Effect of pyridoxal phosphate and tetrahydrofolate bound on human serine hydroxymethyltransferase by molecular dynamic simulation

Abstract

Serine hydroxymethyltransferase (SHMT), a pyridoxal phosphate (PLP)-dependent enzyme, is involved in one-carbon metabolism in multiple biochemical pathways, including the biosynthesis of purine and thymidine. SHMT1 is the enzyme to be studied clinically as a target for cancer chemotherapy. Therefore, the binding mechanism of this enzyme would be investigated. In this study, molecular dynamics simulations for 500 ns was applied on SHMT1 tetramer in six systems with different ligand cofactors (PLP-Lys, L-ser, PLS, PLG, THF, and MTHF) in order to understand its structural dynamics properties. The key residues Y’73, S53, H231, K257, R263 and R402 were found in all ligand cofactor/SHMT1 systems. All ligand cofactors of each SHMT1 system were stabilized by a strong hydrogen bond with S119 and G120 residues. In addition, the PLS and PLG systems showed strong stabilization with SHMT1 rather than THF and MTHF. Among systems, the MTHF/PLG ligands in system 5 showed the highest binding affinity with SHMT1. Our results could be used as theoretical guidance for inhibitor developments toward SHMT1, which targeting anti-cancer inhibitors