Structural basis for the inhibition mechanism of human cystathionine γ-lyase, an enzyme responsible for the production of H2S

Qingxiang Sun, Ruairi Collins, Shufen Huang, Lovisa Holmberg-Schiavone, Ganesh S. Anand, Choon Hong Tan, Susanne Van-den-Berg, Lih Wen Deng, Philip K. Moore, Tobias Karlberg, J. Sivaraman

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

Impairment of the formation or action of hydrogen sulfide (H2S), an endogenous gasotransmitter, is associated with various diseases, such as hypertension, diabetes mellitus, septic and hemorrhagic shock, and pancreatitis. Cystathionine β-synthase and cystathionineγ-lyase (CSE) are two pyridoxal-5′-phosphate (PLP)-dependent enzymes largely responsible for the production of H2S in mammals. Inhibition of CSE by DL-propargylglycine (PAG) has been shown to alleviate disease symptoms. Here we report crystal structures of human CSE (hCSE), in apo form, and in complex with PLP and PLP·PAG. Structural characterization, combined with biophysical and biochemical studies, provides new insights into the inhibition mechanism of hCSE-mediated production of H2S. Transition from the open form of apo-hCSE to the closed PLP-bound form reveals large conformational changes hitherto not reported. In addition, PAG binds hCSE via a unique binding mode, not observed in PAG-enzyme complexes previously. The interaction of PAG-hCSE was not predicted based on existing information from known PAG complexes. The structure of hCSE·PLP·PAG complex highlights the particular importance of Tyr114 in hCSE and the mechanism of PAG-dependent inhibition of hCSE. These results provide significant insights, which will facilitate the structure-based design of novel inhibitors of hCSE to aid in the development of therapies for diseases involving disorders of sulfur metabolism.

Original languageEnglish (US)
Pages (from-to)3076-3085
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number5
DOIs
StatePublished - Jan 30 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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