Identification of a Novel Activator of Mammalian Glutamate Dehydrogenase.
Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of l-glutamate and in animals is highly regulated. GDH in hyperinsulinism/hyperammonemia syndrome patients lacks GTP inhibition, resulting in hypersecretion of insulin upon protein consumption. This suggests insulin secretion could be stimulated with GDH activators. A high-throughput screen yielded one potent activator, N1-[4-(2-aminopyrimidin-4-yl)phenyl]-3-(trifluoromethyl)benzene-1-sulfonamide (75-E10). 75-E10 is ∼1000-fold more efficacious than the synthetic activator, BCH, and is at least as effective as ADP. 75-E10 compound is highly effective at alleviating GTP inhibition and may be binding to the ADP site. Unlike ADP, 75-E10 is activated over a broad range of conditions.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston , 301 University Boulevard, 5.104D Basic Science Building, Route 0645, Galveston, Texas 77555-0645, United States.
Hong Q
HQ
Smith
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston , 301 University Boulevard, 5.104D Basic Science Building, Route 0645, Galveston, Texas 77555-0645, United States.
Thomas J
TJ
Smith
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D000598:Amino Acids, Cyclic / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D055162:Biocatalysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000378:metabolism / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*
D000598:Amino Acids, Cyclic; D020536:Enzyme Activators; C000619505:N1-(4-(2-aminopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzene-1-sulfonamide; D011743:Pyrimidines; D013449:Sulfonamides; D009243:NAD; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; D006160:Guanosine Triphosphate; D005969:Glutamate Dehydrogenase