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Description

4-hydroxy-3-methylbut-2-enyl diphosphate reductase (UniProt: P62623, also known as EC:1.17.7.4, HMBPP reductase, 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate reductase) is encoded by the ispH (also known as lytB, yaaE, b0029, JW0027) gene (Gene ID: 944777) in E. coli. IspH is an enzyme that catalyzes the conversion of 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate (HMBPP) into a mixture of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). It contains a central iron-sulfur cluster that serves as an electron transfer cofactor in the active site. IspH acts in the terminal step of the methyl erythritol phosphate (MEP) pathway for isoprenoid precursor biosynthesis that is essential for survival of Gram-negative bacteria, mycobacteria, and apicomplexans. It operates at an optimum pH of 7.0. Its substrate binding site is localized in amino acids 225-227. Since MEP pathway is absent in human, inhibitors of IspH are attractive targets for the development of antibiotics. More recently, ester-based prodrug of C23 analog have been described that inhibit IspH and are highly potent against Gram-negative bacteria. (Ref.: Singh, KS., et al. (2021). Nature 589(7843), 597-602, Grawert, T., et al. (2004). J. Am. Chem. Soc. 126(40), 12847-12855).