Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.1.22 (cystathionine beta-synthase)
 965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrogen sulfide (H2S) has been observed in relatively high concentrations in the mammalian brain and has been shown to act as a neuromodulator. However, there is confusion in the literature regarding the actual source of H2S production. Reactions catalyzed by the cystathionine beta-synthase enzyme (CBS) are one possible source for the production of H2S. Here we show that the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S. The production of H2S by this reaction is at least 50 times more efficient than that produced by hydrolysis of cysteine alone via beta-elimination. Kinetic studies demonstrate that the Km and Kcat for cysteine is 3-fold higher and 2-fold lower, respectively, than that for serine. Consistent with these data, in vitro reconstitution studies show that at physiologically relevant concentrations of serine, homocysteine, and cysteine, about 5% of the cystathionine formed is from cysteine. We also show that AdoMet stimulates this H2S producing reaction but that there is no evidence for stimulation by calcium and calmodulin as reported previously. In summary, these results confirm the ability of CBS to produce H2S, but show in contrast to prior reports that the major mechanism is via beta-replacement and not cysteine hydrolysis. In addition, these studies provide a biochemical explanation for the previously inexplicable homocysteine-lowering effects of N-acetylcysteine treatments in humans.
 ...
PMID:Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine. 1552 12

Modulation of the ambient redox status by mononuclear phagocytes is central to their role in health and disease. However, little is known about the mechanism of redox regulation during mononuclear phagocyte differentiation and activation, critical cellular steps in innate immunity, and microbial clearance. An important intermediate in GSH-based redox metabolism is homocysteine, which can undergo transmethylation via methionine synthase (MS) or transsulfuration via cystathionine beta-synthase (CBS). The transsulfuration pathway generates cysteine, the limiting reagent in GSH biosynthesis. We now demonstrate that expression of CBS and MS are strongly induced during differentiation of human monocytes and are regulated at the transcriptional and posttranscriptional levels, respectively. The changes in enzyme expression are paralleled by an approximately 150% increase in S-adenosylmethionine (accompanied by a corresponding increase in phospholipid methylation) and a similar increase in GSH. Activation with lipopolysachharide or infection with Mycobacterium smegmatis diminished expression of both enzymes to a significant extent and decreased S-adenosylmethionine concentration by approximately 30% of the control value while GSH and cysteine concentrations increased approximately 100 and 300%, respectively. Blockade of the transsulfuration pathway with propargylglycine suppressed clearance of M. smegmatis by macrophages and inhibited phagolysosomal fusion, whereas N-acetylcysteine promoted phagolysosomal fusion and enhanced mycobacterial clearance 3-fold compared with untreated cells. We posit that regulation of the transsulfuration pathway during monocyte differentiation, activation, and infection can boost host defense against invading pathogens and may represent a heretofore unrecognized antimicrobial therapeutic target.
 ...
PMID:Monocyte differentiation, activation, and mycobacterial killing are linked to transsulfuration-dependent redox metabolism. 1704 19

Cystathionine beta-synthase (CBS) deficient homocystinuria is an inherited metabolic defect that if untreated typically results in mental retardation, thromboembolism and a range of connective tissue disturbances. A knockout mouse model has previously been used to investigate pathogenic mechanisms in classical homocystinuria (Watanabe et al., PNAS 92 (1995) 1585-1589). This mouse model exhibits a semi-lethal phenotype and the majority of mice do not survive the early neonatal period. We report here that the birth incidence of cbs (-/-) mice produced from heterozygous crosses is non-Mendelian and not significantly improved by treatment with either the Hcy lowering compound betaine or the cysteine donor N-acetylcysteine. Betaine treatment did improve survival of cbs (-/-) mice and restored fertility to female cbs (-/-) mice but did so without significantly lowering Hcy levels. Surviving cbs (-/-) mice failed to show any alteration in coagulation parameters compared to wild-type controls. Moribund cbs (-/-) mice exhibited severe liver injury and hepatic fibrosis while surviving cbs (-/-) mice although less severely affected, still exhibited a level of severe liver injury that is not found in the human disease. The hepatopathy observed in this model may offer an explanation for the failure of cbs (-/-) mice to respond to betaine or exhibit a hypercoagulative phenotype. We conclude that although this model provides useful data on the biochemical sequelae of classical homocystinuria, it does not successfully recapitulate a number of important features of the human disease and its use for studying mechanisms in homocystinuria should be treated with caution as the hepatopathy produces changes which could influence the results.
 ...
PMID:Cystathionine beta-synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment. 2063 82