Earl R. Stadtman

The demonstration that oxidatively modified forms of proteins accumulate during aging, oxidative stress, and in some pathological conditions has focused attention on physiological and non-physiological mechanisms for the generation of reactive oxygen species (ROS) 1The abbreviations used are: ROS, reactive oxygen species; MeSOX, methionine sulfoxide reductase; PN, peroxynitrite; GS, glutamine synthetase. 1The abbreviations used are: ROS, reactive oxygen species; MeSOX, methionine sulfoxide reductase; PN, peroxynitrite; GS, glutamine synthetase. and on the modification of biological molecules by various kinds of ROS. Basic principles that govern the oxidation of proteins by ROS were established in the pioneering studies of Swallow (1Swallow A.J. Swallow A.J. Radiation Chemistry of Organic Compounds. Pergamon Press, New York1960: 211-224Google Scholar), Garrison (2Garrison W.M. Chem. Rev. 1987; 87: 381-398Crossref Scopus (632) Google Scholar, 3Garrison W.M. Jayko M.E. Bennett W. Radiat. Res. 1962; 16: 487-502Crossref Scopus (83) Google Scholar), and Scheussler and Schilling (4Schuessler H. Schilling K. Int. J. Radiat. Biol. 1984; 45: 267-281Crossref Scopus (199) Google Scholar) who characterized reaction products formed when proteins were exposed conditions of of studies that the modification of proteins by the of the oxidation by the of and ROS oxidation of of and oxidation of the in the has that forms of ROS products and that for and in some of the and in and of of for and in and of of for of the in oxidative of the by of the of The for reaction by of by of and The formed the by of of the in that by by by The and in in the of in in the of when in the generation of the for of the by the by the the the of the the the the of the the by the the the of the the the of the the of the the by the and of the by the by the and of ROS of and by Garrison (2Garrison W.M. Chem. Rev. 1987; 87: 381-398Crossref Scopus (632) Google Scholar), of the of by and in by in formed and the of the the of the on the that the of formed during of proteins the of and Schilling (4Schuessler H. Schilling K. Int. J. Radiat. Biol. 1984; 45: 267-281Crossref Scopus (199) Google Scholar) that oxidation of by studies of K. Res. 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Google Scholar), by the of in the of of the that govern the oxidation and that that the of in the of oxidatively modified has in of the in that of the The demonstration that oxidatively modified forms of proteins accumulate during aging, oxidative stress, and in some pathological conditions has focused attention on physiological and non-physiological mechanisms for the generation of reactive oxygen species (ROS) 1The abbreviations used are: ROS, reactive oxygen species; MeSOX, methionine sulfoxide reductase; PN, peroxynitrite; GS, glutamine synthetase. 1The abbreviations used are: ROS, reactive oxygen species; MeSOX, methionine sulfoxide reductase; PN, peroxynitrite; GS, glutamine synthetase. and on the modification of biological molecules by various kinds of ROS. Basic principles that govern the oxidation of proteins by ROS were established in the pioneering studies of Swallow (1Swallow A.J. Swallow A.J. Radiation Chemistry of Organic Compounds. Pergamon Press, New York1960: 211-224Google Scholar), Garrison (2Garrison W.M. Chem. Rev. 1987; 87: 381-398Crossref Scopus (632) Google Scholar, 3Garrison W.M. Jayko M.E. Bennett W. Radiat. Res. 1962; 16: 487-502Crossref Scopus (83) Google Scholar), and Scheussler and Schilling (4Schuessler H. Schilling K. Int. J. Radiat. Biol. 1984; 45: 267-281Crossref Scopus (199) Google Scholar) who characterized reaction products formed when proteins were exposed conditions of of studies that the modification of proteins by the of the oxidation by the of and ROS oxidation of of and oxidation of the in the has that forms of ROS products and that for and in some of the and in and of of for and in and of of for of the in oxidative of the by of the of The for reaction by of by of and The formed the by of of the in that by by by The and in in the of in in the of when in the in oxidative of the by of the of The for reaction by of by of and The formed the by of of the in that by by by The and in in the of in in the of when in the generation of the for of the by the by the the the of the the the the of the the by