3MST produces redox regulators Cys-SSH and GSSH as well as signaling molecules H2S and H2Sn

3-Mercaptopyruvate sulfurtransferase (3MST) together with cysteine aminotransferase (CAT) produces hydrogen sulfide (H2S), a well-known toxic gas, from L-cysteine. 3MST also produces H2S from D-cysteine in concert with D-amino acid oxidase (DAO). Cystathionine β–synthase (CBS) and cystathionine γ–lyase (CSE) are also known as H2S producing enzymes. H2S has physiological roles such as the formation of memory, regulation of blood pressure, protection of tissues/organs from various insults including oxidative stress and ischemia, anti-inflammation activity and energy formation.

Fig. 1. Production of H2S, H2Sn, cysteine- and glutathione-persulfide by 3MST, and their mode of activation of target proteins.

3MST also produces hydrogen polyfulfides (H2Sn) which have higher number of (sulfane) sulfur atoms than H2S. H2Sn regulate ion channels, a tumor suppressor, protein kinases involving in the regulation of blood pressure, and transcription factors to up-regulate antioxidant genes. H2Sn can also be produced by the chemical interaction of H2S with nitric oxide (NO) that provides a mechanism of a synergy between H2S and NO.

Cysteine-persulfide (Cys-SSH) is a cysteine whose sulfhydryl group is covalently bound to sulfur (sulfane sulfur). Cys-SSH and its glutathione (GSH) counterpart (GSSH) have been recognized as cellular redox regulators, some of which were previously ascribed to cysteine and GSH. However, the production of Cys-SSH and GSSH is not well understood. In the present study we demonstrated that 3MST produces Cys-SSH, GSSH, and persulfurated proteins (Pro-SSH). It is concluded by the following observations. 1) 3MST produced Cys-SSH and GSSH as well as H2Sn in vitro. 2) Cells expressing 3MST produced persulfurated species greater than a control, while those expressing 3MST defective mutants did not. 3) The administration of L- or D-cysteine to mice increased the levels of persulfurated species in tissues. 4) The levels of persulfurated species in the brains of 3MST knockout mice were less than half of those in the wild-type mouse brains. Although 3MST can also produce polysulfide species such as Cys-SSnH (n > 2) and GSSnH in vitro, persulfurated species are predominantly produced under physiological conditions.

We proposed two potential mechanisms for the production of the persulfurated species: 3MST produces H2Sn which react with cysteine, GSH and protein to produce Cys-SSH, GSSH and Pro-SSH. Alternatively, 3MST directly transfers sulfur to cysteine, GSH and protein without the mediation of H2Sn.

The mode of action of H2Sn is mediated by S-sulfuration (sulfhydration) of the cysteine residues of target proteins that causes the conformational changes, leading to the alternation of activity. Two cysteine residues are involved in the activation of some target proteins by H2Sn: an S-sulfurated cysteine residue by H2Sn may react with a thiol of another cysteine residue to form disulfide bond. Transient receptor potential ankyrin 1 (TRPA1) channels has two cysteine residues responsible for the activation by H2Sn. The same is true for the regulation of a tumor suppressor, phosphatase and tensin homolog (PTEN). An inactive monomer of protein kinase G1a (PKG1a) turns to the active dimer formed through S-sulfuration. Some other proteins such as ATP-dependent K+ (KATP) channels have one cysteine residue responsible for their activation through S-sulfuration.

H2S can modify the activity of target proteins by reducing their cysteine disulfide bond as well as by S-sulfurating cysteine sulfinic acid (Cys-SOH) produced under oxidative stress or S-nitrosylated cysteine (Cys-SNO) generated by NO signaling. S-sulfuration may also play roles even under pathological conditions. For example, cysteine residues of parkin whose disruption is the most common cause of inherited Parkinson’s disease (PD) are S-nitosylated in the brain of PD patients, while those of healthy individuals are S-sulfurated. H2S may be involved in S-sulfuration of Cys-SNO to Cys-SSH.

Hideo Kimura
National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan

Publication

3-Mercaptopyruvate sulfurtransferase produces potential redox regulators cysteine- and glutathione-persulfide (Cys-SSH and GSSH) together with signaling molecules H2S2, H2S3 and H2S.
Kimura Y, Koike S, Shibuya N, Lefer D, Ogasawara Y, Kimura H
Sci Rep. 2017 Sep 5

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