Protein Oxidation in Aging, Disease, and Oxidative Stress

Free radicals and other oxidants have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. The free radicals, both the reactive oxygen species (ROS) and reactive nitrogen species (RNS), are derived from both endogenous sources (mitochondria, peroxisomes, endoplasmic reticulum, phagocytic cells etc.) and exogenous sources (pollution, alcohol, tobacco smoke, heavy metals, transition metals, industrial solvents, pesticides, certain drugs like halothane, paracetamol, and radiation). Free radicals can adversely affect various important classes of biological molecules such as nucleic acids, lipids, and proteins, thereby altering the normal redox status leading to increased oxidative stress. The free radicals induced oxidative stress has been reported to be involved in several diseased conditions such as diabetes mellitus, neurodegenerative disorders (Parkinson’s disease-PD, Alzheimer’s disease-AD and Multiple sclerosis-MS), cardiovascular diseases (atherosclerosis and hypertension), respiratory diseases (asthma), cataract development, rheumatoid arthritis and in various cancers (colorectal, prostate, breast, lung, bladder cancers). This review deals with chemistry, formation and sources, and molecular targets of free radicals and it provides a brief overview on the pathogenesis of various diseased conditions caused by ROS/RNS.

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Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

Oxidative Nucleobase Modifications Leading to Strand Scission

Nitric oxide and superoxide, which are produced by several cell types, rapidly combine to form peroxynitrite. This reaction can result in nitric oxide scavenging, and thus mitigation of the biological effects of superoxide. Also, superoxide can trap and hence modulate the effects of nitric oxide; superoxide dismutase, by controlling superoxide levels, therefore can influence the reaction pathways open to nitric oxide. The production of peroxynitrite, however, causes its own sequelae of events: Although neither .NO nor superoxide is a strong oxidant, peroxynitrite is a potent and versatile oxidant that can attack a wide range of biological targets. The peroxynitrite anion is relatively stable, but its acid, peroxynitrous acid (HOONO), rearranges to form nitrate with a half-life of approximately 1 s at pH 7, 37 degrees C. HOONO exists as a Boltzmann distribution of rotamers; at 5-37 degrees C HOONO has an apparent acidity constant, pKa,app, of 6.8. Oxidation reactions of HOONO can involve two-electron processes (such as an SN2 displacement) or a one-electron transfer (ET) reaction in which the substrate is oxidized by one electron and peroxynitrite is reduced. These oxidation reactions could involve one of two mechanisms. The first mechanism is homolysis of HOONO to give HO. and .NO2, which initially are held together in a solvent cage. This caged pair of radicals (the "geminate" pair) can either diffuse apart, giving free radicals that can perform oxidations, or react together either to form nitrate or to reform HOONO (a process called cage return). A large amount of cage return can explain the small entropy of activation (Arrhenius A-factor) observed for the decomposition of HOONO. A cage mechanism also can explain the residual yield of nitrate that appears to be formed even in the presence of high concentrations of all of the scavengers studied to date, since scavengers capture only free HO. and .NO2 and not caged radicals. If the cage mechanism is correct, the rate of disappearance of peroxynitrite be slower in solvents of higher viscosity, and we do not find this to be the case. The second mechanism is that an activated isomer of peroxynitrous acid, HOONO*, can be formed in a steady state. The HOONO* mechanism can explain the inability of hydroxyl radical scavengers to completely block either nitrate formation or the oxidation of substrates such as methionine, since HOONO* would be less reactive, and therefore more selective, than the hydroxyl radical itself.(ABSTRACT TRUNCATED AT 400 WORDS)

https://www.physiology.org/doi/pdf/10.1152/ajplung.1995.268.5.L699

The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide

Organisms are constantly exposed to various forms of reactive oxygen species (ROS) that lead to oxidation of proteins, nucleic acids, and lipids. Protein oxidation can involve cleavage of the polypeptide chain, modification of amino acid side chains, and conversion of the protein to derivatives that are highly sensitive to proteolytic degradation. Unlike other types of modification (except cysteine oxidation), oxidation of methionine residues to methionine sulfoxide is reversible; thus, cyclic oxidation and reduction of methionine residues leads to consumption of ROS and thereby increases the resistance of proteins to oxidation. The importance of protein oxidation in aging is supported by the observation that levels of oxidized proteins increase with animal age. The age-related accumulation of oxidized proteins may reflect age-related increases in rates of ROS generation, decreases in antioxidant activities, or losses in the capacity to degrade oxidized proteins.

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Protein oxidation and aging

Peroxynitrite is stable, but its acid, HOONO, either rearranges to form nitrate or oxidizes nearby biomolecules. We report here the reactions of HOONO with methionine and the methionine analog 2-keto-4-thiomethylbutanoic acid (KTBA). These oxidations proceed by two competing mechanisms. The first yields the sulfoxide; the second-order rate constants, k2, for this process for methionine and KTBA are 181 +/- 8 and 277 +/- 11 M-1.s-1, respectively, at pH 7.4 and 25 degrees C. In the second mechanism, methionine or KTBA undergoes a one-electron oxidation that ultimately gives ethylene. We propose that the one-electron oxidant is an activated form of peroxynitrous acid, HOONO*, that is formed in a steady state mechanism. The ratios of the second-order rate constants for the ethylene-producing reaction (k*2) and the first-order rate constant to produce nitric acid (kN) for methionine and KTBA, k*2/kN, are 1250 +/- 290 and 6230 +/- 1390 M-1, respectively. Both ceric and peroxydisulfate ions also oxidize KTBA to ethylene, confirming a one-electron transfer mechanism. The yields of neither MetSO nor ethylene are affected by several hydroxyl radical scavengers, suggesting that a unimolecular homolysis of HOONO to HO. and .NO2 is not involved in these reactions. HOONO* gives hydroxyl radical-like products from various substrates but displays more selectivity than does the hydroxyl radical; thus, HOONO* is incompletely trapped by typical HO. scavengers. However, a mechanism involving dissociation of HOONO* to caged radicals cannot be ruled out at this time.

https://www.pnas.org/content/pnas/91/23/11173.full.pdf

One- and two-electron oxidations of methionine by peroxynitrite.

A practical method for preparing peroxynitrite solutions of low ionic strength and free of hydrogen peroxide

Stopped-Flow Kinetic Study of the Reaction of Ascorbic Acid with Peroxynitrite

Peroxynitrite is a versatile and important biological oxidant that is produced from the reaction of nitric oxide and superoxide radicals. Two mechanisms have been proposed to rationalize oxidation ...

Insensitivity of the Rate of Decomposition of Peroxynitrite to Changes in Viscosity; Evidence against Free Radical Formation

Transformation of sulfamethoxazole by sulfidated nanoscale zerovalent iron activated persulfate: Mechanism and risk assessment using environmental metabolomics.

Xia Jin

Papers

One- and two-electron oxidations of methionine by peroxynitrite.

A practical method for preparing peroxynitrite solutions of low ionic strength and free of hydrogen peroxide

Stopped-Flow Kinetic Study of the Reaction of Ascorbic Acid with Peroxynitrite

Insensitivity of the Rate of Decomposition of Peroxynitrite to Changes in Viscosity; Evidence against Free Radical Formation

Transformation of sulfamethoxazole by sulfidated nanoscale zerovalent iron activated persulfate: Mechanism and risk assessment using environmental metabolomics.