Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase

Janish Desai, Yi Liang Liu, Hongli Wei, Weidong Liu, Tzu Ping Ko, Rey Ting Guo, Eric Oldfield

Research output: Contribution to journalArticle

Abstract

We report the first structure of heptaprenyl diphosphate synthase from Staphylococcus aureus (SaHepPPS), together with an investigation of its mechanism of action and inhibition. The protein is involved in the formation of menaquinone, a key electron transporter in many bacteria, including pathogens. SaHepPPS consists of a “catalytic ” subunit (SaHepPPS-2) having two “DDXXD” motifs and a “regulatory” subunit (SaHepPPS-1) that lacks these motifs. High concentrations of the substrates, isopentenyl diphosphate and farnesyl diphosphate, inhibit the enzyme, which is also potently inhibited by bisphosphonates. The most active inhibitors (Ki∼200 nm) were N-alkyl analogues of zoledronate containing ∼C6alkyl side chains. They were modestly active against S. aureus cell growth, and growth inhibition was partially “rescued” by the addition of menaquinone-7. Because SaHepPPS is essential for S. aureus cell growth, its structure is of interest in the context of the development of menaquinone biosynthesis inhibitors as potential antibiotic leads.

Original languageEnglish (US)
Pages (from-to)1915-1923
Number of pages9
JournalChemMedChem
DOIs
StatePublished - Jan 1 2016

Keywords

  • Staphylococcus aureus
  • bisphosphonates
  • heptaprenyl diphosphate synthase
  • menaquinone biosynthesis
  • substrate-induced inhibition

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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