6NBA

Crystal structure of Human Cystathionine gamma lyase with S-3-Carboxpropyl-L-Cysteine

Summary for 6NBA

• Entry DOI: 10.2210/pdb6nba/pdb
• Descriptor: Cystathionine gamma-lyase, 2-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]ACRYLIC ACID (3 entities in total)
• Functional Keywords: lyase, complex
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 178267.24

Authors

Kim, H.,Yadav, P.K.,Banerjee, R.,Cho, U.-S. (deposition date: 2018-12-06, release date: 2019-06-12, Last modification date: 2023-10-11)

Primary citation

Yadav, P.K.,Vitvitsky, V.,Kim, H.,White, A.,Cho, U.S.,Banerjee, R.
S-3-Carboxypropyl-l-cysteine specifically inhibits cystathionine gamma-lyase-dependent hydrogen sulfide synthesis.
J.Biol.Chem., 294:11011-11022, 2019

PubMed Abstract: Hydrogen sulfide (HS) is a gaseous signaling molecule, which modulates a wide range of mammalian physiological processes. Cystathionine γ-lyase (CSE) catalyzes HS synthesis and is a potential target for modulating HS levels under pathophysiological conditions. CSE is inhibited by propargylglycine (PPG), a widely used mechanism-based inhibitor. In this study, we report that inhibition of HS synthesis from cysteine, but not the canonical cystathionine cleavage reaction catalyzed by CSE , is sensitive to preincubation of the enzyme with PPG. In contrast, the efficacy of -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 γ-elimination reaction of cystathionine and HS synthesis from cysteine by human CSE with values of 50 ± 3 and 180 ± 15 μm, respectively. We noted that CPC spared the other enzymes involved either directly (cystathionine β-synthase and mercaptopyruvate sulfurtransferase) or indirectly (cysteine aminotransferase) in HS biogenesis. CPC also targeted CSE in cultured cells, inhibiting transsulfuration flux by 80-90%, as monitored by the transfer of radiolabel from [S]methionine to GSH. The 2.5 Å 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 HS synthesis, and reports on an alternative inhibitor, CPC, which could be used as a scaffold to develop more potent HS biogenesis inhibitors.

PubMed: 31160338
DOI: 10.1074/jbc.RA119.009047

Experimental method

X-RAY DIFFRACTION (2.495 Å)