inhibits the ATPase activity of nucleotide-depleted F₁ (392). In contrast, it is inhibitory neither to native F₁ nor to nucleotide-depleted F₁ in the presence of either ADP or ATP.

PCMB, PCMS, and mersalyl are polar organic mercurials that target F₀ of mitochondrial ATP synthase. Both PCMB and PCMS inhibit the ATP synthesis and ATPase activities of bovine heart ATP synthase. Thiols modified by the mercurials are different from those modified by NEM (438). In contrast to the case for NEM, inhibition by mercurials is reversed almost completely (PCMB) or partially (PCMS) by addition of dithiothreitol. Moreover, the binding of mercurials protects the ATP synthase from irreversible inhibition by DCCD. Mersalyl also inhibits proton conductivity by F₀ from bovine heart mitochondria. Here, the inhibition is much more potent than that observed with PCMB and PCMS (445). Although mersalyl has no inhibitory effect at concentration of up to ≤50 μM, it inhibits proton conduction at higher concentrations (∼70% inhibition at 130 μM).

The sulfhydryl-reactive agents 2,2′-dithiobispyridine and N-(7-dimethylamino-4-methyl-coumarinyl)-maleimide also inhibit proton conductivity by F₀ from bovine heart mitochondria (445). N-(7-Dimethylamino-4-methyl-coumarinyl)-maleimide has stronger inhibitory potencies than 2,2′-dithiobispyridine and NEM. N-(7-dimethylamino-4-methyl-coumarinyl)-maleimide shows no inhibition up to a concentration of 200 μM and inhibits proton conduction by 60% at 400 μM.

His Residue Modifiers

Diethyl pyrocarbonate and Rose bengal are His residue-modifying reagents (Fig. 10D and Table 22). Diethyl pyrocar-bonate modifies the ATP synthase β subunit, completely preventing the binding of phosphate. It also blocks the binding of ATP to a Mg²⁺-dependent low-affinity site (203, 381, 445). In contrast, the ADP binding capacity of the β subunit is not affected by modification with diethyl pyrocarbonate (203). Diethyl pyrocarbonate also modifies F₀ from E. coli, inducing inhibition of proton uptake (381).

TABLE 22.

His and other amino acid residue modifiers

Name	Molecular formula	Other names	Inhibitory potency, I₅₀ (reference)
Diethyl pyrocarbonate	C₆H₁₀O₅	Baycovin; diethyl dicarbonate; diethyl oxydiformate; pyrocarbonic acid diethyl ester	>50% inhibition at 3 mM (E. coli F₀, liposome proton uptake) (381)
Rose bengal	C₂₀H₂Cl₄I₄Na₂O₅	Bengal rose	75-85% inhibition at 0.2 μM (bovine heart F₁-ATPase) (139)
Iodine	I₂		40 μM (rat liver MF₁-ATPase) (314)

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Rose bengal photooxidizes His residues of β subunits, causing conformational instability in F₁ (139). About 60% of the His residues are photooxidized, causing 50% inactivation. This photochemical damage is prevented by various phenanthroline compounds.

Others

Iodine is an electron-dense heavy atom that reacts with and inactivates F₁ (314). It behaves like a typical covalent inhibitor in its modification of amino acid residues. MgATP, MgADP, and phosphate fail to protect F₁ from inhibition by iodine. Iodine preferentially labels the ATP synthase β subunit, although it also labels α and γ subunits to some extent. About 10 atoms of iodine are incorporated per F₁ (rat liver mitochondria) under conditions where the labeling proceeds in a linear fashion. About two atoms of iodine are incorporated per β subunit.

PHYSICAL INHIBITORY FACTORS

High Hydrostatic Pressure

High hydrostatic pressure of above 60 to 80 MPa inactivates both F₁ and the complete ATP synthase (F₀F₁) (Table 23) (105, 310, 377). At below 60 to 80 MPa, the hydrostatic pressure shows stimulatory effects on ATPase activity. However, both membrane-bound and isolated F₀F₁ from mitochondria are inhibited reversibly at high hydrostatic pressure, while soluble F₁-ATPase is inactivated irreversibly due to reassociation with an altered hydrodynamic radius after decompression (105). In contrast to the case for the isolated mitochondrial ATP synthase, the inhibition of the isolated ATP synthase from chloroplasts is irreversible, showing no restoration after decompression (377). The inactivation is dependent on protein concentration (377). Inhibition by high hydrostatic pressure is believed to be associated with dissociation that impairs contacts essential for transmission of conformational information between those subunits needed for rotational catalysis (105, 377).

