Citric Acid Cycle: The Central Oxidative Pathway
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The citric acid cycle (CAC) is a key metabolic pathway that occurs in the mitochondria of cells. It involves the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins to carbon dioxide. During each turn of the cycle, NAD+ and FAD are reduced to NADH and FADH2 to generate energy in the form of ATP through oxidative phosphorylation. Overall, the complete oxidation of one acetyl-CoA molecule in the CAC and respiratory chain produces 12 ATP molecules, capturing the energy from nutrients. The cycle plays a central role in cellular respiration and the production of energy.
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Citric Acid Cycle: The Central Oxidative Pathway
- 1. Citric Acid Cycle R.C. Gupta Professor and Head Dept. of Biochemistry National Institute of Medical Sciences Jaipur, India
- 2. Citric acid cycle (CAC) is a metabolic pathway in which acetyl CoA is oxidized Acetyl CoA is obtained from diverse sources Intermediates of this pathway can be used to synthesize a variety of compounds CAC is a cyclic pathway
- 3. Several scientists contributed to the discovery of citric acid cycle The complete cycle was described by Hans Adolf Krebs Hans A. Krebs
- 4. âą Krebs cycle âą Tricarboxylic acid cycle âą Central oxidative pathway Citric acid cycle is also known as: EMB-RCG
- 5. Location The pathway is present in all the cells having mitochondria Enzymes of this pathway are located in the mitochondria EMB-RCG
- 6. Acetyl CoA, a two-carbon compound With the condensation of: The cycle begins ... Citrate, a six-carbon compound to form: Oxaloacetate, a four-carbon compound with
- 7. By a series of reactions ⊠Citrate is re-converted into oxaloacetate These are oxidized to water in the respiratory chain A number of reducing equivalents are also removed Two carbon atoms are removed as carbon dioxide in these reactions
- 9. CAC begins with the entry of acetyl group Sources of oxaloacetate Hence, there is no net utilization of oxaloacetate in CAC But oxaloacetate is regenerated at the end Oxaloacetate is the acceptor of acetyl group
- 10. But to increase the overall rate of CAC reactions, the concentration of intermediates has to be raised Reactions which lead to net entry of intermediates into the cycle are known as anaplerotic reactions
- 11. An important anaplerotic reaction is synthesis of oxaloacetate from pyruvate ATP provides energy for the formation of covalent bond Biotin is required as a coenzyme This reaction is catalysed by pyruvate carboxylase
- 12. Pyruvate carboxylase is an allosteric enzyme; it is activated by acetyl CoA CH â C3 â COOH + CO2 + ATP Pyruvate carboxylase Biotin O = C â COOH | CH â COOH + ADP + Pi2 Oxaloacetate O || Pyruvate
- 13. Oxaloacetate is also formed by a trans- amination reaction between aspartate and a-ketoglutarate H2NâCHâCOOH | CH2âCOOH Aspartate GOT, PLP O=CâCOOH | CH2âCOOH Oxaloacetate O || HOOCâCH2âCH2âCâCOOH a-Ketoglutarate NH2 | HOOCâCH2âCH2âCHâCOOH Glutamate
- 14. However, the transamination reaction is not anaplerotic One intermediate of citric acid cycle, oxaloacetate, is formed at the expense of another, a-ketoglutarate
- 15. Sources of acetyl CoA Acetyl CoA occupies a unique place in metabolism It can be formed from: Glucose Fatty acids Amino acids EMB-RCG
- 16. Pyruvate is an important source of acetyl CoA Pyruvate is formed from glucose, lactate and some amino acids Amino acids forming pyruvate are glycine, alanine, serine, threonine, cysteine, tryptophan and hydroxyproline
- 17. Fatty acid are converted into acetyl CoA by b-oxidation Ketone bodies are also converted into acetyl CoA Some amino acids are directly converted into acetyl CoA Such amino acids are phenylalanine, tyrosine, tryptophan, lysine and leucine
- 18. Oxidative decarboxylation of pyruvate Pyruvate formed from various compounds can be converted into acetyl CoA Conversion of pyruvate into acetyl CoA occurs by oxidative decarboxylation
- 19. Oxidative decarboxylation occurs by a series of reactions in mitochondria These reactions are catalysed by pyruvate dehydrogenase complex The complex consists of three enzymes and requires five coenzymes
- 20. The enzymes are: Pyruvate dehydro- genase Dihydrolipoyl acetyl- transferase Dihydrolipoyl dehydro- genase The coenzymes are: TPP Lipoic acid Co A FAD NAD EMB-RCG
