Molecular dynamics simulation of a human thiopurine S-methyltransferase complexed with 6-mercaptopurine model

Wanwimon Mokmak,Sissades Tongsima,Ekachai Jenwitheesuk

doi:10.6026/97320630004059

Abstract

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.

Highlights

Thiopurine drugs including 6-mercaptopurine (6MP), 6thioguanine, and azathioprine have wide clinical applications ranging from immunosuppressants for preventing graft-rejection in organ transplant patients, to treatment of diseases such as childhood acute lymphoblastic leukemia, autoimmune disorder, and inflammatory bowel disease [1,2,3]
The toxicity of these drugs is ameliorated by conversion to methylated forms by the thiopurine Smethyltransferase enzyme (TPMT), which uses S-adenosyl-Lmethionine (AdoMet), as a methyl donor
We modeled the AdoMet is converted to Sadenosylhomocysteine (AdoHcy)(CH2)6MP complex in the human TPMT active site and performed 1300 picoseconds molecular dynamic (MD) simulations to investigate the atomic interactions and dynamic properties of TPMT, AdoHcy, and 6MP

Summary

Background

Thiopurine drugs including 6-mercaptopurine (6MP), 6thioguanine, and azathioprine have wide clinical applications ranging from immunosuppressants for preventing graft-rejection in organ transplant patients, to treatment of diseases such as childhood acute lymphoblastic leukemia, autoimmune disorder, and inflammatory bowel disease [1,2,3]. The co-crystal structure of this complex has not been reported because 6MP is poorly water soluble [8] To address this problem, we modeled the AdoHcy(CH2)6MP complex in the human TPMT active site and performed 1300 picoseconds (ps) molecular dynamic (MD) simulations to investigate the atomic interactions and dynamic properties of TPMT, AdoHcy, and 6MP. The PDB structures of the last 100 ps were extracted from the MD simulated trajectories to generate the average structure, which was subsequently used for 6MP binding mode and the corresponding interaction analysis

Discussion

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Findings

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