IspG Converts an Epoxide Substrate Analogue to (<i>E</i>)-4-Hydroxy-3-methylbut-2-enyl Diphosphate: Implications for IspG Catalysis in Isoprenoid Biosynthesis

Abstract

IspG is an intriguing enzyme in bacteria, parasite, and plant isoprenoid biosynthesis, and its catalytic mechanism remains elusive. We report here the synthesis of (2R,3R)-4-hydroxy-3-methyl-2,3-epoxybutanyl diphosphate (Epoxy-HMBPP), a proposed intermediate in one of the frequently cited mechanistic models. We have also demonstrated that this epoxide analogue is a catalytically competent IspG substrate. This study represents the first mechanistic study of this important enzyme.