Structure and function of biotin-dependent carboxylases

Abstract

Biotin-dependent carboxylases include acetyl-CoA carboxylase (ACC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), geranyl-CoA carboxylase (GCC), pyruvate carboxylase (PC), and urea carboxylase (UC). They contain biotin carboxylase (BC), carboxyltransferase (CT) and biotin-carboxyl carrier protein (BCCP) components. These enzymes are widely distributed in nature and have important functions in fatty acid metabolism, amino acid metabolism, carbohydrate metabolism, polyketide biosynthesis, urea utilization, and other cellular processes. ACCs are also attractive targets for drug discovery against type 2 diabetes, obesity, cancer, microbial infections, and other diseases, and the plastid ACC of grasses is the target of action of three classes of commercial herbicides. Deficiencies in the activities of PCC, MCC or PC are linked to serious diseases in humans. Our understanding of these enzymes has been greatly enhanced over the past few years by the crystal structures of the holoenzymes of PCC, MCC, PC, and UC. The structures reveal unanticipated features in the architectures of the holoenzymes, including the presence of previously unrecognized domains, and provide a molecular basis for understanding their catalytic mechanism as well as the large collection of disease-causing mutations in PCC, MCC and PC. This review will summarize the recent advances in our knowledge on the structure and function of these important metabolic enzymes.

Using the pimeloyl-CoA synthetase adenylation fold to synthesize fatty acid thioesters

“…In fatty acid biosynthesis biotin is an essential carbon dioxide carrier cofactor within large enzyme complexes, such as acetyl-CoA carboxylase (ACC), that catalyse carboxylation of acetyl-CoA to form malonyl-CoA 1 . Biotin (Fig.…”

“…Biotin (Fig. 1a) possesses two fused rings (ureido and thiophane) whose carbon skeleton derives from the unusual C7 α,ω-dicarboxylic acid, pimelic acid (1). Pioneering studies identified the intermediates involved in forming the fused bicyclic structure that have been shown to be conserved in all bacterial species [2][3][4][5] .…”

The cyclic keto-enol insecticide spirotetramat inhibits insect and spider mite acetyl-CoA carboxylases by interfering with the carboxyltransferase partial reaction

“…The herbicidal FOPs, DIMs and phenylpyrazolines all bind to the CT domain (Delye et al, 2005;Kaundun, 2010;Yu et al, 2010). However, the myxobacterial polyketide soraphen A was reported as a nanomolar inhibitor of the biotin carboxylase (BC) domains of fungal ACCs (Weatherly et al, 2004), probably by interfering with BC dimerization (Tong, 2013). Finally, a novel class of bipiperidylcarboxamide CT domain inhibitors of mammalian ACCs was discovered by highthroughput biochemical screening (Corbett et al, 2010).…”

“…Examples are substrate phosphorylations catalyzed by kinases (VanScyoc et al, 2008;Agnew and Timson, 2010), and the inhibition of phosphoribosyltransferase by histidine inhibitors (Tong, 2013).…”

“…Biotin is covalently attached to the H-amino group of a lysine residue of the biotin carboxyl carrier protein (BCCP) domain, so that the lysine side chain and the biotin form a highly flexible arm of about 16 Å. The flexible biotin arm together with additional movements of the whole BCCP domain is thought to facilitate the coupling of the two half-reactions, referred to as the ´swinging domain´ model (Tong, 2013).…”