Regulation of acetyl-CoA carboxylase

Abstract

Acetyl-CoA carboxylase (ACC) catalyses the formation of malonyl-CoA, an essential substrate for fatty acid synthesis in lipogenic tissues and a key regulatory molecule in muscle, brain and other tissues. ACC contributes importantly to the overall control of energy metabolism and has provided an important model to explore mechanisms of enzyme control and hormone action. Mammalian ACCs are multifunctional dimeric proteins (530-560 kDa) with the potential to further polymerize and engage in multiprotein complexes. The enzymatic properties of ACC are complex, especially considering the two active sites, essential catalytic biotin, the three-substrate reaction and effects of allosteric ligands. The expression of the two major isoforms and splice variants of mammalian ACC is tissue-specific and responsive to hormones and nutritional status. Key regulatory elements and cognate transcription factors are still being defined. ACC specific activity is also rapidly modulated, being increased in response to insulin and decreased following exposure of cells to catabolic hormones or environmental stress. The acute control of ACC activity is the product of integrated changes in substrate supply, allosteric ligands, the phosphorylation of multiple serine residues and interactions with other proteins. This review traces the path and implications of studies initiated with Dick Denton in Bristol in the late 1970s, through to current proteomic and other approaches that have been consistently challenging and immensely rewarding.

Maternal Obesity Reduces Milk Lipid Production in Lactating Mice by Inhibiting Acetyl-CoA Carboxylase and Impairing Fatty Acid Synthesis

“…ACC, the rate-limiting enzyme in de novo fatty acid synthesis [35], is enriched in lipogenic tissues such as adipose and the lactating mammary gland [36], [37]. Previous studies have reported decreased expression and activity of lipogenic enzymes, including ACC, in lactating mammary glands related HF feeding and/or obesity [11], [15], [38].…”

Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease

“…Citrate is converted to acetyl-CoA, by the action of adenosine triphosphate citrate lyase (ACL), which is the first step of endogenous fatty acid synthesis (Figure 1). Furthermore, citrate is an allosteric activator of cytoplasmic acetyl-CoA carboxylase (ACC), whose action is to convert acetyl-CoA to malonyl-CoA, thus initiating de novo lipogenesis (25; 26). Malonyl-CoA, is the primary carbon source utilized for endogenous fatty acid synthesis (27).…”

Human acetyl-CoA carboxylase 2 expressed in silkworm Bombyx mori exhibits posttranslational biotinylation and phosphorylation

“…1a) (Bianchi et al 1990; Tanabe et al 1975; Tong 2013). Biotin is covalently attached to lysine within BCCP domain through posttranslational modification, and several serine residues are phosphorylated by protein kinases (Beaty and Lane 1983a; Brownsey et al 2006; Ha et al 1994; Meredith and Lane 1978). We deleted the N-terminal 148 hydrophobic amino acids to enhance the solubility of heterologous protein, which retains core functional modules (Fig.…”

“…Acetyl-CoA carboxylases (ACCs) are biotin-dependent enzymes catalyzing the production of malonyl-CoA from acetyl-CoA, a critical metabolic intermediate in lipid metabolism (Brownsey et al 2006; Kim 1997; Saggerson 2008; Tong 2013; Wakil and Abu-Elheiga 2009). Two different isoforms of ACC, ACC1 and ACC2, partake in lipid metabolism in humans and mammals (Abu-Elheiga et al 1995, 1997; Ha et al 1996).…”

“…Then, carboxybiotin is transferred to the CT domain mediating transfer of the carboxyl group from carboxybiotin to acetyl-CoA to form malonyl-CoA (reaction 2). Besides these core catalytic reactions, ACC activities are allosterically regulated by multiple factors including phosphorylation/dephosphorylation and citrate (Beaty and Lane 1983a; Brownsey et al 2006; Ha et al 1994; Meredith and Lane 1978; Munday et al 1988; Wojtaszewski et al 2003). Thus, ACC with posttranslational biotinylation and properly regulated by allosteric modulators is essential in evaluating the full functionality of multistep reactions to unfold its functional mechanisms and systematic inhibitor discovery efforts.…”