Competitive inhibition of glutamate dehydrogenase reaction.
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.
Choudhury
Rajarshi
R
Biotechnology Group, SBB, Indian Institute of Technology, Powai, Mumbai, India.
Punekar
Narayan S
NS
D000818:Animals; D001230:Aspergillus / Q000201:enzymology; D001234:Aspergillus niger / Q000201:enzymology; D002384:Catalysis / Q000187:drug effects; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D005977:Glutarates / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005971:Glutamates; D005977:Glutarates; D010795:Phthalic Acids; D011725:Pyridines; C059768:isophthalate; C055293:2,4-pyridinedicarboxylic acid; D009249:NADP; C002172:2-methyleneglutaric acid; D005969:Glutamate Dehydrogenase