Comparative modelling of the human UDP-glucuronosyltransferases: Insights into structure and mechanism
Comparative modelling of the human UDP-glucuronosyltransferases: Insights into structure and mechanism
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DOI：
10.1080/00498250601129109
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发表时间：
2007-02-01
期刊：
影响因子：
1.8
通讯作者：
Tracy, T. S.
中科院分区：
文献类型：
--
作者：
Locuson, C. W.;Tracy, T. S.
UDP-葡萄糖醛酸基转移酶 (UGT) 通过催化葡萄糖醛酸与可用氧、氮和硫原子的结合来影响药物和其他外源物质的处置。几种相关的哺乳动物 UGT 亚型的表达对它们在肝脏和其他组织中遇到的底物具有不同的结合亲和力和周转率。由于没有高分辨率结构信息可用于剖析产生不同特异性的酶-底物相互作用，因此进行了搜索以找到用于比较蛋白质建模的最佳可用模板。序列同一性分析用于鉴定一些最近结晶的植物UGT作为微粒体UGT的同源物。由于 UGT 含有罗斯曼折叠基序，预计会与含 UDP 的糖供体底物结合，因此该共有序列用于帮助序列比对，其他被认为参与催化或底物结合的保守残基以及预测的二级结构也是如此。与 UDP 与植物 UGT71G1 模板共结晶相比，UDP-葡萄糖醛酸与 UGT1A1 模型的对接导致均方根偏差仅为 0.37 埃。讨论了为 UGT1A1 生成的比较模型对于糖供体和糖苷配基结合位点以及机制的重要性。
UDP-glucuronosyltranferases (UGTs) affect the disposition of drugs and other xenobiotics by catalysing the conjugation of glucuronic acid to available oxygen, nitrogen, and sulfur atoms. Several related mammalian isoforms of UGT are expressed that have different binding affinities and turnover rates for the substrates they encounter in the liver and other tissues. Because no high-resolution structural information is available to dissect the enzyme-substrate interactions that give rise to different specificities, a search was conducted to find the best available templates to use for comparative protein modelling. Sequence identity analysis was used to identify some recently crystallized plant UGTs as homologues of microsomal UGTs. Because UGTs contain a Rossman fold motif predicted to bind the UDP-containing sugar donor substrate, this consensus sequence was used to aid sequence alignment, as were other conserved residues thought to be involved in catalysis or substrate binding, and the predicted secondary structure. Docking of UDP-glucuronic acid to a model of UGT1A1 resulted in a root mean square deviation of only 0.37 angstrom vs. UDP co-crystallized with the plant UGT71G1 template. The significance of a comparative model generated for UGT1A1 with respect to both the sugar donor and aglycone binding sites, and mechanism, is discussed.