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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[edit]

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

Reaction steps from glutamine to α-ketoglutarate[edit]

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[edit]

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
  • α-ketoglutarate + NAD+ + CoASH → succinyl-CoA + NADH+H+ + CO2

catalyzing enzyme: α-ketoglutarate dehydrogenase complex

  • succinyl-CoA + GDP + Pi → succinate + GTP

catalyzing enzyme: succinyl-CoA-synthetase, EC 6.2.1.4

  • succinate + FAD → fumarate + FADH2

catalyzing enzyme: succinate dehydrogenase, EC 1.3.5.1

  • fumarate + H2O → malate

catalyzing enzyme: fumarase, EC 4.2.1.2

  • malate + NAD+ → oxaloacetate + NADH + H+

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

  • oxaloacetate + acetyl-CoA + H2O → citrate + CoASH

catalyzing enzyme: citrate synthase, EC 2.3.3.1

Reaction steps from malate to pyruvate and lactate[edit]

The conversion of malate to pyruvate and lactate is catalyzed by

  • NAD(P) dependent malate decarboxylase (malic enzyme; EC 1.1.1.39 and 1.1.1.40) and
  • lactate dehydrogenase (LDH; EC 1.1.1.27)

according to the following equations:

  • malate + NAD(P)+→ pyruvate + NAD(P)H + H+ + CO2
  • pyruvate + NADH + H+ → lactate + NAD+

Intracellular compartmentalization of the glutaminolytic pathway[edit]

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[edit]

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[edit]

  • one ATP by direct phosphorylation of GDP
  • two ATP from oxidation of FADH2
  • three ATP at a time for the NADH + H+ produced within the α-ketoglutarate dehydrogenase reaction, the malate dehydrogenase reaction and the malate decarboxylase reaction.


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[edit]

  • Glutamine is the most abundant amino acid in the plasma and an additional energy source in tumor cells especially when glycolytic energy production is low due to a high amount of the dimeric form of M2-PK.
  • Glutamine and its degradation products glutamate and aspartate are precursors for nucleic acid and serine synthesis.
  • Glutaminolysis is insensitive to high concentrations of reactive oxygen species (ROS).
  • Due to the truncation of the citric acid cycle the amount of acetyl-CoA infiltrated in the citric acid cycle is low and acetyl-CoA is available for de novo synthesis of fatty acids and cholesterol. The fatty acids can be used for phospholipid synthesis or can be released.[31]
  • Fatty acids represent an effective storage vehicle for hydrogen. Therefore, the release of fatty acids is an effective way to get rid of cytosolic hydrogen produced within the glycolytic glyceraldehyde 3-phosphate dehydrogenase (GAPDH; EC 1.2.1.9) reaction.[32]
  • Glutamate and fatty acids are immunosuppressive. The release of both metabolites may protect tumor cells from immune attacks.[33][34][35]
  • It has been discussed that the glutamate pool may drive the endergonic uptake of other amino acids by system ASC.[17]

See also[edit]

citric acid cycle, malate-aspartate shuttle

References[edit]

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  3. ^ a b Zielke, HR; Sumbilla CM, Sevdalian DA, Hawkins RL and Ozand PT (1980). "Lactate: a major product of glutamine metabolism by human diploid fibroblasts". J. Cell. Physiol. 104 (3): 433–441. doi:10.1002/jcp.1041040316. PMID 7419614. 
  4. ^ a b Mc Keehan, WL (1982). "Glycolysis, glutaminolysis and cell proliferation". Cell Bio. Int. Rep. 6 (7): 635–650. doi:10.1016/0309-1651(82)90125-4. PMID 6751566. 
  5. ^ a b c Moreadith RW, RW; Lehninger AL (1984). "The pathways of glutamate and glutamine oxidation by tumor cell mitochondria". J. Biol. Chem. 259 (10): 6215–6221. PMID 6144677. 
  6. ^ a b Zielke, HR; Zielke CL and Ozand PT (1984). "Glutamine: a major energy source for cultured mammalian cells". Fed. Proc. 43 (1): 121–125. PMID 6690331. 
  7. ^ a b Eigenbrodt, E; Fister P; Reinacher M (1985). "New perspectives on carbohydrate metabolism in tumor cells". In: Regulation of Carbohydrate Metabolism, CRC Press, Boca Raton, Fl 2: 141–179. ISBN 0-8493-5263-0. 
  8. ^ a b Lanks, KW (1987). "End products of glucose and glutamine metabolism by L929 cells". J. Biol. Chem. 262 (21): 10093–10097. PMID 3611053. 
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  16. ^ a b Mazurek, S; Zwerschke W, Jansen-Dürr P and Eigenbrodt E (2001). "Effects of the human papilloma virus HPV-16 E7 oncoprotein on glycolysis and glutaminolysis: role of pyuvate kinase type M2 and the glycolytic enzyme complex". Biochem. J. 356 (Pt 1): 247–256. doi:10.1042/0264-6021:3560247. PMC 1221834. PMID 11336658. 
  17. ^ a b Aledo, JC (2004). "Glutamine breakdown in rapidly dividing cells: waste or investment ?". BioEssays 26 (7): 778–785. doi:10.1002/bies.20063. PMID 15221859. 
  18. ^ a b Rossignol, R; Gilkerson R, Aggeler R, Yamagata K, Remington SJ and Capaldi RA (2004). "Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells". Cancer Res. 64 (3): 985–993. doi:10.1158/0008-5472.CAN-03-1101. PMID 14871829. 
  19. ^ a b Mazurek, S (2007). "Tumor cell energetic metabolome". In: Molecular System Bioenergetics (Saks, V ed.) Wiley-VCH, Weinheim, Germany: 521–540. ISBN 978-3-527-31787-5. 
  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 2476215. PMID 18387799. 
  21. ^ Wolfrom, C; Kadhom N, Polini G, Poggi J, Moatti N and Gautier M (1989). "Glutamine dependency of human skin fibroblasts: modulation of hexoses". Exp. Cell Res. 183 (2): 303–318. doi:10.1016/0014-4827(89)90391-1. PMID 2767153. 
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External links[edit]


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