- 21. CH3â Câ COOH O || ïȘ T â H CH3â Câ COOH OH | | T CO2 CH3â Câ H OH | | TPyruvate Thiamin pyro- phosphate CoA â SH Coenzyme A O L || CH3 â C ~ S SH S-Acetyl lipoic acid L S â S Oxidised lipoic acid O || CH3â C ~ Sâ CoA Acetyl CoA L SH SH Reduced lipoic acid FAD FADH2 NADH+ + H NAD + ï« ïŹ ï ïź ïŻ EMB-RCG
- 22. Reactions 1 and 2 are catalysed by pyruvate dehydrogenase Reactions 3 and 4 are catalysed by dihydrolipoyl acetyl transferase Reactions 5 and 6 are catalysed by dihydrolipoyl dehydrogenase EMB-RCG Note: Lipoic acid is bonded to a lysine residue of dihydrolipoyl acetyl transferase
- 23. CH3âCâ COOH + CoA â SH + NAD+ â O || CH3âC ~ S â CoA + NADH + H+ + CO2 O || The net reaction catalysed by pyruvate dehydrogenase complex
- 24. A major fate of acetyl CoA is its oxidation in the citric acid cycle This produces a large amount of energy in the form of ATP Fate of acetyl CoA EMB-RCG
- 25. When energy is not required, acetyl CoA is used to synthesize fatty acids Small amounts are used for various acetylation reactions and for synthesis of: Cholesterol Steroid hormones Vitamin D Ketone bodies EMB-RCG
- 26. Reactions of citric acid cycle In the first reaction of the cycle, acetyl CoA reacts with oxaloacetate The acetyl group is transferred from acetyl CoA to oxaloacetate forming citrate CoA is released The reaction is catalysed by citrate synthetase
- 27. The high-energy thio-ester bond of acetyl CoA is broken in this reaction This releases free energy which ensures that the reaction proceeds in the forward direction only EMB-RCG
- 28. O = C â COOH | CH2 â COOH Citrate synthetase O || CH3 â C ~ S â CoA + H2O CoA â SH | HO â C â COOH | Citrate Acetyl CoA Oxaloacetate CH2 â COOH CH2 â COOH EMB-RCG
- 29. In the second reaction, aconitase removes a molecule of water from citrate Citrate is converted into cis-aconitate This reaction is inhibited by fluoro-acetate EMB-RCG
- 30. Aconitase H2O CH2â COOH | C â COOH || CH â COOH cis-Aconitate CH2â COOH | HO â C â COOH | CH2â COOH Citrate EMB-RCG
- 31. In the third reaction, a water molecule is added back to cis-aconitate by aconitase The net result of this and the preceding reaction is that the position of the âOH group is shifted Citrate is converted into isocitrate EMB-RCG
- 32. EMB-RCG Aconitase H2O CH2â COOH | CH â COOH | HOâCH â COOH cis-Aconitate CH2â COOH | C â COOH || CH â COOH Isocitrate
- 33. In the fourth reaction, isocitrate is dehydrogenated to oxalosuccinate The reaction is catalysed by isocitrate dehydrogenase Isocitrate dehydrogenase is present in mitochondria as well as cytosol EMB-RCG
- 34. Mitochondrial isocitrate dehydrogenase uses NAD as an acceptor of reducing equivalents Cytosolic isocitrate dehydrogenase uses NADP as an acceptor of reducing equivalents EMB-RCG
- 35. HO â CH â COOH Isocitrate dehydrogenase CH2â COOH | CH â COOH | O = C â COOH CH2â COOH | CH â COOH | Isocitrate NAD + NADH + H + Oxalosuccinate
- 36. In the fifth reaction, oxalosuccinate is decarboxylated to a-ketoglutarate The reaction is catalysed by isocitrate dehydrogenase in the presence of Mn++ This is the first reaction of the cycle in which a carbon atom is removed as carbon dioxide EMB-RCG
- 37. CH â COOH2 | CH2 | O = C â COOH CH â COOH2 | CH â COOH | O = C â COOH Oxalosuccinate CO2 a-Ketoglutarate Isocitrate dehydrogenase, Mn++
- 38. In the sixth reaction, a-ketoglutarate undergoes oxidative decarboxylation to succinyl CoA This reaction is analogous to oxidative decarboxylation of pyruvate to acetyl CoA It is catalysed by a-ketoglutarate dehydrogenase complex EMB-RCG
- 39. a-Ketoglutarate dehydrogenase complex is made up of: a-Ketoglutarate dehydrogenase Dihydrolipoyl acetyltransferase Dihydrolipoyl dehydrogenase
- 40. a-Ketoglutarate dehyrogenase complex CH2â COOH | CH2 | O = C ~ S â CoA CH2â COOH | CH | O = C â COOH a-Ketoglutarate CO2 + NADH + H+ Succinyl CoA CoA â SH + NAD+
- 41. This is the second reaction in which a carbon atom is removed This is also an example of substrate-linked oxidative phosphorylation Energy released during oxidation of a-keto- glutarate is used to form a high-energy thio- ester bond
- 42. The seventh reaction is splitting of succinyl CoA into succinate and CoA It is catalysed by succinate thiokinase (succinyl CoA synthetase) The energy released in the reaction is used to phosphorylate GDP to GTP GTP can transfer a high-energy phosphate to ADP forming ATP
- 43. GDP + Pi Succinate thiokinase CH2 â COOH | CH2 âCOOH CH2 â COOH | CH2 | O = C ~ S â CoA Succinyl CoA Succinate GTP + CoAâSH
- 44. Succinate is a four-carbon dicarboxylic acid It is converted into oxaloacetate, another four-carbon dicarboxylic acid The conversion occurs by a series of reactions