TABLE 23.

Physical inhibitory factors

Factor	Inhibitory potency (reference)
Hydrostatic pressure	850 bars^a (bovine heart SMP-ATPase, 0.02 mg/ml) (105)
Far-UV irradiation	∼80% inhibition within 15 min at 254 nm (bovine heart SMP-ATPase) (75)
Cold temp	15-60 min^b at 4°C (324), 4-40 min^a at 0°C with different prepn (bovine heart MF₁-ATPase) (308, 309)

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I₅₀.

Half-life.

UV Irradiation

Mitochondrial ATPase activity is inhibited also by far-UV irradiation. UV light at 254 nm results in a time-dependent inhibition of both membrane-bound and soluble F₁. Inhibition reaches its maximum level within 15 min after exposure of SMP to UV (75). This also induces the release of tightly bound adenine nucleotides from F₁. Succinate, a substrate for the electron transport chain, partially protects against the detrimental effects of UV. Inhibition by UV is due to the photochemical modification of the essential Tyr residue located at the active site of F₁ that induces subsequent structural changes in F₁.

Low Temperature

The F₁“catalytic” moiety of the ATP synthase (F₀F₁) is cold labile (308, 309, 324). Its ATPase activity decrease rapidly upon incubation at low temperature. The rate of inactivation is first order, and the half-life varies between 15 and 60 min with different preparations (324). The inactivation is not protected by ATP, ADP, or Mg²⁺ and is reversed by rewarming the enzyme solution under appropriate conditions (309). The inactivation by cold temperature is associated with the dissociation of the enzyme complex into subunits (309).

MISCELLANEOUS INHIBITORS

Polyborates are boron cluster compounds with a unique molecular structure and unusual chemical properties. Among the polyborates, dodecaborates ([B₁₂H₁₂]²⁻) and dicarbononaborates ([C₂B₉H₁₁]⁻) inhibit ATPase activity of MF₁, and dicarbononaborates have much stronger inhibitory potencies than dodecaborates (Fig. 11) (104). One of the dicarbononaborates, dichlorodicarbononaborate ([Cl₂C₂B₉H₁₀]⁻), that contains two chlorides inhibits competitively with respect to ATP the ATPase activities of both membrane-bound and soluble F₁. The inhibition is due to a direct interaction of the reagent with the catalytic F₁ moiety (104).

FIG. 11. — Miscellaneous inhibitors. TCS, tetrachlorosalicylanilide.

Almitrine is a piperazine-like agent that is known to be a respiratory stimulant that enhances respiration by acting as an agonist of peripheral chemoreceptors located on the carotid bodies. This agent inhibits mitochondrial ATP synthase in an uncompetitive manner (336). Also, it does not destroy the electrochemical proton gradient across the mitochondrial membrane that normally drives ATP synthesis (333-335). Thus, mitochondria treated with this agent remain intact despite the fact that this agent has debilitated their ATP synthase.

5-Hydroxynaphthalenedicarboxylic anhydride (HNA) inhibits the mitochondrial ATPase activity induced by 2,4-dinitrophenol and the ATPase activity of SMP induced by Mg²⁺ (165). HNA also inhibits the ATP-energized mitochondrial volume change. The inhibitory effects of HNA are similar to those of rutamycin.

R207910 is a diarylquinoline drug that has antimycobacterial activity. It inhibits mycobacterial ATP synthase and targets subunit c in F₀ (15, 215, 313). The site of action of R207910 seems to be located close to an essential carboxyl residue, Asp61 of subunit c (E. coli sequence), as the mutations Asp32Val (Mycobacterium smegmatis) and Ala63Pro (M. tuberculosis) confer resistance to the drug. Also, the mycobacterial species naturally resistant to R207910 contains Met at position 63 in place of a conserved Ala in all sensitive mycobacteria (15, 181, 313). R207910 is an enantiomeric compound with two chiral centers. It adopts the lowest-energy conformation with the carbon alpha relative to the quinoline moiety R and the carbon beta S (135). The binding of the inhibitor to the binding site in ATP synthase is stereoselective, and its (S,R) stereoisomer is 2 orders of magnitude less inhibitory than R207910 (215). R207910 appears to act specifically on mycobacteria, and the range of MICs of R207910 is 0.03 to 0.12 μg/ml for 99% inhibition of the growth of M. tuberculosis strains (15). The killing effect of M. tuberculosis by R207910 is time dependent rather than concentration dependent (15), and R207910 acts synergically when combined with other tuberculous drugs (183, 237, 238).

