title: Synergistic Allosteric Mechanism of Fructose-1,6-bisphosphate and Serine for Pyruvate Kinase M2 via Dynamics Fluctuation Network Analysis.
abstract: Pyruvate kinase M2 (PKM2) plays a key role in tumor metabolism and regulates the rate-limiting final step of glycolysis. In tumor cells, there are two allosteric effectors for PKM2: fructose-1,6-bisphosphate (FBP) and serine. However, the relationship between FBP and serine for allosteric regulation of PKM2 is unknown. Here we constructed residue/residue fluctuation correlation network based on all-atom molecular dynamics simulations to reveal the regulation mechanism. The results suggest that the correlation network in bound PKM2 is distinctly different from that in the free state, FBP/PKM2, or Ser/PKM2. The community network analysis indicates that the information can freely transfer from the allosteric sites of FBP and serine to the substrate site in bound PKM2, while there exists a bottleneck for information transfer in the network of the free state. Furthermore, the binding free energy between the substrate and PKM2 for bound PKM2 is significantly lower than either of FBP/PKM2 or Ser/PKM2. Thus, a hypothesis of "synergistic allosteric mechanism" is proposed for the allosteric regulation of FBP and serine. This hypothesis was further confirmed by the perturbational and mutational analyses of community networks and binding free energies. Finally, two possible synergistic allosteric pathways of FBP-K433-T459-R461-A109-V71-R73-MG2-OXL and Ser-I47-C49-R73-MG2-OXL were identified based on the shortest path algorithm and were confirmed by the network perturbation analysis. Interestingly, no similar pathways could be found in the free state. The process targeting on the allosteric pathways can better regulate the glycolysis of PKM2 and significantly inhibit the progression of tumor.
authors.affiliation: State Key Laboratory of Microbial metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
authors.forename: Jingxu
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Microbial metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Microbial metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
authors.forename: Chengbo
authors.initials: C
authors.lastname: Gu
authors.affiliation: Departments of Molecular Biology and Biochemistry, Chemical Engineering and Materials Science, Biomedical Engineering, University of California, Irvine, California 92697-3900, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Microbial metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.|Shanghai Center for Bioinformation Technology, 1278 Keyuan Road, Shanghai, 200235, China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Chen
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D004357:Drug Synergism; D004795:Enzyme Stability / Q000187:drug effects; D005635:Fructosediphosphates / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011487:Protein Conformation; D011770:Pyruvate Kinase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D005635:Fructosediphosphates; D012694:Serine; C027652:fructose 2,6-diphosphate; D011770:Pyruvate Kinase