title: Structure, function and selective inhibition of bacterial acetyl-coa carboxylase.
abstract: Acetyl-CoA carboxylase (ACC) catalyses the first committed step in fatty acid biosynthesis: a metabolic pathway required for several important biological processes including the synthesis and maintenance of cellular membranes. ACC employs a covalently attached biotin moiety to bind a carboxyl anion and then transfer it to acetyl-CoA, yielding malonyl-CoA. These activities occur at two different subsites: the biotin carboxylase (BC) and carboxyltransferase (CT). Structural biology, together with small molecule inhibitor studies, has provided new insights into the molecular mechanisms that govern ACC catalysis, specifically the BC and CT subunits. Here, we review these recent findings and highlight key differences between the bacterial and eukaryotic isozymes with a view to establish those features that provide an opportunity for selective inhibition. Especially important are examples of highly selective small molecule inhibitors capable of differentiating between ACCs from different phyla. The implications for early stage antibiotic discovery projects, stemming from these studies, are discussed.
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, North Tce, Adelaide, South Australia 5005, Australia. steven.polyak@adelaide.edu.au
authors.forename: S W
authors.initials: SW
authors.lastname: Polyak
authors.forename: A D
authors.initials: AD
authors.lastname: Abell
authors.forename: M C J
authors.initials: MC
authors.lastname: Wilce
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: G W
authors.initials: GW
authors.lastname: Booker
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis; D006801:Humans; D008958:Models, Molecular
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D000103:Acetyl-CoA Carboxylase