DFT investigation on the mechanism of the deacetylation reaction catalyzed by LpxC

被引:23
|
作者
Robinet, Jesse J. [1 ]
Gauld, James W. [1 ]
机构
[1] Univ Windsor, Dept Chem & Biochem, Windsor, ON N9B 3P4, Canada
来源
JOURNAL OF PHYSICAL CHEMISTRY B | 2008年 / 112卷 / 11期
关键词
D O I
10.1021/jp075415m
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
LpxC is a key enzyme in the biochemical synthesis of Lipid A, an important outer cell-membrane component found in a number of pathogenic bacteria. Using DFT, we have investigated the binding of the substrate within its active site as well as the deacetylation mechanism it catalyzes. The substrate is found to preferentially coordinate to the active site Zn2+ via its carbonyl oxygen between a Zn2+-bound H2O and an adjacent threonine (Thr191). Furthermore, upon substrate binding a nearby Glu78 residue is found to readily deprotonate the remaining Zn2+-bound H2O. Unlike several related metallopeptidases, the mechanism of LpxC is found to proceed via four steps; (i) initial hydroxylation of the substrates' carbonyl carbon to give a gem-diolate intermediate, (ii) protonation of the amide nitrogen by the histidine His265-H+, (iii) a barrier-less change in the active site-intermediate hydrogen-bond network and finally, (iv) C-N bond cleavage. Notably, the rate-determining step of the mechanism of LpxC is found to be the initial hydroxylation while the final C-N bond cleavage occurs with an overall barrier of 23.6 kJ mol(-1). Furthermore, LpxC uses a general acid/base pair mechanism as indicated by the fact that both His265-H+ and Glu78 are accordingly involved.
引用
收藏
页码:3462 / 3469
页数:8
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