期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 132, 期 19, 页码 6719-6727出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja909664j
关键词
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资金
- U.S. Public Health Service (NIH) [AI074233, GM073216, GM65307, GM085774]
- Mississippi Center for Supercomputing Research
We report the inhibition of the Aquifex aeolicus IspH enzyme (LytB, (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate reductase, EC 1.17.1.2) by a series of diphosphates and bisphosphonates. The most active species was an alkryl diphosphate having IC50 = 0.45 mu M (K-i approximate to 60 nM), which generated a very large change in the 9 GHz EPR spectrum of the reduced protein. On the basis of previous work on organometallic complexes, together with computational docking and quantum chemical calculations, we propose a model for alkyne inhibition involving pi (or pi/sigma) metallacycle complex formation with the unique fourth Fe in the Fe4S4 cluster. Aromatic species had less activity, and for these we propose an inhibition model based on an electrostatic interaction with the active site E126. Overall, the results are of broad general interest since they not only represent the first potent IspH inhibitors but also suggest a conceptually new approach to inhibiting other Fe4S4-cluster-containing proteins that are of interest as drug and herbicide targets.
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