Spegazzinine is a dihydroindole alkaloid from Aspidosperma chakensis Spegazzini (103). It inhibits uncompetitively the ATPase activities of both membrane-bound and isolated CF₁ from spinach (10). Spegazzinine inhibits both cyclic and noncyclic photophosphorylation of isolated spinach chloroplasts. It also inhibits the mitochondrial ATPase activity of S. pombe (234) and slightly inhibits the mitochondrial ATPase activity of Tetrahymena pyriformis ST (404). In contrast, spegazzinine has no inhibitory effects on the ATPase activities of ATP synthases from Clostridium pasteurianum (78), Tritrichomonas foetus (235), and mitochondria of Crithidia fasciculata (439).

n-Butanol inhibits the ATPase activities of both membrane-bound and soluble MF₁ (406). It inhibits the isolated F₁ at the same or lower concentrations as it inhibits membrane-bound F₁. Inhibition is temperature dependent. N-Butanol also shows partial inhibition of ATP synthesis.

Tetrachlorosalicylanilide is a lipophilic weak acid known as an H⁺ conductor. It inhibits the ATPase activities of both isolated F₁ and F₀F₁ from Vibrio parahaemolyticus (290, 344). The concentration of tetrachlorosalicylanilide for 50% inhibition of F₀F₁-ATPase activity from V. parahaemolyticus is about 9 to 10 μM (290).

Dihydrostreptomycin is a polycationic aminoglycoside antibiotic drug produced from Streptomyces humidus. It significantly stimulates the ATPase activity of membrane-bound ATP synthase from bovine heart mitochondria in the concentration range of 1 to 5 mM. The stimulation is followed by inhibition at higher concentrations (161). Dihydrostreptomycin also inhibits the ATPase activity of isolated F₁, but the stimulation of the ATPase activity observed in the inhibition of membrane-bound F₁ at low concentrations of dihydrostreptomycin is not observed in the inhibition of isolated F₁. The inhibition of ATPase activity of F₁ by dihydrostreptomycin is noncompetitive. Dihydrostreptomycin also exhibits partial inhibition of proton conductivity of F₀ in the ATP synthase devoid of its catalytic F₁ moiety.

Suramin, a synthetic antiparasitic drug, is an inhibitor of various proteins in different cell types and also inhibits the binding of some growth factors to their receptors. Suramin also binds to ATP synthase and inhibits both F₁-ATPase and membrane-bound F₀F₁-ATPase from mitochondria (28, 173). Suramin acts as a noncompetitive inhibitor of the membrane-bound ATPase and as a strictly competitive inhibitor of purified F₁-ATPase (173). Half-maximal inhibition of rat liver F₁-ATPase occurs at 40 μM suramin.

Bz-423 is an 1,4-benzodiazepine derivative known as a cytotoxic immunomodulatory drug that suppresses disease in lupus-prone mice by inducing apoptosis in autoreactive B and T lymphocytes (193). Bz-423 binds to the OSCP subunit of ATP synthase and inhibits both synthetic and hydrolytic activities of the enzyme. The inhibition of the ATPase activity of ATP synthase by Bz-423 leads to rapid generation of superoxide (O₂⁻) from the respiratory chain within mitochondria and the initiation of apoptosis by the reactive oxygen species. Bz-423 affects both the V_max and K_m of the ATPase activity of ATP synthase and inhibits ATP synthesis in a concentration-dependent fashion.

Dimethyl sulfoxide (DMSO) inhibits the hydrolytic activities of BF₁ and MF₁ strongly at concentrations of above 30 to 40% (9, 345, 440). Inhibition by DMSO is reversible, affecting V_max without a significant change in the K_m (9, 440). In contrast, the synthesis of ATP by soluble F₁ is promoted in the presence of DMSO (94, 197, 346). The effect of DMSO on the promotion of ATP synthesis by isolated F₁ is considered to be due to an increase in affinity of F₁ for phosphate at the catalytic site (197, 345).

Hypochlorous acid (HOCl) is a strong oxidant that is produced as a microbicide in activated neutrophils and monocytes by myeloperoxidase-catalyzed peroxidation of chloride ion (182). HOCl inhibits the ATPase activity of F₁ in a biphasic fashion. The ATPase activity falls rapidly to 20 to 30% at low concentrations of HOCl and then slowly to zero at high concentrations (29). The biphasic mode of inhibition is attributed to two different inhibitory activities of HOCl: oxidative modification of intact F₁ and subunit dissociation of F₁ due to more extensive oxidation (29, 167). The target sites for HOCl are believed to be amino acid residues within nucleophilic side chains (167).

