Kumar Kundan, Dhoke Gaurao V, Sharma Ashok K, Jaiswal Shubham K, Sharma Vineet K
Department of Biological Sciences, Metagenomics and Systems Biology Laboratory, Indian Institute of Science Education and Research Bhopal, Bhopal, India.
J Cell Biochem. 2019 Jul;120(7):11206-11215. doi: 10.1002/jcb.28396. Epub 2019 Jan 30.
The human gut harbors diverse bacterial species in the gut, which play an important role in the metabolism of food and host health. Recent studies have also revealed their role in altering the pharmacological properties and efficacy of oral drugs through promiscuous metabolism. However, the atomistic details of the enzyme-drug interactions of gut bacterial enzymes which can potentially carry out the metabolism of drug molecules are still scarce. A well-known example is the FDA drug amphetamine (a central nervous system stimulant), which has been predicted to undergo promiscuous metabolism by gut bacteria. Therefore, to understand the atomistic details and energy landscape of the gut microbial enzyme-mediated metabolism of this drug, molecular dynamics studies were performed. It was observed that amphetamine binds to tyramine oxidase from the Escherichia coli strain present in the human gut microbiota at the binding site harboring polar and nonpolar amino acids. The stability analysis of amphetamine at the binding site showed that the binding is stable and the free energy for the binding of amphetamine was found to be ~ -51.71 kJ/mol. The insights provided by this study on promiscuous metabolism of amphetamine by a gut enzyme will be very useful to improve the efficacy of the drug.
人类肠道中栖息着多种细菌，它们在食物代谢和宿主健康中发挥着重要作用。最近的研究还揭示了它们通过杂乱代谢改变口服药物的药理性质和疗效的作用。然而，可能参与药物分子代谢的肠道细菌酶与药物相互作用的原子细节仍然很少。一个著名的例子是美国食品药品监督管理局（FDA）批准的药物苯丙胺（一种中枢神经系统兴奋剂），据预测它会被肠道细菌进行杂乱代谢。因此，为了了解这种药物在肠道微生物酶介导的代谢中的原子细节和能量态势，进行了分子动力学研究。研究发现，苯丙胺在人类肠道微生物群中存在的大肠杆菌菌株的酪胺氧化酶的含有极性和非极性氨基酸的结合位点处结合。苯丙胺在结合位点的稳定性分析表明，这种结合是稳定的，并且发现苯丙胺结合的自由能约为-51.71kJ/mol。这项关于肠道酶对苯丙胺进行杂乱代谢的研究提供的见解对于提高该药物的疗效将非常有用。
