Dataset Information

Inhibition of the Fe(4)S(4)-cluster-containing protein IspH (LytB): electron paramagnetic resonance, metallacycles, and mechanisms.

ABSTRACT: 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 alkynyl diphosphate having IC(50) = 0.45 microM (K(i) approximately 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 Fe(4)S(4) 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 Fe(4)S(4)-cluster-containing proteins that are of interest as drug and herbicide targets.

SUBMITTER: Wang K

PROVIDER: S-EPMC2874468 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Inhibition of the Fe(4)S(4)-cluster-containing protein IspH (LytB): electron paramagnetic resonance, metallacycles, and mechanisms.

Wang Ke K Wang Weixue W No Joo-Hwan JH Zhang Yonghui Y Zhang Yong Y Oldfield Eric E

Journal of the American Chemical Society 20100501 19

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 alkynyl diphosphate having IC(50) = 0.45 microM (K(i) approximately 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 calc ...[more]

PMID: 20426416

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Dataset Information

Inhibition of the Fe(4)S(4)-cluster-containing protein IspH (LytB): electron paramagnetic resonance, metallacycles, and mechanisms.

Publications

Inhibition of the Fe(4)S(4)-cluster-containing protein IspH (LytB): electron paramagnetic resonance, metallacycles, and mechanisms.

Similar Datasets

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