Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers

Abstract

. Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am J Physiol Cell Physiol 287: C246 -C256, 2004; 10.1152/ ajpcell.00516.2003.-Except for the role of NO in the activation of guanylate cyclase, which is well established, the involvement of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in signal transduction remains controversial, despite a large body of evidence suggestive of their participation in a variety of signaling pathways. Several problems have limited their acceptance as signaling molecules, with the major one being the difficulty in identifying the specific targets for each pathway and the chemical reactions supporting reversible oxidation of these signaling components, consistent with a second messenger role for ROS and RNS. Nevertheless, it has become clear that cysteine residues in the thiolate (i.e., ionized) form that are found in some proteins can be specific targets for reaction with H 2O2 and RNS. This review focuses on the chemistry of the reversible oxidation of those thiolates, with a particular emphasis on the critical thiolate found in protein tyrosine phosphatases as an example. hydrogen peroxide; thiolate; nitrosothiol; nitric oxide; signal transduction ALTHOUGH THE INVOLVEMENT OF FREE RADICALS in biology was assumed for many years to be restricted to damaging reactions, the discovery of the endogenous generation of NO in mammalian systems and the finding that this small, freely diffusing, chemically unique species participates in specific signal transduction pathways represented an important new paradigm and expanded views of the possible nature of cell communication and/or signaling processes. This novel role in signal transduction for ⅐NO and other reactive nitrogen species (RNS) now extends to reactive oxygen species (ROS) such as H 2 O 2 and is gaining greater acceptance. The skepticism that still exists about these molecules acting as second messengers in various signaling pathways may vanish with better understanding of their chemistry, particularly regarding the differences in reactivity at high concentrations (mainly associated with pathology and toxicology) from those at low concentrations generated under physiological conditions in response to stimuli. Several excellent reviews have been published regarding evidence supporting a role for ROS and RNS in signaling (26,32,75,82,87,117,119), and we (35, 36) previously described the general properties that define a second messenger and showed how ROS and RNS fit into this role. In this review, the main focus is on the chemistry that may provide specificity, a necessary property of second messengers that has remained the most elusive in the study of ROS and RNS. REACTIVE SPECIES AS SECOND MESSENGERSSecond messengers are generated at the time of receptor activation, are short-lived, and act specifically on effectors to transiently alter their activity. Indeed, ROS and RNS can be generated at the time of receptor activation and are short-lived, as a...

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…In addition, methionine, tryptophan, and tyrosine residues are also prone to oxidative modification, although the functional impact of those events in physiological signal transduction remains to be established. Regulation of cell signaling via the cysteine group is best established [30,31], and will therefore be the focus of further discussion. Numerous classes of proteins contain free cysteine residues that are highly conserved across species, suggesting regulatory possibilities, beyond structural roles and metal ion coordination.…”

“…Protein thiols found in consensus motifs wherein the Cys is adjacent to basic and acid residues or aromatic residues often serve as sites of nitrosylation [1]. In addition, transition metals may catalyze S-nitrosylation [1,31].…”

“…Forman and colleagues [31] and Tannenbaum [46] emphasize that S-nitrosylation may involve nitrosative chemistry (nitrosation refers to chemical addition of NO + ), but is not restricted to reactions of NO + . The term nitrosyl, which is mechanism neutral, aptly describes attachment of the NO moiety to a nucleophilic group or transition metal.…”

“…S-nitrosylation is therefore preferred terminology in biological systems where chemical mechanism is rarely known. Needless to say, "-ylation" [31] is standard biochemical nomenclature for posttranslational modifications of proteins. Notably, searches of Pubmed with "S-nitrosation" as the key term yielded a small number of hits, whereas almost 100 papers on "S-nitrosylation"--covering major advances in the field-have been published this year alone.…”

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

“…act as second messengers (1)(2)(3); however, with increased understanding of the chemistry of signaling by reactive species, we will now append the description to include the likelihood that, despite the possibility of non-enzymatic reactions that can be demonstrated in vitro, most ROS and RNS modifications of signaling proteins must be enzyme catalyzed to account for what is observable in the biological context. Nonetheless, there may be some non-enzymatic reactions that occur rapidly enough to account for the biological reaction.…”