TY - JOUR
T1 - Structural basis for the inhibition mechanism of human cystathionine γ-lyase, an enzyme responsible for the production of H2S
AU - Sun, Qingxiang
AU - Collins, Ruairi
AU - Huang, Shufen
AU - Holmberg-Schiavone, Lovisa
AU - Anand, Ganesh S.
AU - Tan, Choon Hong
AU - Van-den-Berg, Susanne
AU - Deng, Lih Wen
AU - Moore, Philip K.
AU - Karlberg, Tobias
AU - Sivaraman, J.
PY - 2009/1/30
Y1 - 2009/1/30
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M805459200
DO - 10.1074/jbc.M805459200
M3 - Article
C2 - 19019829
AN - SCOPUS:59149099843
SN - 0021-9258
VL - 284
SP - 3076
EP - 3085
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
ER -