Glutaminolysis

Glutaminolysis stands for the metabolic reactions deplete the amino acid glutamine to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.

  • 3.1 Energy yield glutaminolysis in tumor cells
  • 3.2 Advantages glutaminolysis for tumor cells

The glutaminolytische pathway

The glutaminolysis used reaction steps of the citric acid cycle and the malate - aspartate shuttle.

Reaction steps of glutamine to α -ketoglutarate

The reaction of the amino acid glutamine to α -ketoglutarate occurs in two reaction steps.

First, a deamination of glutamine to form glutamate and ammonium done by the enzyme glutaminase ( EC 3.5.1.2 ). Then either glutamate is secreted from the cells or further metabolised to α -ketoglutarate. The conversion of glutamate to α -ketoglutarate is about three different metabolic pathways possible. The enzymes involved are

  • Glutamate dehydrogenase ( GlDH, EC 1.4.2.1 )
  • Glutamic pyruvic transaminase ( GPT); Synonym: alanine aminotransferase (ALT, ALT, EC 2.6.1.2 )
  • Glutamic-oxaloacetic transaminase ( GOT); Synonym: aspartate aminotransferase (AST, AST, EC 2.6.1.1 ); a component of the malate - aspartate shuttle

Recruited reaction steps of the TCA cycle and malate - aspartate shuttle

  • α -ketoglutarate NAD CoASH → succinyl -CoA NADH H CO2 Enzyme: α -ketoglutarate dehydrogenase complex
  • Succinyl -CoA GDP Pi → succinate GTP Enzyme: succinyl- CoA synthetase, EC 6.2.1.4
  • Succinate FAD → fumarate FADH2 Enzyme: succinate dehydrogenase, EC 1.3.5.1
  • Fumarate H2O → malate Enzyme: fumarase, EC 4.2.1.2
  • Malate NAD → oxaloacetate NADH H Enzyme: malate dehydrogenase, EC 1.1.1.37 ( component of the malate - aspartate shuttle )
  • Oxaloacetate acetyl -CoA H 2 O → citrate CoASH Enzyme: citrate synthase, EC 2.3.3.1

Reaction steps of malate to pyruvate and lactate

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

  • Malate NAD (P) pyruvate → NAD (P) H H CO2 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 glutaminolysis

The reaction steps glutaminolysis found partly in the mitochondria and partially in the cytosol instead (see metabolism scheme).

Glutaminolysis: an important energy source in tumor cells

Glutaminolysis takes place in all proliferating cells, including lymphocytes, thymocytes, colonocytes, adipocytes, and particularly in tumor cells. In tumor cells, the citric acid cycle is due to inhibition of the enzyme aconitase ( EC 4.2.1.3 ) by high concentrations of oxygen radicals ( reactive oxygen species (ROS ) ) truncated. Aconitase catalyzes the conversion of citrate to isocitrate. On the other hand overexpressing tumor cells, the phosphate -dependent glutaminase and NAD ( P )-dependent malate decarboxylase, together in combination with the remaining reaction steps of the citric acid cycle, the development of a new energy source - the breakdown of the amino acid glutamine to glutamate, aspartate, pyruvate, CO2, allow lactate, alanine and citrate.

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

Energy yield glutaminolysis in tumor cells

  • An adenosine triphosphate ( ATP ) by direct phosphorylation of GDP
  • Two ATP by oxidation of FADH2
  • Three ATP per NADH H , from the α -ketoglutarate dehydrogenase reaction, the malate dehydrogenase reaction and malate decarboxylase response.

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

Benefits glutaminolysis for tumor cells

  • Glutamine is used in all tissues at high concentrations and is an additional source of energy efficient, particularly when the glycolytic energy production is reduced by a high percentage of tumor M2-PK ( dimeric form of M2-PK ).
  • Glutamine and its degradation products glutamate and aspartate are important starting materials for the nucleic acid and serine synthesis.
  • The glutaminolysis is insensitive to high ROS concentrations.
  • Due to the truncation of the citric acid cycle, the proportion of acetyl- CoA, which is introduced into the citric acid cycle is low and acetyl- CoA is the de novo synthesis of fatty acids and cholesterol are available. The fatty acids can be used to phospholipid synthesis and output from the cell to the outside.
  • Fatty acids are rich in hydrogen. For this reason, the release of fatty acids is an efficient way of the cell in the glycolytic glyceraldehyde -3-phosphate dehydrogenase ( GAPDH; EC 1.2.1.9 ) to remove reaction formed hydrogen 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 attack by the immune system.
  • It is further discussed that the glutamate pool supports the endergonic uptake of other amino acids by the ASC system.
Malate-aspartate shuttle Alanine transaminase Aspartate transaminase Succinyl coenzyme A synthetase Isocitric acid Guanosine diphosphate Glyceraldehyde 3-phosphate dehydrogenase Biochemical Journal FEBS Letters Anticancer Research Oncogene (journal)
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