the the the of the the the of the the of the the by the and of the by the of ROS of and by Garrison (2Garrison W.M. Chem. Rev. 1987; 87: 381-398Crossref Scopus (632) Google Scholar), of the of by and in by in formed and the of the the of the on the that the of formed during of proteins the of and Schilling (4Schuessler H. Schilling K. Int. J. Radiat. Biol. 1984; 45: 267-281Crossref Scopus (199) Google Scholar) that oxidation of by studies of K. Res. Scopus Google Scholar) that oxidation of the of and of the of in for by the oxidation The generation of the for of the by the by the the the of the the the the of the the by the the the of the the the of the the of the the by the and of the by the of ROS of and by Garrison (2Garrison W.M. Chem. Rev. 1987; 87: 381-398Crossref Scopus (632) Google Scholar), of the of by and in by in formed and the of the the of the on the that the of formed during of proteins the of and Schilling (4Schuessler H. Schilling K. Int. J. Radiat. Biol. 1984; 45: 267-281Crossref Scopus (199) Google Scholar) that oxidation of by studies of K. Res. 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A number of systems that generate oxygen free radicals catalyze the oxidative modification of proteins. Such modifications mark enzymes for degradation by cytosolic neutral alkaline proteases. Protein oxidation contributes to the pool of damaged enzymes, which increases in size during aging and in various pathological states. The age-related increase in amounts of oxidized protein may reflect the age-dependent accumulation of unrepaired DNA damage that, in a random manner, affects the concentrations or activities of numerous factors that govern the rates of protein oxidation and the degradation of oxidized protein.

Basic mechanisms that underlie the oxygen free radical-promoted oxidation of free amino acids and amino acid residues of proteins are derived from radiolysis studies. Results of these studies indicate that the most common pathway for the oxidation of simple aliphatic amino acids involves the hydroxyl radical-mediated abstraction of a hydrogen atom to form a carbon-centered radical at the alpha-position of the amino acid or amino acid residue in the polypeptide chain. Addition of O2 to the carbon-centered radicals leads to formation of peroxy radical derivatives, which upon decomposition lead to production of NH3 and alpha-ketoacids, or to production of NH3, CO2, and aldehydes or carboxylic acids containing one less carbon atom. As the number of carbon atoms in the amino acid is increased, hydrogen abstraction at other positions in the carbon chain becomes more important and leads either to the formation of hydroxy derivatives, or to amino acid cross-linked products as a consequence of carbon-centered radical recombination processes. alpha-Hydrogen abstraction plays a minor role in the oxidation of aromatic amino acids by radiolysis. Instead, the aromatic ring is the primary site of attack leading to hydroxy derivatives, to ring scission, and in the case of tyrosine to the formation of Tyr-Tyr cross-linked dimers. The basic pattern for the oxidation of amino acids by metal ion-catalyzed reactions (Fenton chemistry) is similar to the alpha-hydrogen abstraction pathway. But unlike the case of oxidation by radiolysis, this Fenton pathway is the major mechanism for the oxidation of all aliphatic amino acids, regardless of chain length, as well as for the oxidation of aromatic amino acids. Curiously, the Fe(III)-catalyzed oxidation of free amino acids is almost completely dependent upon the presence of bicarbonate ion, and is greatly stimulated by iron chelators at chelator/Fe(III) ratios less than 1.0, and is inhibited at chelator/Fe(III) ratios greater than 1.0. It is deduced that the most active catalytic complex is composed of two equivalents of HCO3-, an amino acid, and at least one equivalent of iron; however, two forms of iron, an iron-chelate and another form, must somehow be involved. In contrast to the situation with radiolysis, the aromatic rings of aromatic amino acids are only minor targets for metal-catalyzed reactions. All amino acid residues in proteins are subject to attack by hydroxyl radicals generated by ionizing radiation; however, the aromatic amino acids and sulfur-containing amino acids are most sensitive to oxidation.(ABSTRACT TRUNCATED AT 400 WORDS)