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 usually used as a substrate in 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 low affinity for ammonia (high Michaelis constant <math>K_m</math> of about 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 aminotransferases. In plants, the enzyme can work in either direction depending on environment and stress. Transgenic plants expressing microbial GLDHs are improved in tolerance to herbicide, water deficit, and pathogen infections. They are more nutritionally valuable.
The enzyme represents a key link between catabolic and metabolic pathways, and is, therefore, ubiquitous in eukaryotes.
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.
NAD+(or NADP+) is a cofactor for the glutamate dehydrogenase reaction, producing α-ketoglutarate and ammonium as a byproduct.
Based on which cofactor is used, glutamate dehydrogenase enzymes are divided into the following three classes:
- EC 220.127.116.11: L-glutamate + H2O + NAD+ <math>\rightleftharpoons</math> 2-oxoglutarate + NH3 + NADH + H+
- EC 18.104.22.168: L-glutamate + H2O + NAD(P)+ <math>\rightleftharpoons</math> 2-oxoglutarate + NH3 + NAD(P)H + H+
- EC 22.214.171.124: L-glutamate + H2O + NADP+ <math>\rightleftharpoons</math> 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 changes the Km (Michaelis constant) of the enzyme.
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.
Bovine liver glutamate dehydrogenase was found to be regulated by nucleotides in the late 1950s and early 1960s by Carl Frieden.
 In addition to describing the effects of nucleotides like ADP, ATP and GTP he described in detail the different kinetic behavior of NADH and NADPH. As such it was one of the earliest enzymes to show what was later described as allosteric behavior.
Mutations alter the allosteric binding site of GTP cause permanent activation of glutamate dehydrogenase lead to disorder known as hyperinsulinism-hyperammonemia.
This protein may use the morpheein model of allosteric regulation.
Additionally, Mice GDH shows substrate inhibition by which GDH activity decreases at high glutamate concentrations.
Humans express the following glutamate dehydrogenase isozymes:
- ↑ Mungur R, Glass AD, Goodenow DB, Lightfoot DA (June 2005). "Metabolite Fingerprinting in Transgenic Nicotiana tabacum Altered by the Escherichia coli Glutamate Dehydrogenase Gene". J. Biomed. Biotechnol. 2005 (2): 198–214. PMC 1184043. PMID 16046826. doi:10.1155/JBB.2005.198.
- ↑ 3.0 3.1 Grabowska A, Nowicki M, Kwinta J (2011). "Glutamate dehydrogenase of the germinating triticale seeds: gene expression, activity distribution and kinetic characteristics". Acta Phys. Plant. 33 (5): 1981–90. doi:10.1007/s11738-011-0801-1.
- ↑ Lightfoot DA (2009). "Genes for use in improving nitrogen use efficiency in crops". In Wood, Andrew; Matthew A. Jenks. Genes for Plant Abiotic Stress. Wiley-Blackwell. pp. 167–182. ISBN 0-8138-1502-9.
- ↑ 6.0 6.1 6.2 Van Noorden, Botman (August 2014). "Determination of Glutamate Dehydrogenase Activity and Its Kinetics in Mouse Tissues using Metabolic Mapping (Quantitative Enzyme Histochemistry)" (PDF). Journal of Histochemistry & Cytochemistry 62: 802–12. PMID 25124006. doi:10.1369/0022155414549071. Retrieved 26 September 2014.
- ↑ Wootton JC (February 1983). "Re-assessment of ammonium-ion affinities of NADP-specific glutamate dehydrogenases. Activation of the Neurospora crassa enzyme by ammonium and rubidium ions". Biochem. J. 209 (2): 527–31. PMC 1154121. PMID 6221721.
- ↑ Frieden C (1959). "Glutamic dehydrogenase. II. The effect of various nucleotides on the association-dissociation and kinetic properties". J Biol Chem 234: 815–820. PMID 13654269.
- ↑ Frieden C (1962). "The unusual inhibition of glutamate dehydrogenase by guanosine di- and triphosphate". Biochim Biophys Acta 59: 484–486. PMID 13895207. doi:10.1016/0006-3002(62)90204-4.
- ↑ Frieden C (1963). L-Glutamate Dehydrogenase, in The Enzymes, Vol VII. Academic Press. pp. 3–24.
- ↑ Frieden C (1965). "Glutamate Dehydrogenase. VI. Survey of Purine Nucleotide and Other Effects on the Enzyme from Various Sources". J Biol Chem 240: 2028–2035. PMID 14299621.
- ↑ Monod J, Wyman J, Changeux JP (1965). "On the Nature of Allosteric Transitions: A Plausible Model". J Mol Biol 12: 88–118. doi:10.1016/s0022-2836(65)80285-6.
- ↑ T. Selwood and E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function.". Arch. Biochem. Biophys. 519 (2): 131–43. PMC 3298769. PMID 22182754. doi:10.1016/j.abb.2011.11.020.
Amino acid sequence analysis of glutamate dehydrogenase from different source organisms==External links==