title: The structure and allosteric regulation of mammalian glutamate dehydrogenase.
abstract: Glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate. Only in the animal kingdom is this enzyme heavily allosterically regulated by a wide array of metabolites. The major activators are ADP and leucine, while the most important inhibitors include GTP, palmitoyl CoA, and ATP. Recently, spontaneous mutations in the GTP inhibitory site that lead to the hyperinsulinism/hyperammonemia (HHS) syndrome have shed light as to why mammalian GDH is so tightly regulated. Patients with HHS exhibit hypersecretion of insulin upon consumption of protein and concomitantly extremely high levels of ammonium in the serum. The atomic structures of four new inhibitors complexed with GDH complexes have identified three different allosteric binding sites. Using a transgenic mouse model expressing the human HHS form of GDH, at least three of these compounds were found to block the dysregulated form of GDH in pancreatic tissue. EGCG from green tea prevented the hyper-response to amino acids in whole animals and improved basal serum glucose levels. The atomic structure of the ECG-GDH complex and mutagenesis studies is directing structure-based drug design using these polyphenols as a base scaffold. In addition, all of these allosteric inhibitors are elucidating the atomic mechanisms of allostery in this complex enzyme.
authors.affiliation: Donald Danforth Plant Science Center, 975 North Warson Road, Saint Louis, MO 63132, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Aron
authors.initials: A
authors.lastname: Allen
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Smith
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D007003:Hypoglycemia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D005969:Glutamate Dehydrogenase
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