The structure and allosteric regulation of mammalian glutamate dehydrogenase

Ming Li, Changhong Li, Aron Allen, Charles A. Stanley, Thomas Smith

Research output: Contribution to journalArticle

68 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)69-80
Number of pages12
JournalArchives of Biochemistry and Biophysics
Volume519
Issue number2
DOIs
StatePublished - Mar 15 2012
Externally publishedYes

Fingerprint

Allosteric Regulation
Glutamate Dehydrogenase
Guanosine Triphosphate
Animals
Enzymes
Palmitoyl Coenzyme A
Allosteric Site
Mutagenesis
Deamination
Drug Design
Polyphenols
Tea
Metabolites
Serum
Electrocardiography
Ammonium Compounds
Scaffolds
Leucine
Adenosine Diphosphate
Transgenic Mice

Keywords

  • Allostery
  • Glutamate dehydrogenase
  • Insulin regulation
  • Polyphenols
  • Protein dynamics
  • Subunit communication

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

The structure and allosteric regulation of mammalian glutamate dehydrogenase. / Li, Ming; Li, Changhong; Allen, Aron; Stanley, Charles A.; Smith, Thomas.

In: Archives of Biochemistry and Biophysics, Vol. 519, No. 2, 15.03.2012, p. 69-80.

Research output: Contribution to journalArticle

Li, Ming ; Li, Changhong ; Allen, Aron ; Stanley, Charles A. ; Smith, Thomas. / The structure and allosteric regulation of mammalian glutamate dehydrogenase. In: Archives of Biochemistry and Biophysics. 2012 ; Vol. 519, No. 2. pp. 69-80.
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