Abstract
Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235–263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages.
Highlights
Various endogenous and exogenous compounds in the body are metabolized by the sulfonation process, which is generally initiated by sulfotransferases [1,2]
The mutation of our interest, R213H is located between Loop2 and 3, and its contribution to Sulfotransferase 1A1 (SULT1A1) dysfunction was systematically analyzed by 100 ns molecular dynamics simulation by considering both wild and mutant type structures in the presence and absence of substrate (Figure 1b,c)
The correlative motion in SULTA1 based on the dynamic cross correlation matrix (DCCM) analysis showed that mutation reduced the correlative motions in the loop1 and loop3 of active site as a results structure flexibility is lost in those positions, which was clearly reflected through collective motion analysis by principle component analysis (PCA)
Summary
Various endogenous and exogenous compounds in the body are metabolized by the sulfonation process, which is generally initiated by sulfotransferases [1,2]. Mutation at 213 positions of SULT1A1 exon 7 (rs9282861) [16,17] was reported by multiple studies to be involved in breast cancer progression [18], especially among the postmenopausal Asian women [19,20]. Patients having rs9282861 mutation, which caused the change of an amino acid from arginine to histidine at the 213th position (R213H), may have a higher susceptibility for developing esophageal cancer, due to the lower enzymatic activity and thermal stability that affect the procarcinogens metabolisms [4,8,26,27], including various steroid hormones, neurotransmitters, and non-opiateanalgesics [28,29]. The substitution occurred with amino acid having the same side chain polarity, the mutation was reported to reduce the binding affinity of various substrates, as well as their pharmacokinetic properties [27,30,31]
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