Molecular Impact Of Cofactor And Substrate On The Thermal Stability Of Human Cytosolic Sulfotransferase2A1, A Molecular Dynamics Simulation Study

Human cytosolic sulfotransferases (hSULTs) comprise a super family of phaseⅡ metabolic enzymes and they catalyze the transfer reaction of the sulfate groupfrom the ubiquitous donor3’-phosphoadenosine5’-phosphosulfate (PAPS) tonumerous substrates. HSULTs have a wide tissue distribution in human body and theyplay an important role in the metabolism of hormones and drugs, the bioactivation ofcarcinogens, and the detoxification of xenobiotics. Knowledge of the mechanisticbasis of cofactor and substrate on the thermal stability of hSULTs is crucial forunderstanding the sulfuryl transfer mechanism and metabolism function. So far thesubstrate spectrum of hSULT2A1is the broadest spectrum of hSULTs and it presentsin many tissues with a high expression rate, so we choose hSULT2A1as therepresentative of hSULTs for research. In the research about hSULTs, cofactor(3’-phosphoadenosine5’-phosphate PAP) and the substrate (lithocholic acid LCA) canincrease the thermal stability of hSULT2A1, however experiment methods could notexplain the mechanism well. When doing protein computational simulation at hightemperature, the overall character and order of events in the unfolding process arewell conserved. So we studied the influence mechanism of cofactor (PAP) andsubstrate (LCA) on the thermal stability of hSULT2A1at600K using computationalsimulation and found that these two ligands can increase the thermal stability ofhSULT2A1. These two ligands increase hSULT2A1’s thermal stability by increasingthe thermal stability of the biggest loop and adjacent parts of the loop region inhSULT2A1. When these two ligands present together, the increasing effect is thegreatest, the increasing effect of PAP only is second, and the increasing effect of LCAonly is weak. Then we also studied the influence mechanism of cofactor and substrateon the structure of hSULT2A1at310K using computational simulation and found that the structure of hSULT2A1’s biggest loop and some other adjacent parts will changeafter deleting these two ligands from hSULT2A1. Based on studies usingcomputational simulation at high temperature and body temperature, we concludedthat, when ligands present in hSULT2A1they can interact with hSULT2A1’s the partsaround them, change the chemical profiling and increase the thermal stability of theseparts, and then increase the thermal stability of hSULT2A1. When two ligands presenttogether, they have synergistic effect on increasing the thermal stability ofhSULT2A1.