Structure, function and selective inhibition of bacterial acetyl-coa carboxylase

Steven W Polyak, A D Abell, Matthew Charles James Wilce, Lixin Zhang, Grant William Booker

Research output: Contribution to journalArticleOther

45 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)983 - 992
Number of pages10
JournalApplied Microbiology and Biotechnology
Volume93
Issue number3
DOIs
Publication statusPublished - 2012

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