Structure of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate reductase, the terminal enzyme of the non-mevalonate pathway

Ingo Rekittke, Jochen Wiesner, Rene Röhrich, Ulrike Demmer, Eberhard Warkentin, Weiya Xu, Kathrin Troschke, Martin Hintz, Joo Hwan No, Evert C. Duin, Eric Oldfield, Hassan Jomaa, Ulrich Ermler

Research output: Contribution to journalArticle

Abstract

Molecular evolution has evolved two metabolic routes for isoprenoid biosynthesis: the mevalonate and the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway. The MEP pathway is used by most pathogenic bacteria and some parasitic protozoa (including the malaria parasite, Plasmodium falciparum) as well as by plants, but is not present in animals. The terminal reaction of the MEP pathway is catalyzed by (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) reductase (LytB), an enzyme that converts HMBPP into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Here, we present the structure of Aquifex aeolicus LytB, at 1.65 Å resolution. The protein adopts a cloverleaf or trefoil-like structure with each monomer in the dimer containing three 1/3 domains surrounding a central [Fe3S4] cluster ligated to Cys13, Cys96, and Cys193. Two highly conserved His (His 42 and His 124) and a totally conserved Glu (Glu126) are located in the same central site and are proposed to be involved in ligand nding and catalysis. Substrate access is proposed to occur from the front-side face of the protein, with the HMBPP diphosphate binding to the two His and the 4OH of HMBPP binding to the fourth iron thought to be present in activated clusters, while Glu126 provides the protons required for IPP/DMAPP formation.

Original languageEnglish (US)
Pages (from-to)17206-17207
Number of pages2
JournalJournal of the American Chemical Society
Volume130
Issue number51
DOIs
StatePublished - Dec 24 2008

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Rekittke, I., Wiesner, J., Röhrich, R., Demmer, U., Warkentin, E., Xu, W., Troschke, K., Hintz, M., No, J. H., Duin, E. C., Oldfield, E., Jomaa, H., & Ermler, U. (2008). Structure of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate reductase, the terminal enzyme of the non-mevalonate pathway. Journal of the American Chemical Society, 130(51), 17206-17207. https://doi.org/10.1021/ja806668q