The Diverse Binding Modes Explain the Nanomolar Levels of Inhibitory Activities Against 1-Deoxy-d-Xylulose 5-Phosphate Reductoisomerase from Exhibited by Reverse Hydroxamate Analogs of Fosmidomycin with Varying -Substituents.

It is established that reverse hydroxamate analogs of fosmidomycin inhibit the growth of by inhibiting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate pathway, which is absent in humans. Recent biochemical studies have demonstrated that novel reverse fosmidomycin analogs with phenylalkyl substituents at the hydroxamate nitrogen exhibit inhibitory activities against DXR at the nanomolar level. Moreover, crystallographic analyses have revealed that the phenyl moiety of the -phenylpropyl substituent is accommodated in a previously unidentified subpocket within the active site of DXR. In this study, the crystal structures of DXR in complex with a series of reverse -phenylalkyl derivatives of fosmidomycin were determined to ascertain whether the high inhibitory activities of the derivatives are consistently attributable to the utilization of the subpocket of DXR. While all reverse fosmidomycin derivatives with an -substituted phenylalkyl group exhibit potent inhibitory activity against DXR, the present crystal structure analyses revealed that their binding modes to the DXR are not uniform. In these compounds, the nanomolar inhibitory activities appear to be driven by binding modes distinct from that observed for the inhibitor containing the -phenylpropyl group. The structural information obtained in this study will provide a basis for further design of fosmidomycin derivatives.