Glutaminolysis

Glutaminolysis is a series of biochemical reactions by which the amino acid glutamine is degraded to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.Krebs>cite journal|last = Krebs|first = HA|coauthors = Bellamy D|title = The interconversion of glutamic acid and aspartic acid in respiring tissues|journal = Biochem. J. |year = 1960|volume = 75|pages = 523–529|pmid = 14411856] Reitzer>cite journal|last = Reitzer|first = LJ|coauthors = Wice BM and Kennell D|title = Evidence that glutamine, not sugar, is the major energy source for cultured HeLa-cells|journal = J. Biol. Chem.|year = 1979|volume = 254|pages = 2669–2676|pmid = 429309] Zielke3>cite journal|last = Zielke |first = HR|coauthors = Sumbilla CM, Sevdalian DA, Hawkins RL and Ozand PT|title = Lactate: a major product of glutamine metabolism by human diploid fibroblasts|journal = J. Cell. Physiol. |year = 1980|volume = 104|pages = 433–441|pmid = 7419614|doi = 10.1002/jcp.1041040316] Mc Keehan>cite journal|last = Mc Keehan |first = WL|title = Glycolysis, glutaminolysis and cell proliferation|journal = Cell Bio. Int. Rep. |year = 1982|volume = 6|pages = 635–650|pmid = 6751566|doi = 10.1016/0309-1651(82)90125-4] Moreadith>cite journal|last = Moreadith RW|coauthors = Lehninger AL|title = The pathways of glutamate and glutamine oxidation by tumor cell mitochondria|journal = J. Biol. Chem. |year = 1984|volume = 259|pages = 6215–6221|pmid = 6144677] Zielke7>cite journal|last = Zielke |first = HR|coauthors = Zielke CL and Ozand PT|title = Glutamine: a major energy source for cultured mammalian cells|journal = Fed. Proc. |year = 1984|volume = 43|pages = 121–125|pmid = 6690331] Eigenbrodt8>cite journal|last = Eigenbrodt |first = E|coauthors = Fister P, Reinacher M|title = New perspectives on carbohydrate metabolism in tumor cells|journal = In: Regulation of Carbohydrate Metabolism, CRC Press, Boca Raton, Fl|year = 1985|volume = 2|pages = 141–179|id = ISBN 0-8493-5263-0] Lanks>cite journal|last = Lanks |first = KW|title = End products of glucose and glutamine metabolism by L929 cells|journal = J. Biol. Chem. |year = 1987|volume = 262|pages = 10093–10097|pmid = 3611053] Board>cite journal|last = Board |first = M|coauthors = Humm S and Newsholme EA|title = Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells|journal = Biochem. J. |year = 1990|volume = 265|pages = 503–509|pmid = 2302181] Medina>cite journal|last = Medina |first = MA|coauthors = Nunez de Castro I|title = Glutaminolysis and glycolysis interactions in proliferant cells |journal = Int. J. Biochem. |year = 1990|volume = 22|pages = 681–683|pmid = 2205518|doi = 10.1016/0020-711X(90)90001-J] Goossens>cite journal|last = Goossens |first = V|coauthors = Grooten J and Fiers W|title = The oxidative metabolism of glutamine. A modulator of reactive oxygen intermediate-mediated cytotoxicity of tumor necrosis factor in L929 fibrosarcoma cells|journal = J. Biol. Chem. |year = 1996|volume = 271|pages = 192–196|pmid = 8550558] Mazurek22>cite journal|last = Mazurek |first = S|coauthors = Michel A and Eigenbrodt E|title = Effect of extracellular AMP on cell proliferation and metabolism of breast cancer cell lines with high and low glycolytic rates|journal = J. Biol. Chem. |year = 1997|volume = 272|pages = 4941–4952|pmid = 9030554|doi = 10.1074/jbc.272.8.4941] Eigenbrodt24>cite journal|last = Eigenbrodt |first = E|coauthors = Kallinowski F, Ott M, Mazurek S and Vaupel P|title = Pyruvate kinase and the interaction of amino acid and carbohydrate metabolism in solid tumors|journal = Anticancer Res. |year = 1998|volume = 18|pages = 3267–3274|pmid = 9858894] Piva>cite journal|last = Piva |first = TJ|coauthors = McEvoy-Bowe E|title = Oxidation of glutamine in HeLa cells: role and control of truncated TCA cycles in tumour mitochondria|journal = J. Cell Biochem. |year = 1998|volume = 68|pages = 213–225|pmid = 9443077|doi = 10.1002/(SICI)1097-4644(19980201)68:2<213::AID-JCB8>3.0.CO;2-Y|doilabel = 10.1002/(SICI)1097-4644(19980201)68:2213::AID-JCB83.0.CO;2-Y] Mazurek27>cite journal|last = Mazurek |first = S|coauthors = Eigenbrodt E, Failing K and Steinberg P|title = Alterations in the glycolytic and glutaminolytic pathways after malignant transformation of rat liver oval cells|journal = J. Cell. Physiol. |year = 1999|volume = 181|pages = 136–146|pmid = 10457361|doi = 10.1002/(SICI)1097-4652(199910)181:1<136::AID-JCP14>3.0.CO;2-T|doilabel = 10.1002/(SICI)1097-4652(199910)181:1136::AID-JCP143.0.CO;2-T] Mazurek31>cite journal|last = Mazurek |first = S|coauthors = Zwerschke W, Jansen-Dürr P and Eigenbrodt E|title = 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|journal = Biochem. J. |year = 2001|volume = 356|pages = 247–256|pmid = 11336658|doi = 10.1042/0264-6021:3560247] Aledo>cite journal|last = Aledo |first = JC|title = Glutamine breakdown in rapidly dividing cells: waste or investment ? |journal = Bioessays|year = 2004|volume = 26|pages = 778–785|pmid = 15221859|doi = 10.1002/bies.20063] Rossignol>cite journal|last = Rossignol |first = R|coauthors = Gilkerson R, Aggeler R, Yamagata K, Remington SJ and Capaldi RA|title = Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells|journal = Cancer Res. |year = 2004|volume = 64|pages = 985–993|pmid = 14871829|doi = 10.1158/0008-5472.CAN-03-1101] Mazurek36>cite journal|last = Mazurek |first = S|title = Tumor cell energetic metabolome|journal = In: Molecular System Bioenergetics (Saks, V ed.) Wiley-VCH, Weinheim, Germany |year = 2007 |pages = 521–540|id = ISBN 978-3-527-31787-5]

