1/23/2024 0 Comments Malate oxaloacetate shuttle![]() On the other hand, tumor cells over express phosphate dependent glutaminase and NAD(P)-dependent malate decarboxylase, 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 CO 2, lactate and citrate.īesides glycolysis in tumor cells glutaminolysis is another main pillar for energy production. 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) Aconitase catalyzes the conversion of citrate to isocitrate. Glutaminolysis has been targeted for therapeutic purposes. Glutaminolysis takes place in all proliferating cells, such as lymphocytes, thymocytes, colonocytes, adipocytes and especially in tumor cells. Glutaminolysis: an important energy source in tumor cells 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). Intracellular compartmentalization of the glutaminolytic pathway pyruvate + NADH + H + → lactate + NAD +.malate + NAD(P) +→ pyruvate + NAD(P)H + H + + CO 2.lactate dehydrogenase (LDH EC 1.1.1.27).NAD(P) dependent malate decarboxylase (malic enzyme EC 1.1.1.39 and 1.1.1.40) and.The conversion of malate to pyruvate and lactate is catalyzed by Reaction steps from malate to pyruvate and lactate oxaloacetate + acetyl-CoA + H 2O → citrate + CoASHĬatalyzing enzyme: citrate synthase, EC 2.3.3.1.malate + NAD + → oxaloacetate + NADH + H +Ĭatalyzing enzyme: malate dehydrogenase, EC 1.1.1.37 (component of the malate aspartate shuttle).succinyl-CoA + GDP + P i → succinate + GTPĬatalyzing enzyme: succinyl-CoA-synthetase, EC 6.2.1.4Ĭatalyzing enzyme: succinate dehydrogenase, EC 1.3.5.1.α-ketoglutarate + NAD + + CoASH → succinyl-CoA + NADH+H + + CO 2Ĭatalyzing enzyme: α-ketoglutarate dehydrogenase complex.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 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. ![]() Recruited reaction steps of the citric acid cycle and malate aspartate shuttle The glutaminolytic pathway. glutamate oxaloacetate transaminase (GOT), also called aspartate transaminase (AST), EC 2.6.1.1 (component of the malate aspartate shuttle).glutamate pyruvate transaminase (GPT), also called alanine transaminase (ALT), EC 2.6.1.2.glutamate dehydrogenase (GlDH), EC 1.4.1.2.Glutamate can be excreted or can be further metabolized to α-ketoglutarate.įor the conversion of glutamate to α-ketoglutarate three different reactions are possible: Hydrolysis of the amino group of glutamine yielding glutamate and ammonium.Ĭatalyzing enzyme: glutaminase (EC 3.5.1.2)Ģ. The conversion of the amino acid glutamine to α-ketoglutarate takes place in two reaction steps:Ĭonversion of glutamine to α-ketoglutarateġ. Reaction steps from glutamine to α-ketoglutarate Glutaminolysis partially recruits reaction steps from the citric acid cycle and the malate-aspartate shuttle. Glutaminolysis ( glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO 2, pyruvate, lactate, alanine and citrate. ![]()
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