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Site-directed mutagenesis on human cystathionine-gamma-lyase reveals insights into the modulation of H2S production.

Abstract：

:In recent years, increased interest has been directed towards hydrogen sulfide (H2S) as the third gasotransmitter and its role in various diseases. Cystathionine-gamma-lyase (CSE) is one of the enzymes responsible for the endogenous production of H2S in mammals. With the aid of the crystal structures of human CSE and site-directed mutagenesis studies, we have identified several amino acid residues in CSE that are actively involved in the catalysis of H2S production. Contrary to reports suggesting that Tyr114 is required for substrate binding, our results reveal a significant increase in the production of H2S upon mutation of Tyr114 to phenylalanine. This is attributed to an increased rate of pyridoxal 5'-phosphate (PLP) regeneration due to weakened pi-stacking interactions between Phe114 and PLP. Thr189 is also identified as a crucial residue where hydrogen bonding to Asp187 keeps the latter in an optimal position for hydrogen bonding to the pyridoxal nitrogen of PLP. Furthermore, mutation of Glu339 to lysine, alanine or tyrosine reveals the importance of the hydrophobicity of the 339th amino acid in determining the specificity of the enzyme for the catalysis of alpha,gamma-elimination or alpha,beta-elimination reaction. Our study also shows that the rate of H2S production is increased with increasing exogenous PLP concentration, hence supporting our hypothesis that apo-CSE is formed during the catalysis of H2S production. Taken together, these findings suggest novel routes towards the design of activators or inhibitors that modulate the production of H2S; these modulators may also serve as lead compounds in the development of drugs or mechanistic probes in the study of various H2S-related diseases.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Huang S,Chua JH,Yew WS,Sivaraman J,Moore PK,Tan CH,Deng LW

doi

10.1016/j.jmb.2009.11.058

subject

Has Abstract

pub_date

2010-02-26 00:00:00

pages

708-18

issue

3

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(09)01452-1

journal_volume

396

pub_type

杂志文章

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