Glutaminolysis

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Glutaminolysis stands for the metabolic conversion to break down the amino acid glutamine to glutamate , aspartate , CO 2 , pyruvate , lactate , alanine and citrate .

The glutaminolytic metabolic pathway

Glutaminolysis uses reaction steps of the citric acid cycle and the malate-aspartate shuttle .

Reaction steps from glutamine to α-ketoglutarate

Reaction steps from glutamine to α-ketoglutarate

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

First, the glutamine is deaminated with the formation of glutamate and ammonium by the enzyme glutaminase (EC 3.5.1.2). After that, glutamate is either excreted by the cells or further metabolized to α-ketoglutarate. The conversion of glutamate to α-ketoglutarate is possible via three different metabolic pathways. The enzymes involved are

Recruited reaction steps from the citric acid cycle and malate-aspartate shuttle

Glutaminolysis. Legend: blue = reaction steps of the citric acid cycle; brown = reaction steps of the malate-aspartate shuttle; green = enzymes that are 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

Reaction steps from malate to pyruvate and lactate

The conversion of malate to pyruvate and lactate takes place via the following two reaction steps:

  • Malate + NAD (P) + → pyruvate + NAD (P) H + H + + CO 2
    Enzyme: NAD (P) -dependent malate decarboxylase (malic enzyme; EC 1.1.1.39 and 1.1.1.40) and
  • Pyruvate + NADH + H + → lactate + NAD +
    enzyme: lactate dehydrogenase (LDH; EC 1.1.1.27)

Intracellular compartmentalization of glutaminolysis

The reaction steps of glutaminolysis take place partly in the mitochondria and partly in the cytosol (see metabolic diagram).

Glutaminolysis: an important source of energy in tumor cells

Glutaminolysis takes place in all proliferating cells, such as lymphocytes , thymocytes, colonocytes, adipocytes and especially in tumor cells . 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 oxygen radicals (reactive oxygen species (ROS)). The aconitase catalyzes the conversion of citrate to isocitrate . On the other hand, tumor cells overexpress the phosphate-dependent glutaminase and the NAD (P) -dependent malate decarboxylase, which, in combination with the remaining reaction steps from the citric acid cycle, open up a new energy source - the breakdown of the amino acid glutamine to glutamate, aspartate, pyruvate , CO 2 , lactate, alanine and citrate.

In tumor cells, glutaminolysis is another important source of energy regeneration in addition to glycolysis . High glutamine concentrations stimulate tumor growth and are necessary for cell transformation. Correspondingly, a reduction in the glutamine concentration correlates with a phenotypic and functional differentiation of the cells.

Energy yield of glutaminolysis in tumor cells

  • an adenosine triphosphate (ATP) by direct phosphorylation of GDP
  • two ATP by oxidation of FADH 2
  • three ATP per NADH + H + , from the α-ketoglutarate dehydrogenase reaction, the malate dehydrogenase reaction and the malate decarboxylase reaction.

The activities of glutamate pyruvate transaminase and glutamate dehydrogenase are very low in tumor cells. For this reason, the conversion of glutamate to α-ketoglutarate in tumor cells mainly takes place via the reaction catalyzed by the glutamate oxaloacetate transaminase.

Benefits of glutaminolysis for tumor cells

  • Glutamine occurs in high concentrations in all tissues and is an efficient additional source of energy, especially if the glycolytic energy production is reduced by a high proportion of tumor M2-PK (dimeric form of M2-PK).
  • Glutamine and its breakdown products glutamate and aspartate are important starting materials for nucleic acid and serine synthesis.
  • Glutaminolysis is insensitive to high ROS concentrations.
  • Due to the truncation of the citric acid cycle, the proportion of acetyl-CoA that is introduced into the citric acid cycle is low and acetyl-CoA is available for the new synthesis of fatty acids and cholesterol. The fatty acids can be used for phospholipid synthesis or released from the cells to the outside.
  • Fatty acids are rich in hydrogen. For this reason, the release of fatty acids is an efficient way for the cell to remove the hydrogen formed in the glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.9) reaction from the cells.
  • Glutamate and fatty acids show immunosuppressive effects. It is therefore conceivable that the release of glutamate and fatty acids protects tumor cells from attacks by the immune system.
  • It is further discussed that the glutamate pool supports the endergonic uptake of other amino acids by the ASC system.

See also

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