Critical Review Redox Control of Enzymatic Functions: The Electronics of Life’s Circuitry Marcelo G. Bonini 1,2,3,4 * Marcia E. L. Consolaro 4 Peter C. Hart 1,3 Mao Mao 1,2,3 Andre Luelsdorf Pimenta de Abreu 1,2,3,4 Alyssa M. Master 1,2,3 1 Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA 2 Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA 3 Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA 4 Programa de Biociencias Aplicadas a Farmacia (PBF), Universidade Estadual de Maringa, Maringa, Parana, Brazil Abstract The field of redox biology has changed tremendously over the past 20 years. Formerly regarded as bi-products of the aerobic metabolism exclusively involved in tissue damage, reactive oxygen species (ROS) are now recognized as active participants of cell signaling events in health and in disease. In this sense, ROS and the more recently defined reactive nitrogen species (RNS) are, just like hormones and second messengers, acting as fundamental orchestrators of cell sig- naling pathways. The chemical modification of enzymes by ROS and RNS (that result in functional enzymatic alterations) accounts for a considerable fraction of the transient and per- sistent perturbations imposed by variations in oxidant levels. Upregulation of ROS and RNS in response to stress is a com- mon cellular response that foments adaptation to a variety of physiologic alterations (hypoxia, hyperoxia, starvation, and cytokine production). Frequently, these are beneficial and increase the organisms’ resistance against subsequent acute stress (preconditioning). Differently, the sustained ROS/RNS- dependent rerouting of signaling produces irreversible altera- tions in cellular functioning, often leading to pathogenic events. Thus, the duration and reversibility of protein oxida- tions define whether complex organisms remain “electronically” healthy. Among the 20 essential amino acids, four are particularly susceptible to oxidation: cysteine, methio- nine, tyrosine, and tryptophan. Here, we will critically review the mechanisms, implications, and repair systems involved in the redox modifications of these residues in proteins while analyzing well-characterized prototypic examples. Occasion- ally, we will discuss potential consequences of amino acid oxidation and speculate on the biologic necessity for such events in the context of adaptative redox signaling. V C 2014 IUBMB Life, 66(3):167–181, 2014 Keywords: redox; protein function; oxidants; hydrogen peroxide; peroxynitrite; sulfenic acid; thiol; ysteine; redox signaling Introduction Plentiful oxygen in the terrestrial atmosphere has allowed for the evolution of diverse aerobic life forms but has imposed bio- logical oxidations as a consequence of living on Earth. Fortu- nately, the electronic structure of the oxygen molecule limits its reactivity towards most substrates (1) because considerable activation energy is required to produce the reactive singlet state upon which a molecular orbital is vacated to receive an electron pair from diamagnetic substrates (the vast majority) (Fig. 1) (2). The singlet state, therefore, is the one that actually engages in most oxidations. In the mammalian cell, V C 2014 International Union of Biochemistry and Molecular Biology Volume 66, Number 3, March 2014, Pages 167–181 *Address correspondence to: Marcelo G. Bonini, Department of Medicine, University of Illinois at Chicago, UIC, 909 S. Wolcott Avenue, COMRB 1131, Chicago, IL 60612, USA. Tel: 1312–355-5948; Fax: 312-413-2948. E-mail: mbonini@uic.edu Received 19 February 2014; Accepted 6 March 2014 DOI 10.1002/iub.1258 Published online 26 March 2014 in Wiley Online Library (wileyonlinelibrary.com) IUBMB Life 167