Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity
| Autor: | Sergey E. Tkachenko, Jasmina Marjanovic, Ilya Okun, Robert Haselkorn, Dominika Chalupska, Adam D. Coster, Piotr Gornicki, Alice Ye, Evan Arnold, Caroline Patenode, George L. Anesi, Ying Lu |
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| Rok vydání: | 2010 |
| Předmět: |
DNA
Complementary Biology Isozyme Inhibitory Concentration 50 chemistry.chemical_compound Yeasts Drug Discovery Humans Obesity Enzyme Inhibitors Beta oxidation Cellular compartment chemistry.chemical_classification Multidisciplinary Dose-Response Relationship Drug Organisms Genetically Modified Fatty acid metabolism Fatty Acids Acetyl-CoA carboxylase Biological Sciences Yeast Pyruvate carboxylase Isoenzymes Gene Components Enzyme Biochemistry chemistry Acetyl-CoA Carboxylase |
| Zdroj: | Proceedings of the National Academy of Sciences. 107:9093-9098 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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