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1. INTRODUCTION 1.1. Background The Kreb’s cycle is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetate derived from carbohydrates, fats and proteins into carbon dioxide and chemical energy in the form of adenosine triphosphate(ATP). In addition, the cycle provides precursors of certain amino acids as well as the reducing agent NADH that is used in numerous other biochemical reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism and may have originated abiogenically. The name of this metabolic pathway is derived from citric acid (a type of tricarboxylic acid) that is consumed and then regenerated by this sequence of reactions to complete the cycle. In addition, the cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD+ to NADH, and produces carbon dioxide as a waste byproduct. The NADH generated by the TCA cycle is fed into the oxidative phosphorylation (electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP. In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. In prokaryotic cells, such as bacteria which lack mitochondria, the TCA reaction sequence is performed in the cytosol with the proton gradient for ATP production being across the cell's surface (plasma membrane) rather than the inner membrane of the mitochondrion. 1.2. Objectives: To know the importance of TCA Cycle in energy production To know about the steps involved in TCA cycle 2. Literature Review 2.1. Discovery and Evolution of TCA Cycle Several of the components and reactions of the citric acid cycle were established in the 1930s by the research of the Nobel laureate Albert Szent-Györgyi, for which he received the Nobel Prize in 1937 for his discoveries pertaining to fumaric acid, a key component of the cycle. The citric acid cycle itself was finally identified in 1937 by Hans Adolf Krebswhile at the University of Sheffield, for which he received the Nobel Prize for Physiology or Medicine in 1953. Components of the TCA cycle were derived from anaerobic bacteria, and the TCA cycle itself may have evolved more than once. Theoretically there are several alternatives to the TCA cycle; however, the TCA cycle appears to be the most efficient. If several TCA alternatives had evolved independently, they all appear to have converged to the TCA cycle. 2.2. Overview of TCA Cycle It plays a starring role in both the process of energy production and biosynthesis. The cycle finishes the sugar-breaking job started in glycolysis and fuels the production of ATP in the process. It is also a central hub in biosynthetic reactions, pro viding intermediates that are used to build amino acids and other molecules. TCA cycle involves 10 different reactions and they are as follows: i. Citrate synthesis from oxaloacetate The condensation of acetyl CoA with oxaloacetate forms citrate. The enzyme catalyzing this reaction is citrate synthase. ii. Conversion of citrate into aconitate The citrate formed in the first step is a bit too stable, so the second step moves an oxygen atom to create a more reactive isocitrate molecule. Aconitase performs this isomerization reaction, with the assistance of an iron-sulfur cluster. iii. Formation of isocitrate Aconitate is converted into isocitrate by the enzyme aconitase, but here one molecule of H2O is added to the aconitate. iv. Conversion of oxalosuccinate to alpha keto glutarate Some enzyme, isocitrate dehydrogenase catalyses the conversion of oxalosuccinate into alphaketo glutrate. In this reaction, decarboxylation of oxalosuccinate occurs in the presence of Mn2+. v. Conversion of oxalosuccinate to alpha keto glutrate Same enzyme, isocitrate dehydrogenase catalyses the conversion of oxalosuccinate into alphaketo glutrate. In this reaction decarboxylation of oxalosuccinate occurs in the presence of Mn2+. vi. Formation of succinyl CoA This is the onl.y step in the cycle where ATP is made directly. The bond between succinate and coenzyme A is particularly unstable, and provides the energy needed to build a molecule of ATP. In mitochondria, the enzyme actually creates GTP in the reaction, which is converted to ATP by the enzyme nucleoside diphosphate kinase vii. Formation of succinate Succinate dehydrogenase, found in the membrane, links its citric acid cycle task directly to the electron trans-port chain. It extracts hydrogen atoms from succinate and transfers them first to the carrier FAD and finally to the mobile electron carrier ubiquinone. viii. Formation of fumarese The eight step is performed by fumarase, which adds a water molecule to get everything ready for the final step of the cycle. ix. Conversion of fumarate to malate The enzyme fumarase catalysis the addition of water to fumarate to give malate. x. Formation of oxaloacetate Finally, oxaloacetate is regenerated by the enzyme malate dehydrogenase. NADH is produced in this reaction. This oxaloacetate can again combine with acetyl CoA for next cycle. 