4,4′-Dichlorodiphenyltrichloroethane (DDT) is a synthetic organic insecticide and affects sodium ion channels in the neurons of DDT-sensitive insects, causing repetitive discharge by the increase and prolongation of membrane's negative after-potential, leading to spasms and eventual death. DDT binds to an unidentified 23-kDa protein in the F₀ of mitochondrial ATP synthase and inhibits the ATPase activity of the enzyme (442, 443). The 23-kDa protein is present in DDT-sensitive insects but not in DDT-tolerant insects and mammals, and the prepared DDT-sensitive ATP synthase devoid of the 23-kDa protein is not inhibited by DDT (442, 443).

Diazoxide, a mitochondrial potassium channel activator, is a cardioprotective drug for short-term treatment of malignant hypertension. Diazoxide also binds to MF₁ and potentiates the binding of IF₁ to F₁, inhibiting the ATPase activity of ATP synthase (79, 80). The inhibition by diazoxide is reversible, and the binding of one equivalent of diazoxide to F₁ is sufficient to inhibit the F₁-ATPase activity. The inhibitory effect of diazoxide is ATP dependent, and no inhibition is observed without Mg²⁺-ATP. The binding site of diazoxide is believed to be located within the nucleotide binding domain of the β subunit.

2-Hydroxy-5-nitrobenzyl bromide (HNB) stimulates the hydrolytic activity of F₁ from bovine heart mitochondria at below 0.5 mM but exhibits a concentration-dependent inhibition of F₁ from the same source at above 0.5 mM (26, 27). HNB is a Trp-modifying reagent. Its capacity to activate catalytic activity at below 0.5 mM is attributed to its covalent interaction with a single Trp residue in the ɛ subunit of F₁ (26). In contrast, HNB's inhibitory effect at above 0.5 mM appears to be due to noncovalent, reversible, aspecific binding to F₁. About 50% of the hydrolytic activity is inhibited at 2.5 mM.

A series of derivatives of benzodiazepine, 4-(N-arylimidazole)-substituted benzopyran, and N-[1-aryl-2-(1-imidazolo)ethyl]-guanidine have been synthesized and tested for the treatment of ischemic heart disease as cardioprotective agents (Table 24) (20, 21, 166). During ischemia, ATP is hydrolyzed by mitochondrial ATP synthase, leading to depletion of ATP. To prevent the ATP wastage in ischemia, the ATPase activity of ATP synthase should be inhibited selectively without affecting the ATP synthesis activity of the enzyme. Several inhibitors were proposed as potential compounds for drug design for ischemia.

TABLE 24.

