title: Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase.
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.
authors.affiliation: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, 1110 West Green Street, Urbana, IL, 61801, USA.
authors.forename: Janish
authors.identifier: 0000-0001-5487-1264
authors.initials: J
authors.lastname: Desai
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Matthews Avenue, Urbana, IL, 61801, USA.
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, PRC.
authors.forename: Hongli
authors.initials: H
authors.lastname: Wei
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, PRC.
authors.forename: Weidong
authors.initials: W
authors.lastname: Liu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Taipei, 11529, ROC.
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Ko
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, PRC.
authors.forename: Rey-Ting
authors.initials: RT
authors.lastname: Guo
authors.affiliation: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, 1110 West Green Street, Urbana, IL, 61801, USA. eo@chad.scs.uiuc.edu.|Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Matthews Avenue, Urbana, IL, 61801, USA. eo@chad.scs.uiuc.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C024844:trans-hexaprenyltranstransferase
keywords: Staphylococcus aureus; bisphosphonates; heptaprenyl diphosphate synthase; menaquinone biosynthesis; substrate-induced inhibition