Abstract
Chemical genetic studies on acetyl-CoA carboxylases (ACCs), rate-limiting enzymes in long chain fatty acid biosynthesis, have greatly advanced the understanding of their biochemistry and molecular biology and promoted the use of ACCs as targets for herbicides in agriculture and for development of drugs for diabetes, obesity and cancers. In mammals, ACCs have both biotin carboxylase (BC) and carboxyltransferase (CT) activity, catalyzing carboxylation of acetyl-CoA to malonyl-CoA. Several classes of small chemicals modulate ACC activity, including cellular metabolites, natural compounds, and chemically synthesized products. This article reviews chemical genetic studies of ACCs and the use of ACCs for targeted therapy of cancers.
Highlights
Acetyl-CoA carboxylases (ACCs) are biotin-dependent enzymes in fatty acid de novo biosynthesis that irreversibly catalyze carboxylation of acetyl-CoA to malonyl-CoA [1,2,3,4]
Our studies demonstrated that Aldo-keto reductase 1B10 (AKR1B10) mediates ACC1 stability and increase fatty acid synthesis; knockdown of AKR1B10 inhibits cancer cell growth and triggers apoptosis [55,56,57]
acetyl-CoA carboxylases (ACCs) are important enzymes implicated in fatty acid synthesis and oxidation
Summary
Acetyl-CoA carboxylases (ACCs) are biotin-dependent enzymes in fatty acid de novo biosynthesis that irreversibly catalyze carboxylation of acetyl-CoA to malonyl-CoA [1,2,3,4]. ACC1 and ACC2 are both highly expressed in the liver where fatty acid synthesis and oxidation are both active [6]. ACC1/2 expression is regulated by a group of transcription factors: sterol-regulatory-element binding protein 1 (SREBP-1), liver X receptor, retinoid. Phosphorylation on several critical Ser residues in ACCs is a main posttranslational modification mode, affecting ACC enzyme activity (4). Breast cancer protein 1 (BRCA1) interacts with ACC1 and prevents it from dephosphorylation at Ser 79 and Ser. 1263 [34,35], suggesting a role of BRCA1 in the regulation of ACC1 enzyme activity. 1263 is essential for the interaction of BRCA1 and ACC1
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