通过定量构效关系建模和同源酶分析理解人类尿苷二磷酸葡萄糖醛酸转移酶的底物选择性
Understanding substrate selectivity of human UDP-glucuronosyltransferases through QSAR modeling and analysis of homologous enzymes.
作者信息
Dong Dong, Ako Roland, Hu Ming, Wu Baojian
机构信息
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77030, USA.
出版信息
Xenobiotica. 2012 Aug;42(8):808-20. doi: 10.3109/00498254.2012.663515. Epub 2012 Mar 2.
Abstract
The UDP-glucuronosyltransferase (UGT) enzyme catalyzes the glucuronidation reaction which is a major metabolic and detoxification pathway in humans. Understanding the mechanisms for substrate recognition by UGT assumes great importance in an attempt to predict its contribution to xenobiotic/drug disposition in vivo. Spurred on by this interest, 2D/3D-quantitative structure activity relationships and pharmacophore models have been established in the absence of a complete mammalian UGT crystal structure. This review discusses the recent progress in modeling human UGT substrates including those with multiple sites of glucuronidation. A better understanding of UGT active site contributing to substrate selectivity (and regioselectivity) from the homologous enzymes (i.e. plant and bacterial UGTs, all belong to family 1 of glycosyltransferase (GT1)) is also highlighted, as these enzymes share a common catalytic mechanism and/or overlapping substrate selectivity.
摘要
尿苷二磷酸葡萄糖醛酸基转移酶（UGT）催化葡萄糖醛酸化反应，这是人体主要的代谢和解毒途径。了解UGT识别底物的机制对于预测其在体内对外源化合物/药物处置的贡献至关重要。受此兴趣的推动，在缺乏完整的哺乳动物UGT晶体结构的情况下，已经建立了二维/三维定量构效关系和药效团模型。本综述讨论了在模拟人类UGT底物方面的最新进展，包括那些具有多个葡萄糖醛酸化位点的底物。还强调了从同源酶（即植物和细菌UGT，均属于糖基转移酶家族1（GT1））中更好地理解有助于底物选择性（和区域选择性）的UGT活性位点，因为这些酶具有共同的催化机制和/或重叠的底物选择性。
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