figshare
Browse
ja909664j_si_001.pdf (99.23 kB)

Inhibition of the Fe4S4-Cluster-Containing Protein IspH (LytB): Electron Paramagnetic Resonance, Metallacycles, and Mechanisms

Download (99.23 kB)
journal contribution
posted on 2010-05-19, 00:00 authored by Ke Wang, Weixue Wang, Joo-Hwan No, Yonghui Zhang, Yong Zhang, Eric Oldfield
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 IC50 = 0.45 μM (Ki ≈ 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 π (or π/σ) “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.

History