The molecules containing reducing thiol such as glutathione, cysteine, and redox-responsiveness protein in the living organism functions as the anti-oxidant or oxidative responsive molecules. These molecules are recognized as the most important group of molecules that contribute to maintaining redox homeostasis in the living organism. Persulfides and polysufides (Fig.1), which contain sulfane sulfurs, are attracting much attention in maintaining cellular redox homeostasis.


Fig.1 Chemical species containing sulfane sulfurs

Hydrogen sulfide (H2S), which is known as a highly toxic gas, is the third most gaseous signal molecule besides nitric oxide (NO), and carbon oxide (CO). It is reported that H2SS implicates physiological effects on vasolidation, cytoprotection, insulin secretion, and neurotransmission. Under physiological conditions, approximately 20% of H2SS is undissociated and 80% is dissociated to hydrosulfide ions (peak of 7.0). Hydrogen sulfide is present in the living organism at low levels. The sulfide ion appears to be sensitive to alternations in the redox state (Fig. 2). The molecular mechanisms dictating how H2SS affects cellular signaling and other physiological events remain insufficiently understood1).

Fig.2 Function of hydrogen sulfide in vivo

According to a recent research, polysulfides are generated from H2S in the brain, stimulating signal transduction in the brain (Fig. 3)2). The recent research shows that sodium tetrasulfide (Na2S4) exerts a cellular protection effect against oxidative stress through Keap1/Nrf2 signaling (Fig. 4)3).

Fig.3 Neural transmission by polysulfide
Fig. 4 Cytoprotection by polysulfide

Cysteine persulfide is synthesized from cysteine through two enzymes, cystathionine ?-lyase (CSE), and cystathionine ß-synthase (CBS).It is reported that the high concentration of the cysteine persulfide, and glutathione persulfide are present in the living organism (Fig. 5)4).

Fig.5 Biosynthesis of cysteine persulfide

Persulfide, which contains divalent sulfur atoms bonded to other sulfur atom called sulfane sulfur, plays a different role from hydrogen sulfide. Protein thiols are molecules that act on hydrogen sulfide or per (poly) sulfide. It is necessary to have detailed elucidation of protein thiol to recognize the biological role of the compounds with sulfane sulfur or hydrogen sulfide.

Fig.6 Modification profiles of thiol residues in a protein

References

1) H. Kimura Editor, “Hydrogen Sulfide and its Therapeutic Applications”

2) Y. Kimura, Y. Mikami, K. Osumi, M. Tsugane, J-I. Oka and H. Kimura, “Polysulfides are possible H2S-derived signaling molecules in rat brain”, FASEB. J., 2013, 27, 2451

3) S. Koike, Y. Ogasawara, N. Shibuya, H. Kimura, and K. Ishii, “Polysulfide exerts a protective effect against cytotoxicity caused by t-butylhydroperoxide through Nrf2 signaling in neuroblastoma cells”, FEBS Lett., 2013, 3548

4) T. Ida, T. Sawa, H. Ihara. Y. Tsuchiya, Y. Watanabe, Y. Kumagai, M. Suematsu, H. Motohashi, S. Fujii, T. Matsunaga, M. Yamamoto, K. Ono, N. O. Devarie-Baez, M. Xian, J. M Fukuto, and T. Akaike, “Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling”, Proc Natl Acad Sci U S A.2014, 111, 7606

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