MINIREVIEW PROLOGUE:
Oxidative Modification of Macromolecules Minireview Series*

Martha Vaughan

From the Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

INTRODUCTION
FOOTNOTES


INTRODUCTION

The role in "normal" aging of oxidative damage to cellular components, as well as its part in the morbidity associated with many age-related diseases, has been increasingly recognized and investigated in recent years. Although the concept developed only slowly over several decades, it seems now widely accepted that an important element in normal and premature aging processes, as well as in certain degenerative diseases, is the accumulation of proteins, and DNA and lipids, that have been damaged by oxygen radicals or other reactive oxygen species and no longer function normally. As damaged molecules accumulate, they can contribute to the increasingly inefficient removal of newly generated oxidized products, i.e. a disequilibrium that is self-perpetuated, even autoaccelerated.

These consequences of life in an aerobic environment are counteracted (prevented, repaired, or ameliorated) by numerous biochemical reactions and the enzymes that catalyze them, which have perhaps, to some extent at least, evolved for this purpose. Despite an incomplete understanding of the complex molecular mechanisms that underlie oxidative damage and its reversal or prevention, this appears to be an appropriate time for assessment of the current state of this problem by scientists who have made major contributions, both experimental and conceptual, to its definition and solution.

The series of Minireviews on "Oxidative Modification of Macromolecules" begins in this issue with a contribution from Irwin Fridovich entitled "Superoxide Anion Radical (Obardot 2), Superoxide Dismutases, and Related Matters." Fridovich was the first to show that the superoxide anion radical is a product of numerous enzyme-catalyzed reactions as well as of the "autoxidation" of many drugs and metabolites. He established that superoxide is produced during autoxidation of epinephrine and ferredoxins as well as in reactions catalyzed by xanthine oxidase. Most importantly, he discovered that the injurious effects of the superoxide anion radical are prevented physiologically by the action of a family of superoxide dismutases, which are now recognized as critical components of the antioxidant defense system. Because the subject has become so broad, this Minireview is limited to bringing up to date specific aspects that are of particular interest to the author.

In the second Minireview of the series, entitled "Formation, Prevention, and Repair of DNA Damage by Iron/Hydrogen Peroxide," Ernst S. Henle and Stuart Linn provide an excellent overview and summary of the numerous biochemical reactions that produce reactive oxygen species. Emphasis is on the role of iron-mediated Fenton reactions in DNA damage and its repair. The overall consideration of related cellular reactions involved in removal of oxidizing molecules and restoration or elimination of damaged DNA is valuable also as a basis and background for the other reviews.

The DNA story continues with "Oxidative Decay of DNA" by Kenneth B. Beckman and Bruce N. Ames. The latter author has been an international leader in the field of mutagenesis and genetic toxicology for 25 years. Among his major contributions is the early introduction of methods for measuring oxidative damage, including ways to isolate from urine and quantify products of DNA damage that are excised during repair. Of these, thymine glycol and 8-hydroxy-2-deoxyguanosine are now accepted as a standard measure of oxidative modification of DNA.

"Protein Oxidation in Aging, Disease, and Oxidative Stress" by Barbara S. Berlett and Earl R. Stadtman extends consideration of the subject to the diverse and specialized chemistry as well as the effects of oxidative modification of individual amino acids. Stadtman and his associates over several years have demonstrated site-specific oxidative modifications of susceptible proteins that destroy catalytic or structural function. They have elucidated the chemical mechanisms of many of these amino acid-damaging reactions. They have also established clear relationships between the effects of these reactions in an experimental setting and the properties of damaged proteins accumulated in tissues of aging animals.

In the last Minireview of the series, Daniel Steinberg addresses specifically "Low Density Lipoprotein Oxidation and Its Pathobiological Significance." This is a subject that Steinberg has pursued avidly since the early 1980s. He was among the first to recognize and begin systematically to investigate the biochemistry and pathological significance of oxidatively modified low density lipoprotein (LDL), which is now the subject of widespread interest vis à vis its role in the etiology of atherosclerosis.

Although five Minireviews could not pretend to present a comprehensive summary of the "state of the field" in 1997, it is hoped that the series will convey a sense of the importance, implications, and growing interest in the mechanisms of the oxidative reactions, ways in which they may be prevented or reversed, and failing those alternatives, how the products may be eliminated or repaired. It is notable that although each Minireview is focused on a different topic, one common theme that emerges is the importance of redox cycling of transition metals, especially iron.

Identification and quantification of the products of oxidative modification of DNA, proteins, and lipoproteins will enable investigators to define more precisely the types of damage that are found in aging, atherosclerosis, arthritis, and numerous "degenerative" diseases. Knowledge of the chemistry and enzymology of the processes involved in the generation as well as the amelioration of oxidative damage is a necessary basis for rational preventive or therapeutic interventions.


FOOTNOTES

*   These minireviews will be reprinted in the 1997 Minireview Compendium, which will be available in December, 1997. 

©1997 by The American Society for Biochemistry and Molecular Biology, Inc.




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Copyright © 1997 by the American Society for Biochemistry and Molecular Biology.