Synergistic Allosteric Mechanism Of PKM2

Pyruvate kinase is a rate-limiting enzyme which plays an important role in the last step of glycosis.In previous studies,it has been found that fructose-1,6-bisphosphate(FBP)is an allosteric regulator for Pyruvate kinase's activity.However,a recent study has found that its isoform PKM2 is very active in tumor cells,and serine also has the function of allosteric regulation for PKM2.Althogh more and more allsosteric regulations in biosomes were reported recently,we were still confused by the allosteric mechanisms.And in this thesis,we tried to illustrate the allosteric regulation mechanism and the relationship between the two allosteric regulators in PKM2 via molecular dynamics simulation and dynamics correlation network analysis which was a newly found method.The results showed there might be a synergistic allosteric regulation for the two regulators.We also found two potential allosteric pathways for PKM2 via network analysis.One is FBP-K433-T459-R461-A109-V71-R73-MG2-substrate,and another is Ser-I47-C49-R73-MG2-substrate.They all have a common residue R73,which has never been reported and found very important in our research.We hope the method used in this thesis may be helpful for other allosteric regulation research.And we also hope the allosteric pathways and key residues we found in PKM2 can be assist for the treatment of cancers.