Competitive inhibition of glutamate dehydrogenase reaction

• Published in: FEBS letters Vol. 581; no. 14; pp. 2733 - 2736
• Main Authors: Choudhury, Rajarshi, Punekar, Narayan S.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 12.06.2007
• Subjects: 2-Methyleneglutarate; Animals; Aspergillus - enzymology; Aspergillus niger - enzymology; Catalysis - drug effects; Cattle; Competitive inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glutamate dehydrogenase; Glutamate Dehydrogenase - antagonists & inhibitors; Glutamate Dehydrogenase - metabolism; Glutamates - metabolism; Glutarates - chemistry; Glutarates - pharmacology; Kinetics; Liver - enzymology; Methacrylate; Molecular Structure; NADP - metabolism; Phthalic Acids - pharmacology; Pyridines - pharmacology; Glutamate dehydrogenase; 2-Methyleneglutarate; Competitive inhibitors; Methacrylate
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2007.05.032

Irrespective of their pyridine nucleotide specificity, all glutamate dehydrogenases share a common chemical mechanism that involves an enzyme bound ‘iminoglutarate’ intermediate. Three compounds, structurally related to this intermediate, were tested for the inhibition of purified NADP-glutamate dehydrogenases from two Aspergilli, as also the bovine liver NAD(P)-glutamate dehydrogenase. 2-Methyleneglutarate, closely resembling iminoglutarate, was a potent competitive inhibitor of the glutamate dehydrogenase reaction. This is the first report of a non-aromatic structure with a better glutamate dehydrogenase inhibitory potency than aryl carboxylic acids such as isophthalate. A suitably located 2-methylene group to mimic the iminium ion could be exploited to design inhibitors of other amino acid dehydrogenases.