Miscellaneous inhibitors

Name or abbreviation	Molecular formula	Other names	Inhibitory potency (reference)
Dicarbopolyborate	C₂B₉H₁₁ (Dicarbononaborate)		Mercapto and chloro derivatives of dicarbononaborates, ∼95% inhibition at 500-800 μM (rat liver MF₁-ATPase) (104); dichlorodicarbononaborate, 170 μM^b (rat liver MF₁-ATPase) (104)
Almitrine	C₂₆H₂₉F₂N₇	6-(4-(Bis(4-fluorphenyl)methyl)-1-piperazinyl)-N,N′-di-2-propenyl-1,3,5-triazin-2,4-diamin; 2,4-bis(allylamino)-6-(4-(bis(p-fluorophenyl)methyl)-1-piperazinyl)-s-triazine	30 μM^a (S. cerevisiae mitochondria, ATPase) (336)
5-Hydroxy-1,2-naphthalene dicarboxylic anhydride	C₁₂H₆O₄	6-Hydroxynaphtho(1,2-c)furan-1,3-dione; 5-hydroxynaphthalenedicarboxylic anhydride	Complete inhibition of ATPase induced by gramicidin at 30 μM (rat liver SMP-ATPase) (165)
R207910	C₃₂H₃₁BrN₂O₂	1-(6-Bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol; TMC207; compound J	2.5 nM^a (M. smegmatis membrane vesicles, ATP synthesis) (215); 99% inhibition in the range of 0.03-0.12 μg/ml (M. tuberculosis, growth) (15)
Spegazzinine	C₂₁H₂₈N₂O₃		18.5-24 μg inhibitor/mg protein^a (S. pombe ATPase activity of cell extracts) (234); 100 μM^a (spinach CF₁-ATPase) (10); 80 μM^a (spinach chloroplasts, photophosphorylation) (10)
n-Butanol	C₄H₁₀O	1-Butanol; propyl carbinol; n-butyl alcohol; 1-hydroxybutane; butyl hydroxide; Hemostyp; methylolpropane; propylcarbinol; propylmethanol	160 mM^a (bovine heart MF₁-ATPase) (406)
TCS	C₁₃H₇Cl₄NO₂	TCSA; tetrachlorosalicylanilide; 3,3′,4′,5-tetrachlorosalicylanilide; 3,5-dichlorosalicyl 3,4-dichloroanilide; 3,5-dichloro-N-(3,4-dichlorophenyl)-2-hydroxy-benzamide	9-10 μM^a (F₀F₁-ATPase from V. parahaemolyticus) (290); 71% inhibition at 25 μM (V. parahaemolyticus F₁-ATPase) (344)
Dihydrostreptomycin	C₂₁H₄₁N₇O₁₂	Abiocine; Vibriomycin	38 mM^b (bovine heart SMP- and isolated MF_1-ATPase) (161)
Suramin	C₅₁H₄₀N₆O₂₃S₆	Belganyl; Naganol	40 μM^a (rat liver MF₁-ATPase) (28); 0.7 μg/ml^a (C. fasciculata MF₁-ATPase) (173)
Bz-423	C₂₇H₂₁ClN₂O₂	Bz-48	5 μM^a (Ramos cells, ATP synthesis) (193)
DMSO	C₂H₆OS	Dimethyl sulfoxide	> 95% inhibition at 40% DMSO (vol/vol) (EF₁-ATPase) (9); ∼60% inhibition at 50% DMSO (TF₁-ATPase) (440)
Hypochlorous acid	HOCl		75% inhibition at 125 μM HOCl/g cells (EF₁-ATPase) (167); 50 μmol inhibitor/g cells^a (EF₁-ATPase) (29)
DDT	C₁₄H₉C_l5	4, 4′-Dichlorodiphenyltri-chloroethane; 4, 4′-DDT; p,p′-DDT; 1,1′-(2,2,2-trichloroethylidene)bis (4-chlorobenzene); Agritan; Chlorophenothan; 1,1,1-trichloro-2,2-bis(4,4′-dichlorodiphenyl) ethane; Detoxan	50% lethal dose of 11 μg/mg (A. melllifera)
Diazoxide	C₈H₇ClN₂O₂S	7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide; Eudemine; Hyperstat; Hypertonalum	K_d of IF₁ to F₁, 250 nM with 1 diazoxide equivalent/F₁ from 760 nM without diazoxide (bovine MF₁-ATPase) (80)
HNB	C₇H₆BrNO₃	2-Hydroxy-5-nitrobenzyl bromide; Koshland's reagent I; 2-bromomethyl-4-nitrophenol; α-bromo-4-nitro-o-cresol	2.5 mM^a (bovine heart MF₁-ATPase) (27)
N-Sulfonyl or N-alkyl-substituted tetrahydrobenzodiazepine derivatives	C₂₈H₃₀N₄O₃S	1-(1H-Imidazol-4-ylmethyl)-4-[(4-methoxyphenyl)sulfonyl]-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine	77 nM^a (bovine heart MF₀F₁-ATPase) (166)
