S-sulfuration by H2S and H2Sn and by MPST
Mustafa et al. (2009) have demonstated that S-sulfuration of cysteine residues of target proteins as a mode of action of H2S. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is activated through S-sulfuration by H2S (Mustafa et al., 2009). It was later reported that the activity of GAPDH is suppressed by S-sulfuration by H2Sn rather than H2S (Jarosz et al., 2015). S-sulfuration depends on the redox condition of the target cysteine residues; H2S S-sulfurates oxidized cysteine like Cys-SOH or Cys-SNO, while H2Sn S-sulfurate cysteine (Cys-SH) (Fig. 1) (Mishanina et al., 2015). It is possible that the former preparation of GAPDH (Mustafa et al., 2009) might be oxidized of which the activity may be suppressed, then H2S S-sulfurated to activate it. In contrast, the latter preparation (Jarosz et al., 2015) might be under reducing conditions and GAPDH was active, and H2Sn S-sulfurated it to suppress its activity.
H2Sn activate TRPA1channels which have two sensitive cysteine residues at the amino terminus, suggesting that the two residues are S-sulfurated or one of them is S-sulfurate to react with the other to make cysteine disulfide bridge (Nagai et al., 2004; Nagai et al., 2006; Streng et al., 2008; Oosumi et al., 2010; Kimura et al., 2013; Hatakeyama et al., 2015; Kimura, 2015a). A similar mechanism was reported for the regulation of PTEN in which one cysteine residue is S-sulfurated by H2Sn 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).
MPST produces H2S and H2Sn as well as other persulfurated molecules (Fig. 2) (Kimura et al., 2015; Kimura et al., 2017). The endogenous levels of H2S and H2S2 in the brain are 0.030 +0.004 µmol/gram protein (approximately 3.0 µM) and 0.026 + 0.002 µmol/gram protein (2.6 µM), respectively (Koike et al., 2017). Because H2S2 and H2S3 efficiently S-sulfurate cysteine and glutathione to produce cysteine persulfide and glutathione persulfide (Kimura et al., 2017), once H2Sn are produced, cysteine and glutathione exist nearby can immediately be S-sulfurated. Since no enzyme has been identified to mediate the reaction of H2S with heme containing proteins such as haemoglobin, neuroglobin and catalase as well as SQR and cupper/zinc super oxide dismutase (SOD) (Vitvitsky et al, 2015; Ruetz et al., 2017; Olson et al., 2017; Searcy et al., 1995; Searcy, 1996; Olson et al., 2018), H2S must reach these targets by diffusion.
MPST transfers sulfur from 3MP to cysteine as observed in the following. 1) MPST can produces H2S, H2Sn, cysteine persulfide and glutathione persulfide by transferring sulfur to cysteine (Kimura et al., 2015; Kimura et al., 2017). 2) The levels of persulfurated molecules, which were measured as H2S released in the presence of a reducing agent dithiothreitol (DTT) called as bound (sulfane) sulfur (Warenycia et al., 1990; Ogasawara et al., 1993; Ogasawara et al., 1994; Ishigami et al., 2009; Kimura, 2015a), were greater in cells expressing MPST compared to a control (Shibuya et al., 2009). 3) Administration of a substrate cysteine to mice increased the amounts of bound sulfur in tissues expressing MPST, while there was no change in those administered saline (Shibuya et al., 2013). 4) The levels of bound sulfur were less than half in the brains of MPST knockout mice than those in the wild type mice (Kimura et al., 2017). S-sulfuration by MPST is specific but restricted inside cells, while that by diffusion extends the signaling to nearby cells.