H2S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia

Although there is a growing recognition of the significance of hydrogen sulfide (H2S) as a biological signaling molecule involved in vascular and nervous system functions, its biogenesis and regulation are poorly understood. It is widely assumed that desulfhydration of cysteine is the major source of H2S in mammals and is catalyzed by the transsulfuration pathway enzymes, cystathionine beta-synthase and cystathionine gamma-lyase (CSE). In this study, we demonstrate that the profligacy of human CSE results in a variety of reactions that generate H2S from cysteine and homocysteine. The gamma-replacement reaction, which condenses two molecules of homocysteine, yields H2S and a novel biomarker, homolanthionine, which has been reported in urine of homocystinuric patients, whereas a beta-replacement reaction, which condenses two molecules of cysteine, generates lanthionine. Kinetic simulations at physiologically relevant concentrations of cysteine and homocysteine, reveal that the alpha,beta-elimination of cysteine accounts for similar to 70% of H2S generation. However, the relative importance of homocysteine-derived H2S increases progressively with the grade of hyperhomocysteinemia, and under conditions of severely elevated homocysteine (200 mu M), the alpha,beta-elimination and gamma-replacement reactions of homocysteine together are predicted to account for similar to 90% of H2S generation by CSE. Excessive H2S production in hyperhomocysteinemia may contribute to the associated cardiovascular pathology.