Homocysteinylation and Sulfhydration in Diseases

Abstract

Homocysteine (Hcy) is an important intermediate in methionine metabolism and generation of one-carbon units, and its dysfunction is associated with many pathological states. Although Hcy is a non-protein amino acid, many studies have demonstrated protein-related homocysteine metabolism and possible mechanisms underlying homocysteinylation. Homocysteinylated proteins lose their original biological function and have a negative effect on the various disease phenotypes. Hydrogen sulfide (H₂S) has been recognized as an important gaseous signaling molecule with mounting physiological properties. H₂S modifies small molecules and proteins via sulfhydration, which is supposed to be essential in the regulation of biological functions and signal transduction in human health and disorders. This review briefly introduces Hcy and H₂S, further discusses pathophysiological consequences of homocysteine modification and sulfhydryl modification, and ultimately makes a prediction that H₂S might exert a protective effect on the toxicity of homocysteinylation of target protein via sulfhydration. The highlighted information here yields new insights into the role of protein modification by Hcy and H₂S in diseases.

Keywords: Homocysteine; diseases; homocysteinylation; hydrogen sulfide; protein modification; sulfhydration.

Fig. (1)

Pathways of Hcy Metabolism. ① the generative pathway of homocysteine; ‚ the remethylation pathway; ƒ the transsulfuration pathway; „ the homocysteine-thiolactone pathway; … the reversible pathway of homocysteine generation. Abbreviations: Hcy, homocysteine; Met, methionine; AdoMet, adenosylmethionine; AdoHcy, adenosylhomocysteine; Cys, cysteine; HTL, homocysteine thiolactone; N-Hcy-protein, N-homocysteined protein; S-Hcy-protein, S-homocysteined protein; MS, Met synthase; MAT, Met S-adenosyltransferase; CBS, cystathionine β-synthase; CSE, cystathionine γ–lyase; MetRS, methionyl-tRNA synthetase; PON1, paraoxonase 1; SAHH, S-adenosylhomocysteine hydrolase; VB₆, vitamin B₆; VB_12, vitamin B₁₂.

Fig. (2)

Pathways of protein homocysteinylation. Abbreviations: Hcy, homocysteine; MetRS, methionyl-tRNA synthetase; HTL, homocysteine thiolactone.

Fig. (3)

Pathways of H₂S production. Abbreviations: Hcy, homocysteine; Cys, cysteine; SQR, sulfide: quinone oxidoreductase; 3-MP, 3-mercaptopytuvate; CBS, cystathionine β-synthase; D-AAO, D-amino acid oxidase; 3-MST, 3-mercaptopyruvate sulfurtransferase; CAT, cysteine aminotransferase; CSE, cystathionine γ–lyase; VB₆, vitamin B₆.

Fig. (4)

Effects of H₂S or sulfhydration on diseases. H₂S exerts protective effects on vasorelaxation, myocardial injury, redox homeostasis, endothelial injury, and fibrin lysis.