Glutamate Dehydrogenase (GLDH) Enzyme

This gene encodes glutamate dehydrogenase protein; a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. This enzyme has an important role in regulating amino acid induced insulin secretion and activating mutations in this gene are a common cause of congenital hyperinsulinism. This enzyme is allosterically activated by ADP and inhibited by GTP and ATP. The related glutamate dehydrogenase 2 gene on the human X-chromosome originated from this gene via retrotransposition and encodes a soluble form of glutamate dehydrogenase. Multiple pseudogenes of this gene are present in humans.

Function: May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate

Catalytic activity: L-glutamate + H2O + NAD(P)+ = 2-oxoglutarate + NH3 + NAD(P)H.

Enzyme regulation: Subject to allosteric regulation. Activated by ADP. Inhibited by GTP and ATP. ADP can occupy the NADH binding site and activate the enzyme.

Subunit structure: Homohexamer.

Subcellular location: Mitochondrion matrix.

Involvement in disease: Defects in GLUD1 are the cause of familial hyperinsulinemic hypoglycemia type 6 (HHF6) [

MIM:606762]; also known as hyperinsulinism-hyperammonemia syndrome (HHS). Familial hyperinsulinemic hypoglycemia [

MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. In HHF6 elevated oxidation rate of glutamate to alpha-ketoglutarate stimulates insulin secretion in the pancreatic beta cells, while they impair detoxification of ammonium in the liver. Ref.22 Ref.23 Ref.24 Ref.25

Sequence similarities: Belongs to the Glu/Leu/Phe/Val dehydrogenases family.