Karthikeyan Bagavathy Shanmugam, Suvaithenamudhan Suvaiyarasan, Akbarsha Mohammad Abdulkader, Parthasarathy Subbiah
Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli, 620 024, Tamil Nadu, India.
Mahatma Gandhi-Doerenkamp Center (MGDC) for Alternatives to Use of Animals in Life Science Education, Bharathidasan University, Tiruchirappalli, 620 024, Tamil Nadu, India.
Cell Biochem Biophys. 2018 Jun;76(1-2):91-110. doi: 10.1007/s12013-017-0791-8. Epub 2017 Mar 29.
Cytochrome P450 (CYP) 1A and 2B subfamily enzymes are important drug metabolizing enzymes, and are highly conserved across species in terms of sequence homology. However, there are major to minor structural and macromolecular differences which provide for species-selectivity and substrate-selectivity. Therefore, species-selectivity of CYP1A and CYP2B subfamily proteins across human, mouse and rat was analyzed using molecular modeling, docking and dynamics simulations when the chiral molecules quinine and quinidine were used as ligands. The three-dimensional structures of 17 proteins belonging to CYP1A and CYP2B subfamilies of mouse and rat were predicted by adopting homology modeling using the available structures of human CYP1A and CYP2B proteins as templates. Molecular docking and dynamics simulations of quinine and quinidine with CYP1A subfamily proteins revealed the existence of species-selectivity across the three species. On the other hand, in the case of CYP2B subfamily proteins, no role for chirality of quinine and quinidine in forming complexes with CYP2B subfamily proteins of the three species was indicated. Our findings reveal the roles of active site amino acid residues of CYP1A and CYP2B subfamily proteins and provide insights into species-selectivity of these enzymes across human, mouse, and rat.
细胞色素P450（CYP）1A和2B亚家族酶是重要的药物代谢酶，在序列同源性方面在物种间高度保守。然而，存在主要到次要的结构和大分子差异，这导致了物种选择性和底物选择性。因此，当使用手性分子奎宁和奎尼丁作为配体时，通过分子建模、对接和动力学模拟分析了CYP1A和CYP2B亚家族蛋白在人、小鼠和大鼠中的物种选择性。以人CYP1A和CYP2B蛋白的可用结构为模板，采用同源建模预测了小鼠和大鼠CYP1A和CYP2B亚家族的17种蛋白的三维结构。奎宁和奎尼丁与CYP1A亚家族蛋白的分子对接和动力学模拟揭示了这三个物种之间存在物种选择性。另一方面，对于CYP2B亚家族蛋白，未表明奎宁和奎尼丁的手性在与这三个物种的CYP2B亚家族蛋白形成复合物中的作用。我们的研究结果揭示了CYP1A和CYP2B亚家族蛋白活性位点氨基酸残基的作用，并为这些酶在人、小鼠和大鼠中的物种选择性提供了见解。
