Abstract
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.
MeSH terms
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Adenosine Diphosphate / metabolism
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Adenosine Diphosphate / pharmacology
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Allosteric Regulation / drug effects
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Amino Acids, Cyclic / metabolism
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Amino Acids, Cyclic / pharmacology
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Animals
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Binding, Competitive
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Biocatalysis / drug effects
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Enzyme Activators / metabolism
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Enzyme Activators / pharmacology*
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Glutamate Dehydrogenase / chemistry
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Glutamate Dehydrogenase / metabolism*
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Glutamic Acid / metabolism*
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Guanosine Triphosphate / metabolism
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Guanosine Triphosphate / pharmacology
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Humans
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Kinetics
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Models, Molecular
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NAD / metabolism*
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Protein Binding
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Protein Domains
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Pyrimidines / metabolism
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Pyrimidines / pharmacology*
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Spectrometry, Fluorescence
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Sulfonamides / metabolism
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Sulfonamides / pharmacology*
Substances
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Amino Acids, Cyclic
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Enzyme Activators
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N1-(4-(2-aminopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzene-1-sulfonamide
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Pyrimidines
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Sulfonamides
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NAD
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2-aminobicyclo(2,2,1)heptane-2-carboxylic acid
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Glutamic Acid
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Adenosine Diphosphate
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Guanosine Triphosphate
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Glutamate Dehydrogenase