Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine

Abstract

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 ([Formula: see text]), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals andNO 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.

A stress-induced Tyrosine tRNA depletion response mediates codon-based translational repression and growth suppression

“…Aberrantly generated tRFs derived from pre-tRNA introns have been linked with human neuronal degeneration (Karaca et al, 2014;Schaffer et al, 2014). Furthermore, by reacting with nucleic acids, proteins, and lipids, reactive oxygen species can cause global cellular dysfunction (Cross et al, 1987;Radi, 2018). Consistent with this, oxidative stress has been implicated or associated with a myriad of human diseases including Parkinson's, ALS, Alzheimer's, cardiovascular disease, and cancer pathogenesis (Cervantes Gracia et al, 2017;Lin and Beal, 2006;Piskounova et al, 2015).…”

Reactive oxygen, nitrogen, and sulfur species in human male fertility. A crossroad of cellular signaling and pathology

“…Such nonclassical signaling is based on reaction of ˙NO with its most common intracellular targets O 2 or O 2 •− and the formation of RNS (nitrogen dioxide, ˙NO 2 ; peroxynitrite, ONOO − ; nitroxyl, HNO; dinitrogen trioxide, N 2 O 3 ; and dinitrogen tetroxide, N 2 O 4 ). These RNS are more reactive than the ˙NO itself and have potential to modify cysteine and tyrosine residues in target proteins . S‐nitrosylation and S‐glutathionylation are reversible processes, the equilibrium of which can be shifted by activities of reductases, that is, thioredoxin and S‐nitrosoglutathione reductase .…”

“…These RNS are more reactive than the˙NO itself and have potential to modify cysteine and tyrosine residues in target proteins. 74,75 S-nitrosylation and S-glutathionylation are reversible processes, the equilibrium of which can be shifted by activities of reductases, that is, thioredoxin and S-nitrosoglutathione reductase. 76,77 Tyrosine nitration, which is mainly mediated by ONOO − , is mostly irreversible modification that are generally responsible for cytotoxic effects oḟ NO because it potentially causes alteration, loss, or gain of important protein functions.…”

Pinpointing of cysteine oxidation sites in vivo by high-resolution proteomics reveals mechanism of redox-dependent inhibition of STING

“…ROS act as second messengers in cellular signaling through reversible oxidative posttranslational modifications of cysteine residues (Cys ox-PTMs) that allow modulation of protein structure, interaction with protein partners and ligand, localization and activity (7)(8)(9). Reversible Cys ox-PTMs consist of a variety of modifications, the most widely studied being S-sulfenylation (Cys-SOH), S-glutathionylation (Cys-SSG) and disulfide (S-S) (7).…”