	C₂₂H₂₃F₃N₄O₂S	1-(1H-Imidazol-4-ylmethyl)-2-(2-phenylethyl)-4-[(trifluoromethyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine	77 nM^a (bovine heart MF₀F₁-ATPase) (166)
	C₃₁H₃₆N₄O₂S	4-[(4-tert-Butylphenyl)sulfonyl]-1-(1H-imidazol-4-ylmethyl)-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine	8 nM^a (bovine heart MF₀F₁-ATPase) (166)
	C₃₂H₃₈N₄O₂S	4-[(4-tert-Butylphenyl)sulfonyl]-1-[(5-methyl-1H-imidazol-4-yl)methyl]-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine	77 nM^a (bovine heart MF₀F₁-ATPase) (166)
	C₂₈H₂₈Cl₂N₄O₂S	4-[(3,4-Dichlorophenyl)sulfonyl]-1-[(5-methyl-1H-imidazol-4-yl)methyl]-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine	22 nM^a (bovine heart MF₀F₁-ATPase) (166)
4-(N-Arylimidazole)-substituted benzopyran derivatives	C₂₂H₂₁ClN₄O₂	4-[(4-Chlorophenyl)(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromene-6-carbonitrile	3R, 4S enantiomer, 0.48 μM^a (rat heart MF₀F₁-ATPase) (21) and 4 μM^a (rat heart SMP-ATP synthesis) (21); 3S, 4R enantiomer, 0.24 μM^a (rat heart SMP-ATPase) (21) and 3.8 μM^a (rat heart SMP-ATP synthesis) (21);
	C₂₆H₃₁ClN₄O₄S	4-[(4-Chlorophenyl)(1H-imidazol-2-ylmethyl)amino]-2,2-dimethyl-6-(piperidin-1-ylsulfonyl)-3,4-dihydro-2H-chromen-3-ol	3R, 4S enantiomer (BMS-199264), 0.48 μM^a (rat heart SMP-ATPase) (21), 18 μM^a (rat heart SMP-ATP synthesis) (21); ∼42% inhibition at 3 μM (ischemic rat heart SMP-ATPase) (156)
N-[1-Aryl-2-(1-imidazolo)ethyl]-cyanoguanidine	C₁₉H₁₄Cl₄N₆	2-Cyano-1-(2,4-dichlorophenyl)-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]guanidine	0.6 μM^a (bovine MF₀F₁-ATPase) (20)
derivatives	C₂₁H₁₄Cl₂F₆N₆	1-{1-[2,5-Bis(trifluoromethyl)phenyl]-2-(1H-imidazol-1-yl)ethyl}-2-cyano-3-(2,4-dichlorophenyl)guanidine	0.71 μM^a (bovine MF₀F₁-ATPase) (20)
N-[1-Aryl-2-(1-imidazolo)ethyl]-acylguanidine derivatives	C₂₆H₁₉Cl₃N₆O	N-[(Z)-[(4-Chlorophenyl)amino]{[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]amino}methylidene]-3-cyanobenzamide	Racemic mixture, 33 nM^a (bovine MF₀F_1-ATPase) (20); one enantiomer. 18 nM^a (bovine MF₀F_1-ATPase) (20); the other enantiomer, >100 nM^a (bovine MF₀F₁-ATPase) (20)
	C₂₅H₁₉Cl₄N₅O	4-Chloro-N-[(Z)-[(4-chlorophenyl)amino]{[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]amino}methylidene]benzamide	Racemic mixture, 82 nM^a (bovine MF₀F_1-ATPase) (20)
O-[1-Aryl-2-(1-imidazolo)ethyl]-thiourethane derivatives	C₁₈H₁₄Cl₃N₃OS	O-[1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl] (4-chlorophenyl)carbamothioate	0.43 μM^a (bovine heart MF₀F₁-ATPase) (20); >300 μM^a (bovine heart MF₀F₁, ATP synthesis) (20)
	C₁₈H₁₃Cl₄N₃OS	O-[1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl] (2,4-dichlorophenyl)carbamothioate	30 nM^a (bovine heart MF₀F₁-ATPase) (20)
Dio-9 complex	Unknown (a mixture of at least 9 compounds)		0.7 μg inhibitor/mg protein^a (T. pyriformis SMP-ATPase) (404); ∼500 μg inhibitor/mg protein^a (S. faecalis F₁-ATPase) (169); 6.6 μg/mg protein^a (C. fasciculata SMP-ATPase) (439)
Ethanol	C₂H₅OH	Ethyl alcohol	60% inhibition at about 7 μM (V. parahaemolyticus F₀F₁-ATPase) (290)
Zinc	Zn²⁺		∼100 μM^a (V. parahaemolyticus F₀F₁-ATPase) (290)

