TABLE 1.

Peroxynitrite-induced protein modifications

Protein	Target Residue	Physiological Consequence (Proven or Suspected)	Potential Involvement (Proven or Suspected)	Reference Nos.
Signaling proteins
CD95	Tyr	Reduced Fas-dependent apoptosis	Liver protection in inflammation	1072
Fibroblast growth factor (FGF-I)	Tyr Trp Cys	Impaired fibroblast growth	Resolution of inflammation	43
Insulin	Tyr	Reduced receptor binding	Insulin resistance, diabetes	213
Insulin receptor substrate-1	Tyr	Reduced level and inactivation	Insulin resistance, diabetes	949
MEK kinase	Tyr	ERK activation	Modulation of cell signaling	1434
p130 adhesion protein	Tyr	Neural apoptosis	Stroke, NDD	1100
PECAM-1	Tyr	Impaired phosphorylation (Jurkat cells)	Modulation of cell signaling	941
PI3kinase	Tyr	Reduced Akt phosphorylation and enhanced endothelial cell apoptosis	Endothelial dysfunction, diabetes, atherosclerosis	348
PKC-α	Tyr	Activation in endothelial cells	Endothelial dysfunction (?), nitrate tolerance	5, 195
PKC-α/β	Tyr	Inhibition in neural cells	NDD	689
PKC-ε	Tyr	Activation in cardiomyocytes	Ischemic preconditioning	52
Src kinase hck	Cys	Activation of tyrosine phosphorylation	Modulation of cell signaling	840
Src kinase lyn	Tyr	Activation of tyrosine phosphorylation	Modulation of cell signaling	838
Tyrosine phosphatases	Cys	Inactivation of tyrosine dephosphorylation	Modulation of cell signaling	791, 1254
Metabolic enzymes
Alcohol dehydrogenase	Zn-S	Inactivated metabolic pathway, with Zn release in yeast	Immunity (antimicrobial defenses)	245
Aldolase A	Tyr	Reduced glycolytic activity	Impaired cell energetics	695
α1-Antiproteinase	Met	Inactivation of elastase inhibition	Inflammation, Alzheimer’s disease	1199, 1367, 1369
Arylamine N-acetyltransferase	Cys	Reduction of metabolic activation of xenobiotics in cancer cells	Cancer	285
Carnitine-palmitoyltransferase I	Tyr	Impaired energy metabolism	Septic myocardial dysfunction	417
Creatine kinase	Cys Tyr Trp	Impaired energy metabolism in heart, skeletal muscle, and neurons	Aging, MI, CHF, cardiomyopathy, NDD	654, 703, 740, 877, 878, 883, 1358
Cu,Zn-SOD	Tyr Trp His	Reduced superoxide dismutation, enhanced peroxynitrite formation, catalyzed nitration reactions	NDD (mainly amyotrophic lateral sclerosis)	15, 1404
Cytochrome P-450	Tyr	Enzyme inactivation	Impaired drug metabolism	282, 284, 772
eNOS	Zn-S	Endothelial dysfunction	Inflammation, diabetes, atherosclerosis, CHF	1469, 1474
GAPDH	Cys Tyr	Reduced glycolysis, impaired energetics	Cardiovascular and neurological diseases	157, 1192
Glutamine synthetase	Tyr Met	Reduced ammonia elimination by liver Impaired metabolism in bacteria	Sepsis, liver diseases Antimicrobial defense	89, 90, 460
Glutathione-S-transferase	Tyr	Stimulated activity in liver	Improved antioxidant defenses	633
GroEL	Met	Impaired chaperone activity in bacteria	Immunity (antimicrobial defenses)	673
Heme oxygenase	Cys Tyr	Inactivation in rat spleen and brain	Reduced antioxidant defenses	679
Indoleamine dioxygenase	Tyr	Inactivation in human monocytes	Impaired immune processes	415
iNOS	Heme Tyr	Inhibition of NO synthesis and peroxynitrite generation	Inflammation, shock	582, 732, 1078
Isocitrate dehydrogenase	Tyr	Impaired tricarboxylic acid cycle in liver	Liver diseases (alcohol)	738
Lysozyme	Trp	Inhibition of lytic activity (henn egg)		16
MMP-2	Cys	Enzyme activation (heart, brain)	MI, CHF, cardiomyopathy, stroke	495, 971, 1085, 1345
Mn-SOD	Tyr	Impaired superoxide dismutation, enhanced formation of peroxynitrite in mitochondria	NDD, I/R, aging, CHF, graft rejection, diabetes, inflammation	27, 690, 826, 828, 830, 1311, 1397
Phosphogluconate dehydratase	Fe-S	Impaired glycolysis in bacteria	Immunity (antimicrobial defenses)	669
Prostacyclin (PGI2) synthase	Tyr	Inhibition of endothelial PGI2 synthesis	Endothelial dysfunction, diabetes, I/R, CHE, atherosclerosis, nitrate tolerance	39, 290, 549, 1130, 1466, 1472, 1473
Prostaglandin H2 synthase	Tyr	Disturbed vascular PG synthesis	Atherosclerosis	303, 304
Ribonucleotide reductase	Tyr	Inactivation leading to inhibition of DNA synthesis	Cytostasis, antimicrobial defenses, NDD	490, 748
