Inhibition of Class A and C β-Lactamases by Diaroyl Phosphates
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- 作者：Sudipta Majumdar ; R. F. Pratt
- 刊名：Biochemistry
- 出版年：2009
- 出版时间：September 8, 2009
- 年：2009
- 卷：48
- 期：35
- 页码：8285-8292
- 全文大小：866K
- 年卷期：v.48,no.35(September 8, 2009)
- ISSN：1520-4995
文摘
A series of diaroyl phosphates was employed to assess the general reactivity of this class of molecule against classical class A and class C β-lactamases. The compounds were found, in general, to be inhibitory substrates of both classes of enzyme. In each case, they reacted rapidly with the enzyme (104 to 106 s−1 M−1) to yield transiently stable intermediates, most likely acyl-enzymes, which slowly (10−3 to 10−1 s−1) regenerated free enzyme. In certain cases, side branches from direct turnover produced EII complexes (“substrate” inhibition), more inert EI′ complexes, and, in one case, a completely inactive EI′ complex. Deacylation, but not acylation, was enhanced by electron-withdrawing substituents. Acylation rates were enhanced by hydrophobic substitution, both in the diaroyl phosphate and at the enzyme active site. The latter factor led to the general order of β-lactamase acylation rates: class D (previous results) > class C > class A. It is likely that nanomolar inhibitors of all serine β-lactamases could be achieved by rational exploitation of diacyl phosphates.