Bioorganometallic chemistry with IspG and IspH: Structure, function, and inhibition of the [Fe4S4] proteins involved in isoprenoid biosynthesis

Weixue Wang, Eric Oldfield

Research output: Contribution to journalReview article

Abstract

Enzymes of the methylerythritol phosphate pathway of isoprenoid biosynthesis are attractive anti-infective drug targets. The last two enzymes of this pathway, IspG and IspH, are [Fe4S4] proteins that are not produced by humans and catalyze 2 H+/ 2 e- reductions with novel mechanisms. In this Review, we summarize recent advances in structural, mechanistic, and inhibitory studies of these two enzymes. In particular, mechanistic proposals involving bioorganometallic intermediates are presented, and compared with other mechanistic possibilities. In addition, inhibitors based on substrate analogues as well as developed by rational design and compound-library screening, are discussed. The results presented support bioorganometallic catalytic mechanisms for IspG and IspH, and open up new routes to anti-infective drug design targeting [Fe4S4] clusters in proteins. A mission based on inside information: The methylerythritol phosphate pathway is an attractive anti-infective drug target. The last two enzymes of this pathway, IspG and IspH, are [Fe4S4] proteins that catalyze 2 H+/2 e- dehydroxylation reactions. Recent progress in the elucidation of their biosynthetic mechanisms opens up new routes to the design of inhibitors that target these [Fe 4S4] enzymes.

Original languageEnglish (US)
Pages (from-to)4294-4310
Number of pages17
JournalAngewandte Chemie - International Edition
Volume53
Issue number17
DOIs
StatePublished - Apr 22 2014

Keywords

  • EPR spectroscopy
  • bioinorganic chemistry
  • biophysics
  • enzyme catalysis
  • terpenoids

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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