Succinyl CoA:3-oxoacid CoA transferase	Tyr	Altered metabolism of ketone bodies	Diabetes, sepsis (cardiac dysfunction)	844, 1299
Tryptophan hydroxylase	Cys	Impaired serotonin biosynthesis	Cardiovascular diseases, NDD	719
Tyrosine hydroxylase	Cys Tyr	Impaired neuronal dopamine synthesis	Parkinson’s disease	103, 718, 720, 721, 1005
Xanthine oxidase	Mo ctr	Inhibition of superoxide and peroxynitrite generation	Inflammation, shock	735, 736
Mitochondrial respiratory and structural enzymes				1058, 1059, 1062
NADH dehydrogenase (complex I)	Tyr Cys	Impaired cellular energy metabolism	Inflammation, shock, I/R, CHF, diabetes, NDD, aging, graft rejection	146, 919, 1016
Succinate dehydrogenase (complex II)	Tyr Cys	Impaired cellular energy metabolism	Same as above	111, 1092
Cytochrome c reductase (complex III)	Tyr Cys	Impaired cellular energy metabolism	Same as above	489, 1016
ATP synthase (complex V)	Tyr Cys	Impaired cellular energy metabolism	Same as above	177, 1059
Aconitase	Fe-S Tyr	Impaired cellular energy metabolism	Same as above	182, 511
Cytochrome c	Tyr Cys	Impaired energy metabolism, increased oxidative damage to mitochondria	Same as above	178, 627, 828, 1275
Adenine nucleotide translocase (ANT)	Cys Tyr	Opening of the permeability transition pore, apoptosis	Same as above	1326
Nicotinamide nucleotide transhydrogenase	Tyr	Reduced NADPH formation, reduced GSH regeneration	Same as above	403
Ionic pumps
Amiloride-sensitive Na+ channel (ENaC)	Tyr	Impaired Na+ transport in alveolar cells	Lung inflammatory diseases	204, 572
Na+-K+-ATPase	Cys	Cytosolic ionic imbalance	Liver and renal dysfunction, stroke, impaired erythrocyte functions	916–918, 1047, 1320
SERCA2A	Tyr	Reduced myocyte contractility in heart and skeletal muscle	MI, CHF, aging	496, 789, 1397
Voltage-gated K+ channels	Tyr	Functional loss of vasodilator influence in coronary arteries	MI, CHF, cardiomyopathy	754
Structural proteins
Actin	Tyr Cys	Impaired actin polymerization, cytoskeletal disorganization	Endothelial dysfunction, gut barrier failure, impaired immune functions of neutrophils	940
α-Actinin	Tyr	Altered structure of cardiomyocytes	CHF, atrial fibrillation	117, 881
α-Synuclein	Tyr	Aggregate formation in neurons (Lewis body)	Parkinson’s disease	22, 443, 1042, 1191
Desmin	Tyr	Altered structure of cardiomyocytes	CHF, atrial fibrillation	881
Glial fibrillary acidic protein	Tyr	Structural alteration in astrocytes and Schwann cells	NDD, stroke, peripheral nerve I/R	459, 531
Myosin heavy chain	Tyr	Altered structure of cardiomyocytes	CHF, atrial fibrillation	881
Neurofilament L	Tyr	Inhibition of unit assembly in neurons	Amyotrophic lateral sclerosis	247
Profilin	Tyr	Impaired actin polymerization	Platelet dysfunction	658, 659
Synaptic proteins (synaptophysin, Munc-18, SNAP25)	Tyr	Promotion of glutamate release	NDD, stroke	317
Tau protein	Tyr	Tau aggregation in neurons	Alzheimer’s disease	1073, 1074
Tubulin	Tyr Cys	Impaired tubulin polymerization, cytoskeletal disorganization	Gut barrier failure (shock, I/R), NDD, cancer	54, 199, 730, 1269
Nuclear proteins and transcription factors
Histone deacetylase 2	Tyr	Increased inflammatory gene expression in lung cells	Lung inflammatory diseases	62, 617
Histones	Tyr	Nitration of H2B, H3, and H4 in tumors	Cancer	515
P53 tumor suppressor	Tyr	Inhibition of p53 DNA binding	Cancer	222, 223
PPARgamma	Tyr	Inhibition of nuclear translocation	Amplification of inflammation	1157
hOGG1 (8-oxoguanine DNA glycosylase)	Zn-S	Inhibition of base excision repair of 8-oxoguanine	Cancer	626
Plasma (and other fluid) proteins
VLDL	Tyr	Accumulation during hypercholesterolemia	Atherosclerosis	903
Fibrinogen	Tyr	Impaired hemostasis	Coagulation disorders	943, 953
HDL lipoprotein	Tyr	Accumulation in atherosclerotic intima	Atherosclerosis	1019
LDL lipoprotein	Tyr	Induces accumulation of oxidized cholesteryl esters in arterial walls	Atherosclerosis	742, 1287
Plasminogen	Tyr	Reduced fibrinolytic activity	Diabetes, atherosclerosis	488, 952
Surfactant protein A	Tyr	Reduced aggregation of lipids (lung)	Lung inflammation	1315, 1453, 1454

CHF, chronic heart failure; NDD, neurodegenerative disorders; I/R, ischemia/reperfusion; MI, myocardial infarction.