Glutamate dehydrogenase: Structure, allosteric regulation, and role in insulin homeostasis

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

Research output: Contribution to journalArticle

25 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 and inhibitors include GTP, palmitoyl CoA, and ATP. 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 blocked 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)433-445
Number of pages13
JournalNeurochemical Research
Volume39
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Fingerprint

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

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Biochemistry

Cite this

Glutamate dehydrogenase : Structure, allosteric regulation, and role in insulin homeostasis. / Li, Ming; Li, Changhong; Allen, Aron; Stanley, Charles A.; Smith, Thomas.

In: Neurochemical Research, Vol. 39, No. 3, 03.2014, p. 433-445.

Research output: Contribution to journalArticle

Li, Ming ; Li, Changhong ; Allen, Aron ; Stanley, Charles A. ; Smith, Thomas. / Glutamate dehydrogenase : Structure, allosteric regulation, and role in insulin homeostasis. In: Neurochemical Research. 2014 ; Vol. 39, No. 3. pp. 433-445.
@article{3acdae5d7b4b4988891259d321118fbb,
title = "Glutamate dehydrogenase: Structure, allosteric regulation, and role in insulin homeostasis",
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 and inhibitors include GTP, palmitoyl CoA, and ATP. 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 blocked 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.",
keywords = "Allostery, Glutamate dehydrogenase, Insulin regulation, Polyphenols, Protein dynamics, Subunit communication",
author = "Ming Li and Changhong Li and Aron Allen and Stanley, {Charles A.} and Thomas Smith",
year = "2014",
month = "3",
doi = "10.1007/s11064-013-1173-2",
language = "English (US)",
volume = "39",
pages = "433--445",
journal = "Neurochemical Research",
issn = "0364-3190",
publisher = "Springer New York",
number = "3",

}

TY - JOUR

T1 - Glutamate dehydrogenase

T2 - Structure, allosteric regulation, and role in insulin homeostasis

AU - Li, Ming

AU - Li, Changhong

AU - Allen, Aron

AU - Stanley, Charles A.

AU - Smith, Thomas

PY - 2014/3

Y1 - 2014/3

N2 - 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 and inhibitors include GTP, palmitoyl CoA, and ATP. 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 blocked 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.

AB - 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 and inhibitors include GTP, palmitoyl CoA, and ATP. 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 blocked 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.

KW - Allostery

KW - Glutamate dehydrogenase

KW - Insulin regulation

KW - Polyphenols

KW - Protein dynamics

KW - Subunit communication

UR - http://www.scopus.com/inward/record.url?scp=84896704629&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896704629&partnerID=8YFLogxK

U2 - 10.1007/s11064-013-1173-2

DO - 10.1007/s11064-013-1173-2

M3 - Article

C2 - 24122080

AN - SCOPUS:84896704629

VL - 39

SP - 433

EP - 445

JO - Neurochemical Research

JF - Neurochemical Research

SN - 0364-3190

IS - 3

ER -