title: Interaction between glutamate dehydrogenase (GDH) and L-leucine catabolic enzymes: intersecting metabolic pathways.
abstract: Branched-chain amino acids (BCAAs) catabolism follows sequential reactions and their metabolites intersect with other metabolic pathways. The initial enzymes in BCAA metabolism, the mitochondrial branched-chain aminotransferase (BCATm), which deaminates the BCAAs to branched-chain α-keto acids (BCKAs); and the branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC), which oxidatively decarboxylates the BCKAs, are organized in a supramolecular complex termed metabolon. Glutamate dehydrogenase (GDH1) is found in the metabolon in rat tissues. Bovine GDH1 binds to the pyridoxamine 5'-phosphate (PMP)-form of human BCATm (PMP-BCATm) but not to pyridoxal 5'-phosphate (PLP)-BCATm in vitro. This protein interaction facilitates reamination of the α-ketoglutarate (αKG) product of the GDH1 oxidative deamination reaction. Human GDH1 appears to act like bovine GDH1 but human GDH2 does not show the same enhancement of BCKDC enzyme activities. Another metabolic enzyme is also found in the metabolon is pyruvate carboxylase (PC). Kinetic results suggest that PC binds to the E1 decarboxylase of BCKDC but does not effect BCAA catabolism. The protein interaction of BCATm and GDH1 promotes regeneration of PLP-BCATm which then binds to BCKDC resulting in channeling of the BCKA products from BCATm first half reaction to E1 and promoting BCAA oxidation and net nitrogen transfer from BCAAs. The cycling of nitrogen through glutamate via the actions of BCATm and GDH1 releases free ammonia. Formation of ammonia may be important for astrocyte glutamine synthesis in the central nervous system. In peripheral tissue association of BCATm and GDH1 would promote BCAA oxidation at physiologically relevant BCAA concentrations.
authors.affiliation: Department of Human Nutrition, Foods & Exercise, Virginia Tech, Blacksburg, VA 24061, United States. susanh5@vt.edu
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hutson
authors.forename: Mohammad Mainul
authors.initials: MM
authors.lastname: Islam
authors.forename: Ioannis
authors.initials: I
authors.lastname: Zaganas
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D004734:Energy Metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005969:Glutamate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000502:physiology*; D060066:Protein Interaction Maps / Q000502:physiology; D051381:Rats
chemical_list: D000597:Amino Acids, Branched-Chain; D009097:Multienzyme Complexes; D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human; C521120:GLUD2 protein, human; D007930:Leucine