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Citric acid cycle From Wikipedia, the free encyclopedia

The citric acid cycle — also known as the tricarboxylic acid cycle (TCA cycle), the Krebs cycle, or recently in certain former Soviet Bloc countries the Szent-Györgyi-Krebs cycle[1][2] — is a series of enzyme-catalysed chemical reactions, which is of central importance in all living cells, especially those that use oxygen as part of cellular respiration. In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion.

In aerobic organisms, the citric acid cycle is part of a metabolic pathway involved in the chemical conversion of carbohydrates, fats and proteins into carbon dioxide and water to generate a form of usable energy. Other relevant reactions in the pathway include those in glycolysis and pyruvate oxidation before the citric acid cycle, and oxidative phosphorylation after it. In addition, it provides precursors for many compounds including some amino acids and is therefore functional even in cells performing fermentation. Its centrality to many paths of biosynthesis suggest that it was one of the earliest formed parts of the cellular metabolic processes, and may have formed abiogenically.[3]

The components and reactions of the citric acid cycle were established in the 1930s by seminal work from the Nobel laureates Albert Szent-Györgyi and Hans Adolf Krebs.

A simplified view of the process

The citric acid cycle begins with the transfer of a two-carbon acetyl group from acetyl-CoA to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).
The citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO2. The carbons lost as CO2 originate from what was oxaloacetate, not directly from acetyl-CoA. The carbons donated by acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of the acetyl-CoA-donated carbons as CO2 requires several turns of the citric acid cycle. However, because of the role of the citric acid cycle in anabolism, they may not be lost, since many TCA cycle intermediates are also used as precursors for the biosynthesis of other molecules.[4]
Most of the energy made available by the oxidative steps of the cycle is transferred as energy-rich electrons to NAD+, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced.
Electrons are also transferred to the electron acceptor Q, forming QH2.
At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Steps

Two carbon atoms are oxidized to CO2, the energy from these reactions being transferred to other metabolic processes by GTP (or ATP), and as electrons in NADH and QH2. The NADH generated in the TCA cycle may later donate its electrons in oxidative phosphorylation to drive ATP synthesis; FADH2 is covalently attached to succinate dehydrogenase, an enzyme functioning both in the TCA cycle and the mitochondrial electron transport chain in oxidative phosphorylation. FADH2, therefore, facilitates transfer of electrons to coenzyme Q, which is the final electron acceptor of the reaction catalyzed by the Succinate:ubiquinone oxidoreductase complex, also acting as an intermediate in the electron transport chain.[5]

Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that produces GTP from GDP, and another that produces ATP from ADP.[7] Plants have the type that produces ATP (ADP-forming succinyl-CoA synthetase).[6] Several of the enzymes in the cycle may be loosely-associated in a multienzyme protein complex within the mitochondrial matrix.[8]

The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by nucleoside-diphosphate kinase to form ATP (the catalyzed reaction is GTP + ADP → GDP + ATP).[5]

Regulation

Although pyruvate dehydrogenase is not technically a part of the citric acid cycle, its regulation is included here.

The regulation of the TCA cycle is largely determined by substrate availability and product inhibition. NADH, a product of all dehydrogenases in the TCA cycle with the exception of succinate dehydrogenase, inhibits pyruvate dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and also citrate synthase. Acetyl-coA inhibits pyruvate dehydrogenase, while succinyl-CoA inhibits succinyl-CoA synthetase and citrate synthase. When tested in vitro with TCA enzymes, ATP inhibits citrate synthase and α-ketoglutarate dehydrogenase; however, ATP levels do not change more than 10% in vivo between rest and vigorous exercise. There is no known allosteric mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration changes less than 10%.[10]

Calcium is used as a regulator. It activates pyruvate dehydrogenase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase.[11] This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway.

Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in glycolysis that catalyses formation of fructose 1,6-bisphosphate,a precursor of pyruvate. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme.

Recent work has demonstrated an important link between intermediates of the citric acid cycle and the regulation of hypoxia-inducible factors (HIF). HIF plays a role in the regulation of oxygen homeostasis, and is a transcription factor that targets angiogenesis, vascular remodeling, glucose utilization, iron transport and apoptosis. HIF is synthesized consititutively, and hydroxylation of at least one of two critical proline residues mediates their interaction with the von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This reaction is catalysed by prolyl 4-hydroxylases. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.[12]

Major metabolic pathways converging on the TCA cycle

Several catabolic pathways converge on the TCA cycle. Reactions that form intermediates of the TCA cycle in order to replenish them (especially during the scarcity of the intermediates) are called anaplerotic reactions.

