C75 [4-Methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic Acid] Activates Carnitine Palmitoyltransferase-1 in Isolated Mitochondria and Intact Cells without Displacement of Bound Malonyl CoA
| العنوان: | C75 [4-Methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic Acid] Activates Carnitine Palmitoyltransferase-1 in Isolated Mitochondria and Intact Cells without Displacement of Bound Malonyl CoA |
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| المؤلفون: | Joanne S. Kays, Craig D. Hammond, Thomas W. Seng, Tiffanie R. Skillman, Lorri Burris, Nengyu Yang |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 312:127-133 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | endocrine system, endocrine system diseases, Mitochondria, Heart, Enzyme activator, chemistry.chemical_compound, Carnitine palmitoyltransferase 1, 4-Butyrolactone, Yeasts, Tumor Cells, Cultured, medicine, Animals, Humans, heterocyclic compounds, Carnitine, Carnitine O-palmitoyltransferase, neoplasms, Beta oxidation, Pharmacology, Carnitine O-Palmitoyltransferase, biology, Malonyl Coenzyme A, Recombinant Proteins, digestive system diseases, Rats, Enzyme Activation, Fatty acid synthase, Malonyl-CoA, Biochemistry, chemistry, biology.protein, Molecular Medicine, medicine.drug |
| الوصف: | Carnitine palmitoyltransferase 1beta (CPT-1beta) is a key regulator of the beta oxidation of long-chain fatty acids in skeletal muscle and therefore a potential therapeutic target for diseases associated with defects in lipid metabolism such as obesity and type 2 diabetes. C75 [4-methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid] is an alpha-methylene-butyrolactone that has been characterized as both an inhibitor of fatty acid synthase and more recently, an activator of CPT-1 (Thupari et al., 2002). Using human CPT-1beta expressed in the yeast Pichia pastoris, we demonstrate that C75 can activate the skeletal muscle isoform of CPT-1 and overcome inactivation of the enzyme by malonyl CoA, an important physiological repressor of CPT-1, and the malonyl CoA mimetic Ro25-0187 [{5-[2-(naphthalen-2-yloxy)-ethoxy]-thiophen-2-yl}-oxo-acetic acid]. We also show that C75 can activate CPT-1 in intact hepatocytes to levels similar to those achieved with inhibition of acetyl-CoA carboxylase, the enzyme that produces malonyl CoA. Finally, we demonstrate that concentrations of C75 sufficient for activation of CPT-1 do not displace bound malonyl CoA. We conclude that CPT-1 is an activator of human CPT-1beta and other CPT-1 isoforms but that it does not activate CPT-1 through antagonism of malonyl CoA binding. |
| تدمد: | 1521-0103 0022-3565 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c686d2d2f28ce33f3054d1239d3de0eaTest https://doi.org/10.1124/jpet.104.074104Test |
| رقم الانضمام: | edsair.doi.dedup.....c686d2d2f28ce33f3054d1239d3de0ea |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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