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首页> 外文期刊>Biochemical Pharmacology >Insight into tartrate inhibition patterns in vitro and in vivo based on cocrystal structure with UDP-glucuronosyltransferase 2B15
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Insight into tartrate inhibition patterns in vitro and in vivo based on cocrystal structure with UDP-glucuronosyltransferase 2B15

机译：基于UDP-葡糖醛阳糖基转移酶2B15的COCRYSTAL结构在体外和体内体内洞察酒石酸抑制模式

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摘要

Glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGTs), is a crucial substance metabolism and elimination process that mostly occurs in the liver to protect the body from toxic substances and maintain homeostasis. The reaction functions well in a uridine diphosphate glucuronic acid (UDPGA) -dependent manner in vivo. However, the mechanism for recognizing UDPGA or analog has not been reported so far. Here, through X-ray crystallography, we present a 1.78 angstrom cocrystal structure of the C-terminal domain of UDP-glucuronosyltransferase 2B15 (2B15CTD, K284-H451) bound by tartrate, which reveals the detailed recognition mechanism of UDPGA analog at the active site. Using surface plasmon resonance techniques, protein thermal shift studies, and limited proteolysis, we determine that tartrate stabilizes the conformation of 2B15CTD thermodynamically. The biochemical analysis further elucidates that two residues, S312 and T374, are essential for the interactions between 2B15CTD and tartrate. We also investigate the pharmacological effects of tartrate on UGTs based on the cocrystal structure of UGT2B15 and experiments performed in vitro and in vivo. In brief, the LC-MS/MS analysis shows that tartrate has a significant inhibitory effect towards UGT2B15 (K-i = 91 mu M), and oral administration of tartrate to FVB mice can reduce the relative plasma concentration of glucuronide. These results reveal an unexpected physiological role of tartrate in the maintenance of UGTs function. Therefore, tartrate is a potential inhibitor of UGTs, and the excess tartrate in the diet may disturb body homeostasis and inhibit the metabolism of UGT substrates by interfering with glucuronidation.
机译：由UDP-葡糖醛糖基三烷基酶（UGT）催化的葡萄糖醛酸钠是一种重要的物质代谢和消除过程，主要发生在肝脏中，以保护身体免受有毒物质和维持稳态。反应在体内尿苷二磷酸葡糖醛酸（UDPGA）依赖性效果良好。然而，到目前为止尚未报告识别UDPGA或类似物的机制。这里，通过X射线晶体学，我们介绍了通过酒石酸酯的UDP-葡糖糖基三烷基转移酶2b15（2b15ctd，K284-H451）的C-末端结构域的1.78埃埃斯特罗斯结构。揭示了在活性位点的UDPGA类似物的详细识别机制。使用表面等离子体共振技术，蛋白质热换档研究和有限的蛋白水解，我们确定酒石酸酯稳定2b15ctd热力学的构象。生物化学分析进一步阐明了，两个残基S312和T374对于2B15CTD和酒石酸酯之间的相互作用是必不可少的。我们还研究基于UGT2B15的COCRYSTAL结构的酒石酸酯对UGT的药理作用，并在体外和体内进行实验。简而言之，LC-MS / MS分析表明，酒石酸酯对UGT2B15（K-I =91μm）具有显着的抑制作用，并且吲哚酮酸酯的酒石酸酯的口服给予葡糖醛酸葡萄糖的相对血浆浓度。这些结果揭示了酒石酸术在维护UGTS功能中的意外生理作用。因此，酒石酸含量是UGT的潜在抑制剂，饮食中的多余酒石酸盐可能会使身体稳态扰乱，并通过干扰葡糖醛酸化来抑制UGT基质的代谢。

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