6nba | pdb_00006nba
Crystal structure of Human Cystathionine gamma lyase with S-3-Carboxpropyl-L-Cysteine
Structural highlights
Disease[CGL_HUMAN] Defects in CTH are the cause of cystathioninuria (CSTNU) [MIM:219500]. It is an autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion.[1] [2] Function[CGL_HUMAN] Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function.[3] [4] [5] Publication Abstract from PubMedHydrogen sulfide (H2S) is a gaseous signaling molecule, which modulates a wide range of mammalian physiological processes. Cystathionine gamma-lyase (CSE) catalyzes H2S synthesis and is a potential target for modulating H2S levels under pathophysiological conditions. CSE is inhibited by propargylglycine (PPG), a widely used mechanism-based inhibitor. In this study, we report that inhibition of H2S synthesis from cysteine but not the canonical cystathionine cleavage reaction catalyzed by CSE in vitro, is sensitive to pre-incubation of the enzyme with PPG. In contrast, the efficacy of S-3-carboxpropyl-L-cysteine (CPC) a new inhibitor described herein, was not dependent on the order of substrate/inhibitor addition. We observed that CPC inhibited the gamma-elimination reaction of cystathionine and H2S synthesis from cysteine by human CSE with Ki values of 50 +/- 3 microM and 180 +/- 15 microM, respectively. We noted that CPC spared the other enzymes involved either directly (cystathionine beta-synthase, mercaptopyruvate sulfurtransferase) or indirectly (cysteine aminotransferase) in H2S biogenesis. CPC also targeted CSE in cultured cells inhibiting transsulfuration flux by 80-90% as monitored by the transfer of radiolabel from [35S]-methionine to glutathione. The 2.5A resolution crystal structure of human CSE in complex with the CPC-derived aminoacrylate intermediate, provided a structural framework for the molecular basis of its inhibitory effect. In summary, our study reveals a previously unknown confounding effect of PPG, widely used to inhibit CSE-dependent H2S synthesis, and reports on an alternative inhibitor, CPC, which could be used as a scaffold to develop more potent H2S biogenesis inhibitors. S-3-Carboxypropyl-L-cysteine specifically inhibits cystathionine gamma-lyase-dependent hydrogen sulfide synthesis.,Yadav PK, Vitvitsky V, Kim H, White A, Cho US, Banerjee R J Biol Chem. 2019 Jun 3. pii: RA119.009047. doi: 10.1074/jbc.RA119.009047. PMID:31160338[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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