Crystal structures of mutant IspH proteins reveal a rotation of the substrate's hydroxymethyl group during catalysis

Ingrid Span, Tobias Gräwert, Adelbert Bacher, Wolfgang Eisenreich, Michael Groll

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Isoprenoids derive from two universal precursors, isopentenyl diphosphate and dimethylallyl diphosphate, which in most human pathogens are synthesized in the deoxyxylulose phosphate pathway. The last step of this pathway is the conversion of (E)-1-hydroxy-2-methylbut-2-enyl-4-diphosphate into a mixture of isopentenyl diphosphate and dimethylallyl diphosphate catalyzed by the iron-sulfur protein IspH. The crystal structures reported here of the IspH mutant proteins T167C, E126D and E126Q reveal an alternative substrate conformation compared to the wild-type structure. Thus, the previously observed alkoxide complex decomposes, and the substrate's hydroxymethyl group rotates to interact with Glu126. The carboxyl group of Glu126 then donates a proton to the hydroxyl group to enable water elimination. The structural and functional studies provide further knowledge of the IspH reaction mechanism, which opens up new routes to inhibitor design against malaria and tuberculosis.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalJournal of Molecular Biology
Volume416
Issue number1
DOIs
StatePublished - 10 Feb 2012

Keywords

  • IspH
  • LytB
  • iron-sulfur protein
  • isoprenoid biosynthesis
  • non-mevalonate pathway

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