دورية أكاديمية
State-Dependent Allosteric Inhibition of the Human SLC13A5 Citrate Transporter by Hydroxysuccinic Acids, PF-06649298 and PF-06761281.
| العنوان: | State-Dependent Allosteric Inhibition of the Human SLC13A5 Citrate Transporter by Hydroxysuccinic Acids, PF-06649298 and PF-06761281. |
|---|---|
| المؤلفون: | Rives ML; Molecular and Cellular Pharmacology, Discovery Sciences, Janssen R&D, LLC., San Diego, California (M.-L.R., M.S., A.D.W.) and Cardiovascular and Metabolism Discovery, Janssen R&D, LLC., Springhouse, Pennsylvania, (B.Z., S.A.H.)., Shaw M; Molecular and Cellular Pharmacology, Discovery Sciences, Janssen R&D, LLC., San Diego, California (M.-L.R., M.S., A.D.W.) and Cardiovascular and Metabolism Discovery, Janssen R&D, LLC., Springhouse, Pennsylvania, (B.Z., S.A.H.)., Zhu B; Molecular and Cellular Pharmacology, Discovery Sciences, Janssen R&D, LLC., San Diego, California (M.-L.R., M.S., A.D.W.) and Cardiovascular and Metabolism Discovery, Janssen R&D, LLC., Springhouse, Pennsylvania, (B.Z., S.A.H.)., Hinke SA; Molecular and Cellular Pharmacology, Discovery Sciences, Janssen R&D, LLC., San Diego, California (M.-L.R., M.S., A.D.W.) and Cardiovascular and Metabolism Discovery, Janssen R&D, LLC., Springhouse, Pennsylvania, (B.Z., S.A.H.)., Wickenden AD; Molecular and Cellular Pharmacology, Discovery Sciences, Janssen R&D, LLC., San Diego, California (M.-L.R., M.S., A.D.W.) and Cardiovascular and Metabolism Discovery, Janssen R&D, LLC., Springhouse, Pennsylvania, (B.Z., S.A.H.) awickend@its.jnj.com. |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 2016 Dec; Vol. 90 (6), pp. 766-774. Date of Electronic Publication: 2016 Oct 17. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | Malates/*pharmacology , Phenylbutyrates/*pharmacology , Pyridines/*pharmacology , Succinates/*pharmacology , Symporters/*antagonists & inhibitors, Allosteric Regulation/drug effects ; Carbon Radioisotopes ; Citric Acid/metabolism ; HEK293 Cells ; Humans ; Ion Channel Gating/drug effects ; Malates/chemistry ; Models, Biological ; Patch-Clamp Techniques ; Phenylbutyrates/chemistry ; Pyridines/chemistry ; Substrate Specificity/drug effects ; Succinates/chemistry ; Symporters/metabolism |
| مستخلص: | In the liver, citrate is a key metabolic intermediate involved in the regulation of glycolysis and lipid synthesis and reduced expression of the hepatic citrate SLC13A5 transporter has been shown to improve metabolic outcomes in various animal models. Although inhibition of hepatic extracellular citrate uptake through SLC13A5 has been suggested as a potential therapeutic approach for Type-2 diabetes and/or fatty liver disease, so far, only a few SLC13A5 inhibitors have been identified. Moreover, their mechanism of action still remains unclear, potentially limiting their utility for in vivo proof-of-concept studies. In this study, we characterized the pharmacology of the recently identified hydroxysuccinic acid SLC13A5 inhibitors, PF-06649298 and PF-06761281, using a combination of 14 C-citrate uptake, a membrane potential assay and electrophysiology. In contrast to their previously proposed mechanism of action, our data suggest that both PF-06649298 and PF-06761281 are allosteric, state-dependent SLC13A5 inhibitors, with low-affinity substrate activity in the absence of citrate. As allosteric state-dependent modulators, the inhibitory potency of both compounds is highly dependent on the ambient citrate concentration and our detailed mechanism of action studies therefore, may be of value in interpreting the in vivo effects of these compounds. (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.) |
| المشرفين على المادة: | 0 (Carbon Radioisotopes) 0 (Malates) 0 (PF-06649298) 0 (PF-06761281) 0 (Phenylbutyrates) 0 (Pyridines) 0 (SLC13A5 protein, human) 0 (Succinates) 0 (Symporters) 2968PHW8QP (Citric Acid) |
| تواريخ الأحداث: | Date Created: 20161105 Date Completed: 20170509 Latest Revision: 20170509 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1124/mol.116.106575 |
| PMID: | 27754898 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0111 |
|---|---|
| DOI: | 10.1124/mol.116.106575 |