The citric acid cycle is the third step in carbohydrate catabolism (the breakdown of sugars). Glycolysis breaks glucose (a six-carbon-molecule) down into pyruvate (a three-carbon molecule). In eukaryotes, pyruvate moves into the mitochondria. It is converted into acetyl-CoA by decarboxylation and enters the citric acid cycle.

In protein catabolism, proteins are broken down by proteases into their constituent amino acids. The carbon backbone of these amino acids can become a source of energy by being converted to acetyl-CoA and entering into the citric acid cycle.

In fat catabolism, triglycerides are hydrolyzed to break them into fatty acids and glycerol. In the liver the glycerol can be converted into glucose via dihydroxyacetone phosphate and glyceraldehyde-3-phosphate by way of gluconeogenesis. In many tissues, especially heart tissue, fatty acids are broken down through a process known as beta oxidation, which results in acetyl-CoA, which can be used in the citric acid cycle. Beta oxidation of fatty acids with an odd number of methylene groups produces propionyl CoA, which is then converted into succinyl-CoA and fed into the citric acid cycle.[13]

The total energy gained from the complete breakdown of one molecule of glucose by glycolysis, the citric acid cycle, and oxidative phosphorylation equals about 30 ATP molecules, in eukaryotes. The citric acid cycle is called an amphibolic pathway because it participates in both catabolism and anabolism.

Notes

1. Archives Internationales de Pharmacodynamie Et de Therapie. H. Engelcke.
2. Altmann, Hans-Werner; Büchner, Franz (1962). Handbuch der allgemeinen Pathologie. Springer.
3. Lane, Nick (2010), "Life Ascending: the 10 great innovations of evolution" (Profile)
4. Wolfe, R. R.; Jahoor, F. (1990) (PDF). Recovery of labeled CO.2 during the infusion of C-1- vs C-2-labeled acetate: implications for tracer studies of substrate oxidation. Am J Clin Nutr. 51(2):248-52. PMID 2106256
5. Berg, J. M.; Tymoczko, J. L.; Stryer, L. (2002). Biochemistry (5th ed.). WH Freeman and Company. pp. 465–484, 498–501. ISBN 0-7167-4684-0.
6. Buchanan; Gruissem; Jones (2000). Biochemistry & molecular biology of plants (1st ed.). American society of plant physiology. ISBN 0-943088-39-9.
8. Johnson, JD; Mehus, JG; Tews, K; Milavetz, BI; Lambeth, DO (1998). "Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes". J Biol Chem 273 (42): 27580–6. doi:10.1074/jbc.273.42.27580. PMID 9765291.
9. Barnes, SJ; Weitzman, PD (June 1986). "Organization of citric acid cycle enzymes into a multienzyme cluster". FEBS Lett. 201 (2): 267–70. doi:10.1016/0014-5793(86)80621-4. PMID 3086126.
10. Rich, PR (2003). "The molecular machinery of Keilin's respiratory chain". Biochem. Soc. Trans. 31 (Pt 6): 1095–105. doi:10.1042/BST0311095. PMID 14641005.
11. Voet, D.; Voet, J. G. (2004). Biochemistry (3rd ed.). New York: John Wiley & Sons, Inc.. p. 615.
12. Denton, Richard M.; Randle, Philip J.; Bridges, Barbara J.; Cooper, Ronald H.; Kerbey, Alan L.; Pask, Helen T.; Severson, David L.; Stansbie, David et al. (October 1975). "Regulation of mammalian pyruvate dehydrogenase". Mol Cell Biochem 9 (1): 27–53. doi:10.1007/BF01731731. PMID 171557.
13. Koivunen, P.; Hirsila, M.; Remes, A. M.; Hassinen, I. E.; Kivirikko, K. I.; Myllyharju, J. (2007). "Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF". J. Biol. Chem. 282 (7): 4524–32. doi:10.1074/jbc.M610415200. PMID 17182618.
14. Halarnkar, P; Blomquist, G (1989). "Comparative aspects of propionate metabolism". Comp. Biochem. Physiol., B 92 (2): 227–31. doi:10.1016/0305-0491(89)90270-8. PMID 2647392.
15. The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"

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