Table 1.

Reported Factors Influencing Protein Tyrosine Nitration Regio-Selectivity and Yields

Factor	Elements	Remarks	Examples	Reference
Protein structure
	Loops	Nearby turn-inducing amino acids (Pro, Gly) favor nitration	Y115, Y76 in RNAse A Y20, Y23 in lysozyme	(109)
	Presence of charged amino acids	Usually, the presence of acid or basic amino acids favors nitration with the participation of hydrogen bond bridges.	Y20, Y23 in lysozyme	(15, 109)
	Nearby cysteine residues	Inhibit nitration reactions via tyrosyl radical repair or consumption of nitrogen dioxide	Y25, Y92, and Y97, which are not nitrated in RNAse A	(109)
		Tyrosine nitration can be inhibited due to intramolecular electron transfer reactions between Cys and Tyr residues.	Y35 in Fe-SODB (T. cruzi) Cys-Tyr peptides	(18, 38, 65)
	Nearby methionine residues	Tyrosine nitration can be enhanced due to intramolecular electron transfer reactions.	Met-Tyr peptides	(44)
	Location of tyrosine residues	Nitration in buried tyrosine residues is hindered if they cannot accommodate the nitro group.		(15)
		Exposure of the aromatic ring to the protein surface	Y76 in RNAse A	(109)
	Electrostatic forces	The presence of nearby positively charged amino acids such as arginine may inhibit nitration due to electrostatic forces.	Y20 in lysozyme has an electrostatic interference with R21.	(109)
	Transition metal centers (Fe, Mn, Cu)	Promote peroxynitrite-dependent nitration	Y34 in MnSOD	(64, 80, 89, 119)
			Y430 in prostacyclin synthase	(24)
	Hemeperoxidase-binding sites	Promote hemoperoxidase-dependent nitration	Y18, Y166, and Y192 in apoA1	(34, 99)
			Y115 and RNAse A	(109)
	Heme properties and microenvironment	Some hemes promote peroxynitrite-mediated nitration via intermediate formation of oxidizing oxo-heme(IV) species.	Y430 in prostacyclin synthase Y99, Y347, and Y430 in CytC P450	(24, 123)
		Other hemes inhibit peroxynitrite-depedent nitration via its isomerization to nitrate; thus, nitration of these proteins likely reflects a peroxynitrite-independent mechanism.	Oxyhemoglobin plant leghemoglobin	(67, 96)
	Consensus sequence (lack of)	The existence of a consensus sequence for nitration has not been demonstrated, with the secondary and tertiary structures being the most important factors to determine selectivity rather than a sequence homology.		(15, 109)
Nitration mechanism
	Peroxynitrite dependent	Regio-specific nitration by transition metals	Y34 MnSOD	(64, 80, 89, 119)
		Nitration of solvent-exposed tyrosines in the presence of CO2	Y48, Y74, and Y97 in CitC	(14)
		Promotes nitration of tyrosines that are associated to hydrophobic biostructures	Transmembrane KALP spanning peptides Y294, Y295 in SERCA	(13, 50, 118)
	Hemeperoxidase dependent	Mainly directed toward solvent-exposed residues	Y9, Y11 in MnSOD Y18 in apoA1	(112)
Redox environment
	Endogenous antioxidants	Glutathione inhibits nitration by a combination of mechanisms, with the most relevant being nitrogen dioxide consumption.		(20, 21, 36)
		Ascorbate inhibits nitration by interactions with oxidizing/nitrating intermediates and also by repair of the tyrosyl radical back to tyrosine.		(40, 51)
		Uric acid is a strong inhibitor of nitration by consuming oxidizing/nitrating intermediates and by interfering in the catalytic cycle of heme peroxidases.		(20, 105)
	Lipid peroxidation processes	Fuel nitration reactions in proteins associated to hydrophobic biostructures by promoting the one-electron oxidation of tyrosine		(10, 12, 13)
Physicochemical properties of the milieu
	Hydrophobicity	Limits the diffusion of charged reactive species such as carbonate radicals		(94)
		Excludes hydrophilic anti-nitrating compounds; reactive species such as nitrogen dioxide can concentrate and live longer.		(10, 104)
	pH	pH changes influence peroxynitrite-dependent nitration yields.		(12)
		Acidic conditions favor nitrite-dependent nitration.	Pepsin	(92, 93)