Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2

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.

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“…5A) [108,174]. Structures of the human and bovine ACC2 CT domain have been reported at 3.2 Å and 2.4 Å resolution, respectively [112,175].…”

Section: Acetyl-coa Carboxylase (Acc)mentioning

confidence: 99%

Structure and function of biotin-dependent carboxylases

Tong

2012

Cell. Mol. Life Sci.

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357

338

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“…87 Finally, it should be noted that compounds belonging to the spirochromanones class of molecules, which are structural analogs of CP-640186, were found to inhibit both isoforms of human carboxyltransferase. 88 Crystal structures of these inhibitors bound to either the carboxyltransferase domain of yeast acetyl-CoA carboxylase or the yeast nine-residue variant version demonstrated that these inhibitors likewise bind in the same site as CP-640186. 86 …”

Section: Inhibitors Of Carboxyltransferasementioning

confidence: 99%

The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms

2012

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Biotin is the major cofactor involved in carbon dioxide metabolism. Indeed, biotindependent enzymes are ubiquitous in nature and are involved in a myriad of metabolic processes including fatty acid synthesis and gluconeogenesis. The cofactor, itself, is composed of a ureido ring, a tetrahydrothiophene ring, and a valeric acid side chain. It is the ureido ring that functions as the CO 2 carrier. A complete understanding of biotin-dependent enzymes is critically important for translational research in light of the fact that some of these enzymes serve as targets for antiobesity agents, antibiotics, and herbicides. Prior to 1990, however, there was a dearth of information regarding the molecular architectures of biotin-dependent enzymes. In recent years there has been an explosion in the number of three-dimensional structures reported for these proteins. Here we review our current understanding of the structures and functions of biotindependent enzymes. In addition, we provide a critical analysis of what these structures have and have not revealed about biotin-dependent catalysis.

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“…Because human ACC1 and ACC2 produce two separate pools of malonyl-CoA with dramatically different functions, isozyme-specific inhibitors are highly desirable. The current arsenal of small-molecule inhibitors of mammalian ACC includes several classes of compounds with different chemical cores and submicromolar IC 50 and, in some cases, a modest isozyme specificity (22)(23)(24)(25)(26)(27). No drugs targeting human ACC have yet been developed, based on these compounds or others.…”

Section: Fatty Acid Metabolism | Human Healthmentioning

confidence: 99%

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

Marjanovic

Chalupská

Patenode

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In "proof of concept" experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 μM IC 50 and having no effect on human ACC1 at 100 μM.fatty acid metabolism | human health

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Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2

Cited by 53 publications

References 8 publications

Structure and function of biotin-dependent carboxylases

Structure and function of biotin-dependent carboxylases

The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

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Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2

Cited by 53 publications

References 8 publications

Structure and function of biotin-dependent carboxylases

Structure and function of biotin-dependent carboxylases

The enzymes of biotin dependent CO2 metabolism: What structures reveal about their reaction mechanisms

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

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The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms