Structural and Functional Disruption of Thiopurine S‑Methyltransferase by the A80P Variant: A Simulation and...

Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme involved in the metabolism of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. Genetic polymorphisms in TPMT can reduce enzyme activity and increase the risk of adverse drug reactions. One such variant, TPMT2 (A80P), has been reported to impair TPMT function. In this study, we used molecular dynamics simulations, molecular docking, and umbrella sampling to investigate how the A80P mutation affects TPMT's structure and its interaction with the cofactor S-adenosylmethionine (SAM). Our results indicate that the mutation increases structural flexibility, reduces stability, and weakens SAM binding, suggesting compromised enzymatic function. Although TPMT2 is not directly linked to acute myeloid leukemia (AML), identifying its prevalence in AML patients has clinical value due to the potential use of thiopurines in treatment. We screened 50 AML patients and 50 healthy controls from northern India for the TPMT2 variant using PCR-based genotyping. The variant was absent in all individuals tested. These findings support the importance of population-specific pharmacogenetic screening. Tailoring genetic tests to local variant frequencies can improve cost-effectiveness, reduce unnecessary testing, and contribute to safer, more personalized cancer therapy.