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:

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:
*glutamate dehydrogenase (GlDH) , EC 1.4.2.1
*glutamate pyruvate transaminase (GPT), also called alanine transaminase (ALT), EC 2.6.1.2
*glutamate oxaloacetate transaminase (GOT), also called aspartate transaminase (AST), EC 2.6.1.1 (component of the malate aspartate shuttle)

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

*α-ketoglutarate + NAD+ + CoASH → succinyl-CoA + NADH+H+ + CO2
catalyzing enzyme: α-ketoglutarate dehydrogenase complex

*succinyl-CoA + GDP + Pi → succinate + GTPcatalyzing enzyme: succinyl-CoA-synthetase, EC 6.2.1.4

*succinate + FAD → fumarate + FADH2catalyzing enzyme: succinate dehydrogenase, EC 1.3.5.1

*fumarate + H2O → malatecatalyzing 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 + CoASHcatalyzing 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

*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

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.Krebs/>Reitzer/>Zielke3/>Mc Keehan/>Moreadith/>Zielke7/>Eigenbrodt8/>Lanks/>Medina/>Goossens/>Mazurek22/>.Eigenbrodt24/>Piva/>Mazurek31/>Rossignol/>Mazurek36/> 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) [cite journal|last = Gardner |first = PR|coauthors = Raineri I, Epstein LB and White CW|title = Superoxide radical and iron modulate aconitase activity in mammalian cells|journal = J. Biol. Chem. |year = 1995|volume = 270|pages = 13399–13405|pmid = 7768942|doi = 10.1074/jbc.270.22.13399] [cite journal|last = Kim |first = KH|coauthors = Rodriguez AM, Carrico PM and Melendez JA|title = Potential mechanisms for the inhibition of tumor cell growth by manganese superoxide dismutase|journal = Antioxid. Redox. Signal. |year = 2001|volume = 3|pages = 361–373|pmid = 11491650|doi = 10.1089/15230860152409013] 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,Board/> [cite journal|last = Matsuno |first = T|coauthors = Goto I|title = Glutaminase and glutamine synthetase activities in human cirrhotic liver and hepatocellular carcinoma|journal = Cancer Res. |year = 1992|volume = 52|pages = 1192–1194|pmid = 1346587] [cite journal|last = Aledo |first = JC|coauthors = Segura JA, Medina MA, Alonso FJ, Nunez de Castro I and Marquez J|title = Phosphate-activated glutaminase expression during tumor development|journal = FEBS Lett. |year = 1994|volume = 341|pages = 39–42|pmid = 8137919|doi = 10.1016/0014-5793(94)80236-X] Lobo>cite journal|last = Lobo |first = C|coauthors = Ruiz-Bellido MA, Aledo JC, Marquez J, Nunez De Castro I and Alonso FJ|title = Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells|journal = Biochem. J. |year = 2000|volume = 348|pages = 257–261|pmid = 10816417|doi = 10.1042/0264-6021:3480257] [cite journal|last = Mazurek| first = S|coauthors = Grimm H, Oehmke M, Weisse G, Teigelkamp S and Eigenbrodt E|title = Tumor M2-PK and glutaminolytic enzymes in the metabolic shift of tumor cells|journal = Anticancer Res. |year = 2000|volume = 20|pages = 5151–5154|pmid = 11326687] 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.Lobo/> [cite journal|last = Turowski |first = GA|coauthors = Rashid Z, Hong F, Madri JA and Basson MD|title = Glutamine modulates phenotype and stimulates proliferation in human colon cancer cell lines|journal = Cancer Res. |year = 1994|volume = 54|pages = 5974–5980|pmid = 7954430] On the other hand a reduction of glutamine correlates with phenotypical and functional differentiation of the cells. [cite journal|last = Spittler |first = A|coauthors = Oehler R, Goetzinger P, Holzer S, Reissner CM, Leutmezer J, Rath V, Wrba F, Fuegger R, Boltz-Nitulescu G and Roth E|title = Low glutamine concentrations induce phenotypical and functional differentiation of U937 myelomonocytic cells|journal = J. Nutr. |year = 1997|volume = 127|pages = 2151–2157|pmid = 9349841]

Energy efficacy of glutaminolysis in tumor cells

*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.Moreadith/> [cite journal|last = Matsuno |first = T|title = Pathway of glutamate oxidation and its regulation in HuH13 line of human hepatoma cells|journal = J. Cell. Physiol. |year = 1991|volume = 148|pages = 290–294|pmid = 1679060|doi = 10.1002/jcp.1041480215]

Advantages of glutaminolysis in tumor cells

*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. [cite journal|last = Parlo |first = RA|coauthor = Coleman PS|title = Enhanced rate of citrate export from cholesterol-rich hepatoma mitochondria. The truncated Krebs cycle and other metabolic ramifications of mitochondrial membrane cholesterol|journal = J. Biol. Chem. |year = 1984|volume = 259|pages = 9997–10003|pmid = 6469976]
*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. [cite journal|last = Mazurek |first = S|coauthors = Grimm H, Boschek CB, Vaupel P and Eigenbrodt E|title = Pyruvate kinase type M2: a crossroad in the tumor metabolome|journal = Brit. J. Nutr. |year = 2002|volume = 87|pages = S23–S29|pmid = 11895152|doi = 10.1079/BJN2001455]
*Glutamate and fatty acids are immunosuppressive. The release of both metabolites may protect tumor cells from immune attacks. [cite journal|last = Eck |first = HP|coauthors = Drings P and Dröge W|title = Plasma glutamate levels, lymphocyte reactivity and death in patients with bronchial carcinoma|journal = J. Cancer Res. Clin. Oncol. |year = 1989|volume = 115|pages = 571–574|pmid = 2558118|doi = 10.1007/BF00391360 ] [cite journal|last = Grimm |first = H|coauthors = Tibell A, Norrlind B, Blecher C, Wilker S, and Schwemmle K|title = Immunoregulation by parental lipids: impact of the n-3 to n-6 fatty acid ratio|journal = J. Parenter. Enteral. Nutr. |year = 1994|volume = 18|pages = 417–421|pmid = 7815672|doi = 10.1177/0148607194018005417] [cite journal|last = Jiang |first = WG|coauthors = Bryce RP and Hoorobin DF|title = Essential fatty acids: molecular and cellular basis of their anti-cancer action and clinical implications|journal = Crit. Rev. Oncol. Hematol. |year = 1998|volume = 27|pages = 179–209|pmid = 9649932|doi = 10.1016/S1040-8428(98)00003-1]
*It has been discussed that the glutamate pool may drive the endergonic uptake of other amino acids by system ASC.Aledo/>

ee also

citric acid cycle,
malate-aspartate shuttle

References

External links

* [http://www.metabolic-database.com/html/glutaminolysis_main_page.html The glutaminolytic pathway]


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