Enzymatic mechanisms regulating protein S-nitrosylation: implications in health and disease

Abstract

Nitric oxide participates in cellular signal transduction largely through S-nitrosylation of allosteric and active-site cysteine thiols within proteins, forming S-nitrosoproteins (SNO-proteins). S-nitrosylation of proteins has been demonstrated to affect a broad range of functional parameters including enzymatic activity, subcellular localization, protein–protein interactions, and protein stability. Analogous to other ubiquitous posttranslational modifications that are regulated enzymatically, including phosphorylation and ubiquitinylation, accumulating evidence suggests the existence of enzymatic mechanisms for regulating protein S-nitrosylation. In particular, studies have led to the identification of multiple enzymes (nitrosylases and denitrosylases) that participate in targeted S-nitrosylation or denitrosylation of proteins in physiological settings. Nitrosylases are best characterized in the context of transnitrosylation in which a SNO-protein transfers an NO group to an acceptor protein (Cys-to-Cys transfer), but examples of transnitrosylation catalyzed by metalloproteins (Metal-to-Cys transfer) also exist. By contrast, denitrosylases remove the NO group from SNO-proteins, ultimately using reducing equivalents derived from NADH or NADPH. Here, we focus on the recent discoveries of nitrosylases and denitrosylases and the notion that their aberrant activities may play roles in health and disease.

STAT3 Regulation by S-Nitrosylation: Implication for Inflammatory Disease

“…Growing body of evidence suggests that S-nitrosylation is one of the major signal transduction mechanisms regulating various cellular functions, similar to other post-translational modification. S-nitrosylation-mediated biological regulations under physiological conditions are mediated via low molecular mass RSNOs, such as GSNO (8) and relevant enzyme system and protein carrier, such as GSNO reductase, thioredoxin, thioredoxin reductase, and glyceraldehyde-3-phosphate dehydrogenase (1,16,40,43).…”

“…S-nitrosylation-mediated regulation of cellular mechanisms is an evolving scientific field as during the recent past more than 3000 proteins are reported to be nitrosylated (1,16,43,48). Various protein kinases (10,30,56) and phosphatases (7,20,37) are now known to be regulated by S-nitrosylation mechanism (1,16,43,48) and in case of kinase the activity may be regulated by direct inhibition or activation of its activity or by modulating the accessibility of the substrate to kinase.…”

How widespread is stable protein S-nitrosylation as an end-effector of protein regulation?

“…Strong parallels have been drawn between protein S-nitrosation and other well-established posttranslational modifications, especially phosphorylation [21,22]. Kinases are often co-localised with their substrates, with additional selectivity achieved by consensus motifs in the primary sequence of a target protein that is phosphorylated.…”

Gas biology: small molecular medicine

“…Their delineation of the molecular and cellular basis for these effects is truly elegant physiology. The crosstalk between O 2 sensing and NO signaling is extensive and includes increased expression of inducible NOS (also known as iNOS or NOS2) under hypoxic conditions that is mediated by HIF-1 [4,5] and the regulation of HIF-1 activity by S-nitrosylation of a cysteine residue in the HIF-1α subunit [6].Puneet Anand and Jonathan Stamler (Case Western Reserve University) provide a global view of protein Snitrosylation and its effects on protein function [7]. They describe several different molecular mechanisms by which proteins are nitrosylated and counteracting mechanisms by which they are denitrosylated, which is analogous to the phosphorylation and dephosphorylation of proteins by kinases and phosphatases.…”

“…Puneet Anand and Jonathan Stamler (Case Western Reserve University) provide a global view of protein Snitrosylation and its effects on protein function [7]. They describe several different molecular mechanisms by which proteins are nitrosylated and counteracting mechanisms by which they are denitrosylated, which is analogous to the phosphorylation and dephosphorylation of proteins by kinases and phosphatases.…”