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Glutaminolysis (''
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
'' + '' -lysis'') is a series of biochemical reactions by which the amino acid
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
is lysed to
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, aspartate, CO2, pyruvate, lactate,
alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side ...
and
citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in the ...
.Krebs>Reitzer>Zielke3>Mc Keehan">Moreadith>Zielke7>Eigenbrodt8>Lanks>Board>Medina Medina,, ', "the radiant city"; or , ', (), "the city" officially Al Madinah Al Munawwarah (, , Turkish: Medine-i Münevvere) and also commonly simplified as Madīnah or Madinah (, ), is the Holiest sites in Islam, second-holiest city in Islam, ...
>Goossens>Mazurek22>Eigenbrodt24>Piva Piva may refer to: * Piva (river), a river in Montenegro and Bosnia and Herzegovina * Piva, Montenegro, a region in Montenegro and tribe * Piva River, Bougainville, Papua New Guinea * Piva Trail, Bougainville, Papua New Guinea ** Battle for Piva Tr ...
>Mazurek27>Mazurek31>Aledo>Rossignol>Mazurek36>DeBerardinis>


The glutaminolytic pathway

Glutaminolysis partially recruits reaction steps from the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
and the
malate-aspartate shuttle The malate-aspartate shuttle (sometimes simply the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryo ...
.


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 Glutaminase (, ''glutaminase I'', ''L-glutaminase'', ''glutamine aminohydrolase'') is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells ...
(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 Glutamate dehydrogenase (GLDH, GDH) is an enzyme observed in both prokaryotes and eukaryotic mitochondria. The aforementioned reaction also yields ammonia, which in eukaryotes is canonically processed as a substrate in the urea cycle. Typical ...
(GlDH), EC 1.4.1.2 *glutamate pyruvate transaminase (GPT), also called
alanine transaminase Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first characte ...
(ALT), EC 2.6.1.2 *glutamate oxaloacetate transaminase (GOT), also called
aspartate transaminase Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase (GOT, SGOT), is a pyridoxal phosphate (PLP)-dependent transaminase enzyme () that was first described by Arthur ...
(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 + GTP catalyzing enzyme: succinyl-CoA-synthetase, EC 6.2.1.4 *succinate + FAD → fumarate + FADH2 catalyzing enzyme:
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates i ...
, EC 1.3.5.1 *fumarate + H2O → malate catalyzing enzyme:
fumarase Fumarase (or fumarate hydratase) is an enzyme () that catalyzes the reversible hydration/dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial isoenzyme is involved in the Krebs cycle and ...
, EC 4.2.1.2 *malate + NAD+ → oxaloacetate + NADH + H+ catalyzing enzyme:
malate dehydrogenase Malate dehydrogenase () (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate ...
, EC 1.1.1.37 (component of the malate aspartate shuttle) *oxaloacetate + acetyl-CoA + H2O → citrate + CoASH catalyzing enzyme:
citrate synthase The enzyme citrate synthase E.C. 2.3.3.1 (previously 4.1.3.7)] exists in nearly all living cells and stands as a pace-making enzyme in the first step of the citric acid cycle (or Krebs cycle). Citrate synthase is localized within eukaryotic cel ...
, 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 Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from on ...
(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 A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
,
thymocytes A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thym ...
, colonocytes,
adipocytes Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
and especially in
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
cells.Krebs/>Reitzer/>Zielke3/>Mc Keehan"/>Moreadith/>Zielke7/>Eigenbrodt8/>Lanks/>Medina Medina,, ', "the radiant city"; or , ', (), "the city" officially Al Madinah Al Munawwarah (, , Turkish: Medine-i Münevvere) and also commonly simplified as Madīnah or Madinah (, ), is the Holiest sites in Islam, second-holiest city in Islam, ...
/>Goossens/>Mazurek22/>Eigenbrodt24/>Piva Piva may refer to: * Piva (river), a river in Montenegro and Bosnia and Herzegovina * Piva, Montenegro, a region in Montenegro and tribe * Piva River, Bougainville, Papua New Guinea * Piva Trail, Bougainville, Papua New Guinea ** Battle for Piva Tr ...
/>Mazurek31/>Rossignol/>Mazurek36/>Wolfrom> Glutaminolysis has been targeted for therapeutic purposes. 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 In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...
(ROS) 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/>Lobo> 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/> On the other hand, a reduction of glutamine correlates with phenotypical and functional differentiation of the cells.


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/>


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 Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
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 In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
and
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
. The fatty acids can be used for phospholipid synthesis or can be released. *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. *Glutamate and fatty acids are immunosuppressive. The release of both metabolites may protect tumor cells from immune attacks. *It has been discussed that the glutamate pool may drive the endergonic uptake of other amino acids by system ASC.Aledo/> *Glutamine can be converted to citrate without NADH production, uncoupling NADH production from biosynthesis.


See also

*
Citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
*
Malate-aspartate shuttle The malate-aspartate shuttle (sometimes simply the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryo ...


References

{{reflist


External links


The glutaminolytic pathway
Metabolism Biochemistry