Signalling by hydrogen sulfide and polysulfides via protein S‐sulfuration

Abstract

Hydrogen sulfide (H2S) is a signalling molecule that regulates neuronal transmission, vascular tone, cytoprotection, inflammatory responses, angiogenesis, and oxygen sensing. Some of these functions have recently been ascribed to its oxidized form polysulfides (H2Sn), which can be produced by 3‐mercaptopyruvate sulfurtransferase (MPST), also known as a H2S‐producing enzyme. H2Sn activate ion channels, tumour suppressors, transcription factors, and protein kinases. H2Sn S‐sulfurate (S‐sulfhydrate) cysteine residues of these target proteins to modify their activity by inducing conformational changes through the formation of a disulfide bridge between the two cysteine residues involved. The chemical interaction between H2S and NO also generates H2Sn, which may be a chemical entity that exerts the synergistic effect of H2S and NO. MPST also produces redox regulators cysteine persulfide (CysSSH), GSH persulfide (GSSH), and persulfurated proteins. In addition to MPST, haemoproteins such as haemoglobin, myoglobin, neuroglobin, and catalase as well as SOD can produce H2Sn, and sulfide quinone oxidoreductase and cysteinyl tRNA synthetase can make GSSH and CysSSH. This review focuses on the recent progress in the study of the production and physiological roles of these persulfurated and polysulfurated molecules. Linked Articles This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

Hydrogen sulfide signaling in the central nervous system -Comparison with nitric oxide-

“…H 2 S induces Ca 2+ influx in astrocytes by activating transient receptor potential ankyrin 1 (TRPA1) channels, and we later found hydrogen polysulfide (H 2 S n , n > 2) more effectively activate the channels than H 2 S does (Nagai et al, 2004;Nagai et al, 2006;Oosumi et al, 2010;Kimura et al, 2013). H 2 S 2 and H 2 S 3 were identified in the brain, and MPST produces H 2 S n , and other persulfurated molecules such as cysteine persulfide, glutathione persulfide, and persulfurated proteins (Kimura et al, 2015;Kimura et al, 2017;Koike et al, 2017;Nagahara et al, 2018a;Nagahara et al, 2018b; see also Kimura, 2020).…”

“…Synergistic effect of H 2 S with NO on vascular relaxation led to the identification of two mechanisms (Hosoki et al, 1997). One is that the chemical interaction between H 2 S and NO produces H 2 S n , nitosothiol, thionitrous acid (HSNO), and nitrosopersulfide (HSSNO) that have the relaxation effect greater than each parental molecule (Nagai et al, 2006;Whiteman et al, 2006;Oosumi et al, 2010;Filipovic et al, 2012;Ebenhardt et al, 2014;Stubbert et al, 2014;Cortese-Krott et al, 2015;Moustafa and Habara, 2016;Miyamoto et al, 2017; See also Kimura, 2020). Another mechanism is that H 2 S and NO mutually regulate their synthesizing enzymes (Zhao et al, 2001;Minamishima et al, 2009;Kondo et al, 2013;King et al, 2014;Kimura, 2016).…”

“…A similar mechanism was reported for the regulation of PTEN in which one cysteine residue is S-sulfurated by H 2 S n then reacts with another non-S-sulfurated one to produce a cysteine disulfide bond, leading to the conformational change (Greiner et al, 2013). Protein kinase G1α is inactive at its monomer, while it is activated by forming dimer which is generated by S-sulfuration of one cysteine residue of a monomer that reacts with a counterpart cysteine residue of another monomer to produce cysteine disulfide bridge between the two (Stubbert et al, 2014;Kimura, 2020).…”

Hydrogen sulfide signalling in the CNS ‐ Comparison with NO

“…In this case, however, S-sulfuration of the two specific cysteine residues by sulfur transferases, if any, may not have any advantage on specificity to activate the channels compared to the diffusion of H 2 S n . S-sulfuration is compared to phosphorylation, in which kinases incorporate phosphate to residues of serine, threonine and tyrosine (Kimura, 2020). H 2 S and H 2 S n are able to S-sulfurate cysteine residues of proteins even in cells surrounding the producing cells but do not S-sulfurate the specific residues.…”

A Red Fluorescent Protein-Based Probe for Detection of Intracellular Reactive Sulfane Sulfur

“…Therefore, they are usually referred to as reactive sulfane sulfur, which actually functions in biological systems. In contrast, RS n R is relatively inert at physiological pH, which may work as a reservoir of cellular sulfane sulfur [ 9 , 10 , 11 , 12 ].…”