title: Anti-HIV siamycin I directly inhibits autophosphorylation activity of the bacterial FsrC quorum sensor and other ATP-dependent enzyme activities.
abstract: Siamycin I disrupts growth and quorum sensing in Enterococcus faecalis. Using purified intact protein, we demonstrate here that quorum membrane sensor kinase FsrC is a direct target of siamycin I, reducing pheromone-stimulated autophosphorylation activity by up to 91%. Inhibition was non-competitive with ATP as substrate. Other ATP-binding enzymes were also inhibited, including nine other membrane sensor kinases of E. faecalis, Rhodobacter sphaeroides PrrB, porcine Na(+)-dependent ATPase and the catalytic subunit of bovine protein kinase A, but not bacterial β-galactosidase, confirming targeted inhibition of a wide range of ATP dependent reactions, and elucidating a likely mechanism underlying the lethality of the inhibitor.
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Pikyee
authors.initials: P
authors.lastname: Ma
authors.forename: Kenzo
authors.initials: K
authors.lastname: Nishiguchi
authors.forename: Hayley M
authors.initials: HM
authors.lastname: Yuille
authors.forename: Lianne M
authors.initials: LM
authors.lastname: Davis
authors.forename: Jiro
authors.initials: J
authors.lastname: Nakayama
authors.forename: Mary K
authors.initials: MK
authors.lastname: Phillips-Jones
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002417:Cattle; D013293:Enterococcus faecalis / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D053038:Quorum Sensing / Q000187:drug effects*; D012242:Rhodobacter sphaeroides / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C409033:AgrCfs protein, Enterococcus faecalis; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C094260:siamycin I; D001616:beta-Galactosidase; D000251:Adenosine Triphosphatases