Glutaminolysis

Glutaminolysis (glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]

The glutaminolytic pathway

Glutaminolysis partially recruits reaction steps from the citric acid cycle and the malate-aspartate shuttle.

Reaction steps from glutamine to α-ketoglutarate

The conversion of the amino acid glutamine to α-ketoglutarate takes place in two reaction steps:

Conversion of glutamine to α-ketoglutarate

1. Hydrolysis of the amino group of glutamine yielding glutamate and ammonium. Catalyzing enzyme: glutaminase (EC 3.5.1.2)

2. Glutamate can be excreted or can be further metabolized to α-ketoglutarate.

For the conversion of glutamate to α-ketoglutarate three different reactions are possible:

Catalyzing enzymes:

Recruited reaction steps of the citric acid cycle and malate aspartate shuttle

The glutaminolytic pathway. Figure legend: blue color = reaction steps of the citric acid cycle; brown color = reaction steps of the malate aspartate shuttle; green color = enzymes overexpressed in tumors. 1 = glutaminase, 2 = GOT, 3 = α-ketoglutarate dehydrogenase, 4 = succinate dehydrogenase, 5 = fumarase, 6 = malate dehydrogenase, 7a = cytosolic malic enzyme, 7b = mitochondrial malic enzyme, 8 = citrate synthase, 9 = aconitase, 10 = lactate dehydrogenase

catalyzing enzyme: α-ketoglutarate dehydrogenase complex

catalyzing enzyme: succinyl-CoA-synthetase, EC 6.2.1.4

catalyzing enzyme: succinate dehydrogenase, EC 1.3.5.1

catalyzing enzyme: fumarase, EC 4.2.1.2

catalyzing enzyme: malate dehydrogenase, EC 1.1.1.37 (component of the malate aspartate shuttle)

catalyzing enzyme: citrate synthase, EC 2.3.3.1

Reaction steps from malate to pyruvate and lactate

The conversion of malate to pyruvate and lactate is catalyzed by

according to the following equations:

Intracellular compartmentalization of the glutaminolytic pathway

The reactions of the glutaminolytic pathway take place partly in the mitochondria and to some extent in the cytosol (compare the metabolic scheme of the glutaminolytic pathway).

Glutaminolysis: an important energy source in tumor cells

Glutaminolysis takes place in all proliferating cells, such as lymphocytes, thymocytes, colonocytes, adipocytes and especially in tumor cells.[1][2][3][4][5][6][7][8][10][11][12][13][14][16][18][19][21] In tumor cells the citric acid cycle is truncated due to an inhibition of the enzyme aconitase (EC 4.2.1.3) by high concentrations of reactive oxygen species (ROS)[22][23] Aconitase catalyzes the conversion of citrate to isocitrate. On the other hand, tumor cells over express phosphate dependent glutaminase and NAD(P)-dependent malate decarboxylase,[9][24][25][26][27] which in combination with the remaining reaction steps of the citric acid cycle from α-ketoglutarate to citrate impart the possibility of a new energy producing pathway, the degradation of the amino acid glutamine to glutamate, aspartate, pyruvate CO2, lactate and citrate.

Besides glycolysis in tumor cells glutaminolysis is another main pillar for energy production. High extracellular glutamine concentrations stimulate tumor growth and are essential for cell transformation.[26][28] On the other hand, a reduction of glutamine correlates with phenotypical and functional differentiation of the cells.[29]

Energy efficacy of glutaminolysis in tumor cells


Due to low glutamate dehydrogenase and glutamate pyruvate transaminase activities, in tumor cells the conversion of glutamate to alpha-ketoglutarate mainly takes place via glutamate oxaloacetate transaminase.[5][30]

Advantages of glutaminolysis in tumor cells

See also

citric acid cycle, malate-aspartate shuttle

References

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  20. ↑ DeBerardinis, RJ; Sayed N; Ditsworth D; Thompson CB (2008). "Brick by brick: metabolism and tumor growth". Current Opinion in Genetics & Development. 18 (1): 54–61. doi:10.1016/j.gde.2008.02.003. PMC 2476215Freely accessible. PMID 18387799.
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