title: Global view of cognate kinase activation by the human pyruvate dehydrogenase complex.
abstract: The human pyruvate dehydrogenase complex (PDC) comprises four multidomain components, E1, E3, E2 and an E3-binding protein (E3BP), the latter two forming the core as E2·E3BP sub-complex. Pyruvate flux through PDC is regulated via phosphorylation (inactivation) at E1 by four PDC kinases (PDKs), and reactivation by two PDC phosphatases. Up-regulation of PDK isoform gene expression is reported in several forms of cancer, while PDKs may be further activated by PDC by binding to the E2·E3BP core. Hence, the PDK: E2·E3BP interaction provides new therapeutic targets. We carried out both functional kinetic and thermodynamic studies to demonstrate significant differences in the activation of PDK isoforms by binding to the E2·E3BP core: (i) PDK2 needs no activation by E2·E3BP for efficient functioning, while PDK4 was the least effective of the four isoforms, and could not be activated by E2·E3BP. Hence, development of inhibitors to the interaction of PDK2 and PDK4 with E2·E3BP is not promising; (ii) Design of inhibitors to interfere with interaction of E2·E3BP with PDK1 and PDK3 is promising. PDK3 needs E2·E3BP core for activation, an activation best achieved by synergistic combination of E2-derived catalytic domain and tridomain.
authors.affiliation: Department of Chemistry, Rutgers, The State University of New Jersey, Newark, New Jersey 07102, USA.
authors.forename: Elena L
authors.initials: EL
authors.lastname: Guevara
authors.affiliation: Department of Chemistry, Rutgers, The State University of New Jersey, Newark, New Jersey 07102, USA.
authors.forename: Luying
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Jacob School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Birkaya
authors.affiliation: Department of Chemistry, Rutgers, The State University of New Jersey, Newark, New Jersey 07102, USA.
authors.forename: Jieyu
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Rutgers, The State University of New Jersey, Newark, New Jersey 07102, USA.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Nemeria
authors.affiliation: Department of Biochemistry, Jacob School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, USA.
authors.forename: Mulchand S
authors.initials: MS
authors.lastname: Patel
authors.affiliation: Department of Chemistry, Rutgers, The State University of New Jersey, Newark, New Jersey 07102, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Jordan
mesh_terms: D020134:Catalytic Domain; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D007527:Isoenzymes; C000631429:PDK1 protein, human; C000631430:PDK2 protein, human; C000631431:PDK3 protein, human; C000631432:PDK4 protein, human; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D017346:Protein Serine-Threonine Kinases