Fig. 1.

Pathways of H₂S generation in mammalian cells. Cystathionine-β-synthase (CBS; EC 4.2.1.22), cystathionine-γ-lyase (CSE; 4.4.1.1), and 3-mercaptopyruvate sulfurtransferase (3-MST; EC.2.8.1.2) are the three principal enzymes that contribute to the endogenous production of H₂S. CBS and CSE are components of the reverse transsulfuration pathway, a biochemical pathway responsible for the conversion of methionine to cysteine, and catalyze a multitude of reactions that yield H₂S, including the conversion of l-homocysteine to l-homolanthionine (by CSE), the conversion of l-homocysteine and l-cysteine to l-cystathionine (by CBS and CSE), the conversion of l-cystathionine to l-cysteine (by CSE), the conversion of l-cysteine to pyruvate and ammonia (by CSE), and the conversion of l-cysteine to l-serine and l-lanthinonine (by CBS). An additional pathway involves the CSE-dependent conversion of cystine to l-thiocystenine, which, in turn, produces H₂S via thiol-dependent reactions. The third H₂S-producing enzyme, 3-MST, is part of the cysteine catabolism pathway and uses 3-mercaptopyruvate (3-MP) as a substrate. 3-MST works in tandem with aspartate aminotransferase that also possesses cysteine aminotransferase activity (CAT) activity, generating 3-MP from cysteine via a series of reductions that first involve the generation of bound sulfane sulfur. 3-MP, in addition to acting as a substrate of 3-MST, can also produce H₂S spontaneously. In some cells and tissues, d-cysteine can also be a significant substrate for H₂S production; it is converted to 3-MP by d-amino acid oxidase (DAO). Pyridoxal 5′-phosphate (PLP) is a cofactor for CSE, CBS, and CAT.