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.