Impacts of 119 missense variants at functionally important sites of drug-metabolizing human cytosolic sulfotransferase SULT1A1: An in silico study

Sulfotransferase 1A1 (SULT1A1), a major cytosolic sulfotransferase, can catalyze the sulfonation of both endogenous and exogenous compounds. It participates in the metabolism of several drugs and pro-carcinogens. Although certain variants of the SULT1A1 are known to alter responses to drugs and increase susceptibility to various cancers, the effects of the majority of SULT1A1 variants are still unknown. In the present study, we predicted the potential pathogenicity of 119 missense variants at 96 functionally important sites of SULT1A1, and examined the effects of these variants on the enzyme's structure and stability using state-of the-art in silico tools. Additionally, we applied molecular docking and protein dynamics simulation techniques to assess the impacts of missense variants on SULT1A1-cofactor binding affinity and SULT1A1 residue fluctuation profile, respectively. Based on the extent of reduction in SULT1A1 stability, alteration in structure, decrease in cofactor binding affinity and changes in the flexibility of cofactor and substrate-interacting loops, we suggest that further experimental studies should particularly focus on 25 variants (P47L, K48T, S49A, G50R, G50S, W53R, C70G, C70R, A86D, H108D, H108N, S138F, M145I, Y169D, Y193F, T227P, M232L, V243D, M248T, G259A, G259V, A261S, G262A, G262E, F268S). Besides, our study sheds light on the possible mechanism of altered functionality of some already known detrimental variants of SULT1A1. Future studies may look into the prospects of using these variants as pharmacogenetic markers.