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I₅₀.

K_i.

N-Sulfonyl- or N-alkyl-substituted tetrahydrobenzodiazepine derivatives inhibit the mitochondrial ATPase activity of ATP synthase (166). The inhibition of ATP synthesis by these derivatives is much less potent than their inhibition of ATP hydrolysis. The derivatives with an N-sulfonyl moiety seem to have stronger inhibitory potencies than those with an N-alkyl moiety.

4-(N-Arylimidazole)-substituted benzopyran derivatives are inhibitors of ATP hydrolysis of mitochondrial ATP synthase (21, 156). The inhibition of ATP synthesis by these derivatives is about an order of magnitude less potent than that of ATP hydrolysis (21). Both the N-arylimidazole ring and benzopyran seem to be required for inhibition, since the removal of either from the structure causes a dramatic loss of inhibitory potency. BMS-199264 has been tested as a cardioprotective agent in ischemic rat hearts and showed selective inhibition of ATP hydrolase activity with no effect on ATP synthesis (156). It conserved ATP during ischemia, while it had no influence on preischemic ATP concentrations and cardiac function.

Cyano- and acylguanidine derivatives containing imidazoloethyl and aryl groups also inhibit the hydrolytic activity of mitochondrial ATP synthase (20). Inhibition by derivatives of N-[1-aryl-2-(1-imidazolo)ethyl]-cyanoguanidine and N-[1-aryl-2-(1-imidazolo)ethyl]-acylguanidine is selective for ATPase activity. No inhibition of ATP synthesis is observed up to 100 μM. In cyanoguanidine derivatives, the number and position of the chloride in aryl groups are believed to be important for their inhibitory activities. For example, the 2,4-dichloro analog is more potent than 2,3-dichloro and monochloro analogs in inhibiting the ATPase activity of F₁. Two symmetrical enantiomers with an identical chemical composition also have different inhibitory potencies. For instance, one entiomer of N-[(Z)-[(4-chlorophenyl)amino]{[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]amino}methylidene]-3-cyanobenzamide inhibits the ATPase activity of bovine mitochondrial ATP synthase (F₀F₁) with an I₅₀ of 18 nM, whereas the other entiomer has no inhibitory activity on the ATPase activity of the same enzyme (20).

O-[1-Aryl-2-(1-imidazolo)ethyl]-thiourethane derivatives also inhibit the ATPase activity of mitochondrial ATP synthase. Similar to the derivatives of N-[1-aryl-2-(1-imidazolo)ethyl]-cyanoguanidine and N-[1-aryl-2-(1-imidazolo)ethyl]-acylguanidine, the O-[1-aryl-2-(1-imidazolo)ethyl]-thiourethane derivatives also maintain selectivity for inhibition of ATPase activity of ATP synthase over ATP synthesis. For example, substitutions in the 1-aryl-2-imidazoloethyl and aniline moieties affect the inhibitory potencies of the derivatives, and halogen substitution in these moieties also seems to be favorable for promoting inhibition.

Dio-9 is a mixture of at least nine compounds, two of which have antibiotic properties (232). Dio-9 inhibits both ATPase and ATP synthase activities of mitochondria, chloroplasts, and bacteria (124, 125, 163, 169, 431). There is still much to be learned about the structures and chemical actions of the class of compounds comprising Dio-9.

Ethanol inhibits the ATPase activity of F₀F₁ from V. parahaemolyticus at concentrations of above 4% (290). In contrast, ethanol exhibits stimulatory effects on the ATPase activity of F₁.

Zinc strongly inhibits the ATPase activities of both purified and membrane-bound F₀F₁ from V. parahaemolyticus (267, 290). The site of action of the zinc ion is considered to be located within F₀ (290).

CONCLUSIONS

ATP synthase was previously considered to be located only in the mitochondrial inner membrane, the bacterial plasma membrane, and the chloroplast thylakoid membrane. It was also considered to be involved only in the synthesis of ATP or in the generation of a proton gradient. Now, however, significant evidence has accumulated that the ATP synthase is also present on the surfaces of multiple animal cell types and serves as a receptor for various ligands, participating in a number of cellular processes, including angiogenesis, lipid metabolism, the regulation of intercellular pH, and the cytolytic pathway of tumor cells (17, 38, 39, 72, 91, 202, 269). As the multiple roles of the cell surface ATP synthase are now beginning to be understood, this pivotal enzyme complex both at this location and its mitochondrial location is emerging as a molecular target for the treatment of various diseases.

The use of ATP synthase as a molecular target has multiple advantages. First, as it is indispensable for energy metabolism, if selectively targeted, it may be possible to eradicate some types of cancer. It may also provide an ideal target for controlling a number of other diseases because of its complex subunit composition. For example, it has been demonstrated already that a lupus drug, Bz-423, targets the OSCP of F₀, whereas an antimycobacterial drug, R207910, binds to subunit c of F₀ (15, 193, 313). In addition, it has been shown that resveratrol and piceatannol, potential antiangiogenesis agents, block tumor growth by binding to the β subunit of F₁ (143, 449). Lastly, the high inhibitory specificity of ATP synthase inhibitors also suggests that this complex is an excellent target for the development of new insecticidal or herbicidal agents. For example, tentoxin is a strong inhibitor of CF₁-ATPase from certain sensitive species such as spinach, potato, and lettuce, but it has little or no inhibitory effect on the same enzyme from insensitive species such as corn, tobacco, and radish, even though they exhibit high sequence and structural similarity (380). In addition, slight structural modifications of tentoxin can cause dramatic effects on the properties and inhibitory potencies of the inhibitor (316, 351). Finally, the drug R207910, developed for the treatment of tuberculosis, also shows a narrow selectivity in its inhibition of the ATP synthase in mycobacterial species (15).

