Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine
Significance Aerobic life in humans imposes the hazard of excess oxidation in cell and tissue components that may compromise cell function and viability. The formation and accumulation of oxidized products in biomolecules such as proteins and lipids are observed in various pathologies and during the normal aging process. This review article aims to integrate some early and remarkable discoveries in the field, with more recent developments that helped to define a causative role of oxygen radicals, nitric oxide, and peroxynitrite in human physiology and pathology. These aspects of human redox biochemistry contribute to the understanding of the molecular basis of diseases and aging and open avenues for the development of preventive and therapeutic strategies in molecular medicine. Oxygen derived free radicals and related oxidants are ubiquitous and short lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox sensitive cell signaling cascades. On the other hand, nitric oxide *NO) a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of *NO are modulated by its fast reaction with superoxide radical (O2* which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and *NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of *NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens.
Proceedings of the National Academy of Sciences