Mokmak Wanwimon, Tongsima Sissades, Jenwitheesuk Ekachai
National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, 113 Thailand Science Park, Phahonyothin Road, Klong 1, Klongluang, Pathumthani 12120, Thailand.
Bioinformation. 2009 Sep 5;4(2):59-62. doi: 10.6026/97320630004059.
Human thiopurine S-methyltransferase (TPMT) is an essential protein in 6-mercaptopurine (6MP) drug metabolism. To understand the pharmacogenetics of TPMT and 6MP, X-ray co-crystal structures of TPMT complexes with S-adenosyl-L-methionine (AdoMet) and 6MP are required. However, the co-crystal structure of this complex has not been reported because 6MP is poorly water soluble. We used molecular dynamics (MD) simulation to predict the structure of the complex of human TPMT-AdoHcy(CH(2))6MP, where the sulfur atoms of AdoHcy and 6MP were linked by a CH(2) group. After 1300 picoseconds of MD simulation, the trajectory showed that 6MP was stabilized in the TPMT active site by formation of non-bonded interactions between 6MP and Phe40, Pro196 and Arg226 side chains of TPMT. The intersulfur distance between AdoHcy and 6MP as well as the binding modes and the interactions of our TPMT-AdoHcy model are consistent with those observed in the X-ray crystal structure of murine TPMT-AdoHcy-6MP complex. The predicted binding modes of AdoHcy and 6MP in our model are consistent with those observed in murine TPMT X-ray crystal structures, which provides structural insights into the interactions of TPMT, AdoHcy, and 6MP at the atomic level and may be used as a starting point for further study of thiopurine drug pharmacogenetics.
人硫嘌呤 S - 甲基转移酶（TPMT）是 6 - 巯基嘌呤（6MP）药物代谢中的一种重要蛋白质。为了解 TPMT 和 6MP 的药物遗传学，需要 TPMT 与 S - 腺苷 - L - 甲硫氨酸（AdoMet）和 6MP 复合物的 X 射线共晶体结构。然而，由于 6MP 的水溶性较差，该复合物的共晶体结构尚未见报道。我们使用分子动力学（MD）模拟来预测人 TPMT - AdoHcy(CH(2))6MP 复合物的结构，其中 AdoHcy 和 6MP 的硫原子通过一个 CH(2) 基团相连。经过 1300 皮秒的 MD 模拟，轨迹显示 6MP 通过与 TPMT 的 Phe40、Pro196 和 Arg226 侧链形成非键相互作用而稳定在 TPMT 活性位点。我们的 TPMT - AdoHcy 模型中 AdoHcy 和 6MP 之间的硫间距离以及结合模式和相互作用与在小鼠 TPMT - AdoHcy - 6MP 复合物的 X 射线晶体结构中观察到的一致。我们模型中预测的 AdoHcy 和 6MP 的结合模式与在小鼠 TPMT X 射线晶体结构中观察到的一致，这为 TPMT、AdoHcy 和 6MP 在原子水平上的相互作用提供了结构见解，并可作为进一步研究硫嘌呤类药物药物遗传学的起点。
