Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5).
Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5).
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DOI：
10.1038/srep17391
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发表时间：
2015-12-01
影响因子：
4.6
通讯作者：
Erion DM
中科院分区：
文献类型：
--
作者：
Huard K;Brown J;Jones JC;Cabral S;Futatsugi K;Gorgoglione M;Lanba A;Vera NB;Zhu Y;Yan Q;Zhou Y;Vernochet C;Riccardi K;Wolford A;Pirman D;Niosi M;Aspnes G;Herr M;Genung NE;Magee TV;Uccello DP;Loria P;Di L;Gosset JR;Hepworth D;Rolph T;Pfefferkorn JA;Erion DM
柠檬酸盐是一种关键的调节代谢中间体，因为它有助于糖酵解和脂质合成途径的整合。通过阻断钠偶联柠檬酸盐转运蛋白（NaCT或SLC13A5）抑制肝细胞外柠檬酸盐摄取，已被认为是治疗代谢紊乱的潜在治疗方法。NaCT将柠檬酸盐从血液转运到细胞中，与钠离子的转运相结合。本文的研究报告了能够在体外和体内选择性和有效抑制柠檬酸盐通过NaCT转运的新型小二羧酸分子（化合物2）的鉴定和表征。结合和运输实验表明，2特异性结合NaCT在竞争性和立体敏感的方式，并被认为是一个底物运输的NaCT。2的有利药代动力学特性允许在体内实验中评价抑制肝脏柠檬酸盐摄取对代谢终点的影响。
Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.