Glutamate dehydrogenase

Glutamate dehydrogenase (GLDH) is an enzyme, present in most microbes and the mitochondria of eukaryotes, as are some of the other enzymes required for urea synthesis, that converts glutamate to α-Ketoglutarate, and vice versa. In animals, the produced ammonia is, however, usually bled off to the urea cycle. Typically, the α-Ketoglutarate to glutamate reaction does not occur in mammals as glutamate dehydrogenase equilibrium favours the production of ammonia and α-Ketoglutarate. Glutamate dehydrogenase also has a very high affinity for ammonia (1 mM), and therefore toxic levels of ammonia would have to be present in the body for the reverse reaction to proceed (that is, α-Ketoglutarate and ammonia to glutamate and NAD(P)+). In bacteria, the ammonia is assimilated to amino acids via glutamate and amidotransferases.^[1] In plants, the enzyme can work in either direction depending on environment and stress.^[2][3] Transgenic plants expressing microbial GLDHs are improved in tolerance to herbicide, water deficit, and pathogen infections.^[4] They are more nutritionally valuable.^[5]

The enzyme represents a key link between catabolic and metabolic pathways, and is, therefore, ubiquitous in eukaryotes.

Clinical application

GLDH can be measured in a medical laboratory to evaluate the liver function. Elevated blood serum GLDH levels indicate liver damage and GLDH plays an important role in the differential diagnosis of liver disease, especially in combination with aminotransferases. GLDH is localised in mitochondria, therefore practically none is liberated in generalised inflammatory diseases of the liver such as viral hepatitides. Liver diseases in which necrosis of hepatocytes is the predominant event, such as toxic liver damage or hypoxic liver disease, are characterised by high serum GLDH levels. GLDH is important for distinguishing between acute viral hepatitis and acute toxic liver necrosis or acute hypoxic liver disease, particularly in the case of liver damage with very high aminotransferases. In clinical trials, GLDH can serve as a measurement for the safety of a drug.

Cofactors

NAD⁺(or NADP⁺) is a cofactor for the glutamate dehydrogenase reaction, producing α-Ketoglutarate and ammonium as a byproduct.^[3]

Based on which cofactor is used, glutamate dehydrogenase enzymes are divided into the following three classes:

• EC 1.4.1.2: L-glutamate + H₂O + NAD⁺ 2-oxoglutarate + NH₃ + NADH + H⁺
• EC 1.4.1.3: L-glutamate + H₂O + NAD(P)⁺ 2-oxoglutarate + NH₃ + NAD(P)H + H⁺
• EC 1.4.1.4: L-glutamate + H₂O + NADP⁺ 2-oxoglutarate + NH₃ + NADPH + H⁺

Role in flow of nitrogen

Ammonia incorporation in animals and microbes occurs through the actions of glutamate dehydrogenase and glutamine synthetase. Glutamate plays the central role in mammalian and microbe nitrogen flow, serving as both a nitrogen donor and a nitrogen acceptor.

Regulation of glutamate dehydrogenase

In Humans, the activity of glutamate dehydrogenase is controlled through ADP-ribosylation, a covalent modification carried out by the gene sirt4. This regulation is relaxed in response to caloric restriction and low blood glucose. Under these circumstances, glutamate dehydrogenase activity is raised in order to increase the amount of α-Ketoglutarate produced, which can be used to provide energy by being used in the citric acid cycle to ultimately produce ATP.

In microbes, the activity is controlled by the concentration of ammonium and or the like-sized Rubidium ion, which binds to an allosteric site on GDH and change the K_m (Michaelis constant) of the enzyme.^[6]

The control of GDH through ADP-ribosylation is particularly important in insulin-producing β cells. Beta cells secrete insulin in response to an increase in the ATP:ADP ratio, and, as amino acids are broken down by GDH into α-ketoglutarate, this ratio rises and more insulin is secreted. SIRT4 is necessary to regulate the metabolism of amino acids as a method of controlling insulin secretion and regulating blood glucose levels.

Regulation

Allosteric inhibitors:

• Adenosine triphosphate (ATP)
• Guanosine triphosphate (GTP)

Activators:

• Adenosine diphosphate (ADP)
• Guanosine diphosphate (GDP)

Isozymes

Humans express the following glutamate dehydrogenase isozymes:

See also

• Anaplerotic reactions

References

External links

• MeSH Glutamate+dehydrogenase