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

Citations Over TimeTop 23% of 2016 papers

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 ∼C6 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.

Related Papers

• → Interaction with the Small Subunit of Geranyl Diphosphate Synthase Modifies the Chain Length Specificity of Geranylgeranyl Diphosphate Synthase to Produce Geranyl Diphosphate(2002)103 cited
• → Knockdown of F1 epsilon subunit decreases mitochondrial content of ATP synthase and leads to accumulation of subunit c(2009)46 cited
• → The Peripheral Stalk Participates in the Yeast ATP Synthase Dimerization Independently of e and g Subunits(2006)52 cited
• → Geranyl diphosphate synthase in leaves of Pelargonium roseum(1991)28 cited
• → all-trans-nonaprenyl-diphosphate synthase [geranyl-diphosphate specific] 2.5.1.84(2013)