The mitochondrial ATP synthase contains a number of supernumerary subunits that are absent in bacterial or chloroplast counterparts. The plasma membrane ATP synthase found in various types of animal cells also includes more subunit types than the bacterial and chloroplast ATP synthases. The roles of the supernumerary subunits are currently unknown or poorly defined, but evidence is accumulating that these “extra” subunits are also involved in cellular processes other than ATP synthesis. Thus, subunit F₆ has been reported to be associated with regulating blood pressure. Additionally, subunit e has been reported to be involved in the regulation of the expression of the gene for subunit g of the ATP synthase (18) and also for that of the c-myc proto-oncogene (177, 226). The expression level of subunit e has also been shown to be highly sensitive to diverse physiologic changes and stresses. Although the detailed regulatory roles of subunits F₆ and e and the roles of other supernumerary subunits require further investigation, it seems likely that they will be implicated in a multitude of cellular processes that will result in future use of the ATP synthase as a drug target.

In this review, we have provided detailed information about most natural and synthetic inhibitors of ATP synthases reported to date. Figure 12 summarizes the known or proposed sites of these ATP synthase inhibitors. About 270 inhibitors are described here and need further investigations to identify clearly or confirm their sites of actions and inhibitory mechanisms. When this mammoth task is accomplished, it will further heighten consideration of ATP synthase as a major target for new therapies for human and animal diseases and likely contribute also to the discovery of novel agents that may prove valuable in agriculture and other areas. In addition, the rich source of structures and other knowledge about ATP synthase inhibitors already provided in this review will likely prove invaluable as scaffolds for new drug discoveries in the near future.

FIG. 12. — Inhibitory sites of ATP synthase. The inhibitor binding sites in the ATP synthase as revealed by biochemical/structural studies are indicated by red circles, and the binding subunits in which the binding sites have not been completely clarified are indicated by green circles. The coordinates of each subunit in the structural model are the same as in Fig. 1.

Acknowledgments

P.L.P. is supported for work on ATP synthase by National Institutes of Health grants 5R01 CA10951 and 5P01 HL081427.

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PERMALINK

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Sangjin Hong

Peter L Pedersen

Abstract

INTRODUCTION

FIG. 1.

PEPTIDE INHIBITORS

α-Helical Basic Peptide Inhibitors

TABLE 1.

FIG. 2.

Angiostatin and Enterostatin

Tentoxin and Its Derivatives

TABLE 2.

Leucinostatins and Efrapeptins

TABLE 3.

POLYPHENOLIC PHYTOCHEMICALS, ESTROGENS, AND STRUCTURALLY RELATED COMPOUNDS

FIG. 3.

Stilbenes

TABLE 4.

Flavones and Isoflavones

TABLE 5.

Other Polyphenolic Phytochemicals

TABLE 6.

Steroidal Estradiols and Estrogen Metabolites

TABLE 7.

POLYKETIDE INHIBITORS

FIG. 4.

TABLE 8.

ORGANOTIN COMPOUNDS AND STRUCTURAL RELATIVES

FIG. 5.

TABLE 9.

POLYENIC α-PYRONE DERIVATIVES

FIG. 6.

TABLE 10.

CATIONIC INHIBITORS

Amphiphilic Cationic Dyes

FIG. 7.

TABLE 11.

TALAs and Related Compounds

TABLE 12.

Other Organic Cations

TABLE 13.

SUBSTRATES AND SUBSTRATE ANALOGS

Phosphate Analogs

FIG. 8.

TABLE 14.

Divalent Metal Ions

TABLE 15.

Purine Nucleotides and Nucleotide Analogs

TABLE 16.

TABLE 17.

FIG. 9.

TABLE 18.

AMINO ACID MODIFIERS

Amino Group Modifiers

FIG. 10.

TABLE 19.

Carboxyl Group Modifiers

TABLE 20.

Cys and Tyr Residue Modifiers

TABLE 21.

His Residue Modifiers

TABLE 22.

Others

PHYSICAL INHIBITORY FACTORS

High Hydrostatic Pressure

TABLE 23.

UV Irradiation

Low Temperature

MISCELLANEOUS INHIBITORS

FIG. 11.

TABLE 24.

CONCLUSIONS

FIG. 12.

Acknowledgments

REFERENCES

ACTIONS

PERMALINK

RESOURCES