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Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase
Author(s) -
Desai Janish,
Liu YiLiang,
Wei Hongli,
Liu Weidong,
Ko TzuPing,
Guo ReyTing,
Oldfield Eric
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600311
Subject(s) - staphylococcus aureus , biochemistry , atp synthase , protein subunit , enzyme , context (archaeology) , chemistry , farnesyl diphosphate synthase , bacteria , stereochemistry , biology , microbiology and biotechnology , gene , paleontology , genetics
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 ( K i ∼200 n m ) were N ‐alkyl analogues of zoledronate containing ∼C 6 alkyl 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.