2.3. Overall Reaction (1) Acetyl-CoA + Oxaloacetate + H2O → Citrate + CoA-SH + H+ (2) Citrate → Isocitrate (3) Isocitrate + NAD+ → etoglutarate + CO2 + NADH (4) a-Ketoglutarate + NAD+ + CoA-SH → Succinyl-CoA + CO2 + NADH (5) Succinyl-CoA + Pi + GDP → Succinate + GTP + CoA-SH (6) Succinate + E-FAD → Fumarate + E-FADH2 (7) Fumarate + H2O → L-Malate (8) L-Malate + NAD+ → Oxaloacetate + NADH + H+ Acetyl-CoA + 2H2O + 3NAD+ + Pi + GDP + FAD → 2CO2 + 3NADH + GTP + CoA-SH + FADH2 + 2H+ 3. Yield of ATP At this point the yield of ATP is 4 moles per mole of Glucose as it passes through the Krebs cycle This is not much more than the 2 moles which would have been produced from glycolysis However, NADH and FADH2 are energy rich molecules. They are the electron acceptors (oxidizing agents) for the carbon in glucose. Glucose is being "burned" in the TCA cycle, but not by oxygen but by these cofactors, to produce CO2. The oxidation of NADH and FADH2 is highly exergonic and is coupled with the production of ATP from ADP Oxidation of 1 mole NADH produces 3 moles ATP Oxidation of 1 mole FADH2 produces 2 moles ATP Thus total ATP yield = (10 x 3) + (2 x 2) + 4 = 38 moles ATP per mole Glucose Conclusion 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 acetylCoA, which can be used in the citric acid cycle. Beta oxidation of fatty acids with an odd number of methylene bridges produces propionyl CoA, which is then converted into succinyl-CoA and fed into the citric acid cycle. 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. References: Lowenstein JM (1969). Methods in Enzymology, Volume 13: Citric Acid Cycle. Boston: Academic Press. ISBN 0-12-181870-5. Krebs HA, Weitzman PDJ (1987). Krebs' citric acid cycle: half a century and still turning. London: Biochemical Society. ISBN 0-904498-22-0. Wagner, Andreas (2014). Arrival of the Fittest (first ed.). New York: Penguin Group. p. 100. ISBN 9781591846468. Lane, Nick (2009). Life Ascending: The Ten Great Inventions of Evolution. New York: W.W. Norton & Co. ISBN 0-393-06596-0. "The Nobel Prize in Physiology or Medicine 1937". The Nobel Foundation. Retrieved2011-10-26. "The Nobel Prize in Physiology or Medicine 1953". The Nobel Foundation. Retrieved2011-10-26. Gest H (1987). "Evolutionary roots of the citric acid cycle in prokaryotes". Biochem. Soc. Symp. 54: 3–16. PMID 3332996. Meléndez-Hevia E, Waddell TG, Cascante M (September 1996). "The puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution". J. Mol. Evol. 43 (3): 293– 303. doi:10.1007/BF02338838. PMID 8703096. Ebenhöh O, Heinrich R (January 2001). "Evolutionary optimization of metabolic pathways. Theoretical reconstruction of the stoichiometry of ATP and NADH producing systems". Bull. Math. Biol. 63 (1): 21–55. doi:10.1006/bulm.2000.0197.PMID 11146883. Wolfe RR, Jahoor F (February 1990). "Recovery of labeled CO2 during the infusion of C-1- vs C2-labeled acetate: implications for tracer studies of substrate oxidation". Am. J. Clin. Nutr. 51 (2): 248–52. PMID 2106256. Stryer L, Berg J, Tymoczko JL (2002). Biochemistry. San Francisco: W.H. Freeman. ISBN 07167-4684-0. Jones RC, Buchanan BB, Gruissem W (2000). Biochemistry & molecular biology of plants (1st ed.). Rockville, Md: American Society of Plant Physiologists. ISBN 0-943088-39-9. Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO (October 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. 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)806214.PMID 3086126. Stryer L, Berg JM, Tymoczko JL (2002). "Section 18.6: The Regulation of Cellular Respiration Is Governed Primarily by the Need for ATP". Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4684-0.