- 45. In the eighth reaction, two hydrogen atoms are transferred from succinate to FAD The reaction is catalysed by succinate dehydrogenase Succinate dehydrogenase is a flavo- protein having FAD as a prosthetic group
- 46. Succinate dehydrogenase Hâ C â COOH || HOOC â C â H CH2â COOH | CH2â COOH FADH2 Succinate FAD Fumarate
- 47. Fumarase HO â CH â COOH | CH2 â COOH H â C â COOH || HOOC â C â H Fumarate H2O L-Malate In the ninth reaction, fumarate is hydrated to L-malate by fumarase
- 48. In the tenth reaction, L-malate is dehydro- genated to oxaloacetate by malate dehydrogenase NAD accepts the reducing equivalents Thus, oxaloacetate is regenerated and acetyl CoA is oxidised
- 49. Malate dehydrogenase O ââ C â COOH | CH2 â COOH HO â CH â COOH | CH2 â COOH L-Malate NAD+ NADH + H+ Oxaloacetate
- 50. Citric acid cycle Oxaloacetate Acetyl CoA CoA Citrate cis-Aconitate Isocitrate Oxalosuccinate CO2 a-Ketoglutarate CoA Succinyl CoA GDP+Pi CoA+GTP Succinate FAD FADH2 Fumarate H2O L-Malate NAD+ NADH + H+ NAD+ NAD+ NADH+H+ NADH + H+ H2O H2O H2O CO2
- 51. During complete oxidation of one molecule of acetyl Co A in citric acid cycle: These are oxidised in the respiratory chain Energetics Three molecules of NAD are reduced One molecule of FAD is reduced
- 52. Oxidation of three molecules of NADH will phosphorylate nine molecules of ADP to ATP Oxidation of one molecule of FADH2 will phosphorylate two molecules of ADP to ATP Thus, 11 ATP equivalents are formed by oxidative phosphorylation in the respiratory chain per molecule of acetyl Co A oxidised
- 53. One GTP is formed when succinyl CoA is converted into succinate This, in turn, can convert one ADP into one ATP Thus, 12 ATP equivalents are formed on complete oxidation of one molecule of acetyl CoA in citric acid cycle and respiratory chain
- 54. Succinyl CoA to succinate Isocitrate to oxaloacetate NAD+ïź NADH 3 ATP equivalents Reaction Change in coenzyme Energy captured a-Ketoglutarate to succinyl CoA NAD+ïź NADH 3 ATP equivalents Malate to oxaloacetate 3 ATP equivalentsNAD+ïź NADH 2 ATP equivalentsFAD ïź FADH2 Succinate to fumarate 1 ATP equivalentGDPïź GTP 12 ATP equivalentsNet gain
- 55. Eight ATP equivalents are formed when one molecule of glucose is oxidised to two molecules of pyruvate One molecule of NAD is reduced when pyruvate is converted into acetyl CoA This will form three ATP equivalents when it is oxidised in the respiratory chain Energetics of oxidation of glucose
- 56. Conversion of two pyruvate molecules into acetyl CoA will form 6 ATP equivalents Oxidation of two acetyl CoA molecules in CAC will form 24 ATP equivalents Thus, total ATP equivalents formed from complete oxidation of glucose are 8+6+24=38
- 57. Energy of hydrolysis of the terminal phosphate bond of ATP is 7.3 kcal/mol 38 ATP equivalents represent a capture of 38x7.3 = 277.4 kcal energy per mol of glucose Efficiency of oxidation
- 58. Potential energy present in glucose is 686 kcal per mol Hence, efficiency of oxidation of glucose is 277.4 ïž 686 ïŽ 100% or nearly 40%
- 59. Importance of citric acid cycle âą Final catabolic pathway for carbohydrates, lipids and proteins âą Glucose, fatty acids and many amino acids can be synthesized from intermediates of the cycle âą Capture of energy as ATP
- 60. All the carbohydrates can be converted into glucose Glucose is converted into pyruvate in the glycolytic pathway Pyruvate can enter citric acid cycle after its conversion into acetyl CoA Catabolic function
- 61. Oxidation of fatty acids produces acetyl CoA which is oxidised in the CAC Propionyl CoA is formed from fatty acids having an odd number of carbon atoms Propionyl CoA is converted into succinyl CoA which is an intermediate of CAC
- 62. Glycerol Glycerol-3-phosphate Dihydroxyacetone phosphate Pyruvate Glycerol is also released from lipids This can be converted into pyruvate in the glycolytic pathway
- 63. Several amino acids are converted into pyruvate These are glycine, alanine, serine, threonine, cysteine, tryptophan and hydroxyproline Pyruvate is converted into acetyl CoA which enters the citric acid cycle
- 64. Glutamine, arginine, histidine and proline can be converted into glutamate Glutamate can be converted into a-keto- glutarate, an intermediate of CAC Thus, these five amino acids can enter the cycle as a-ketoglutarate
- 65. Valine, isoleucine and methionine can enter CAC as succinyl CoA Phenylalanine and tyrosine are partially converted into fumarate, an intermediate Asparagine and aspartate can enter the cycle as oxaloacetate Leucine and lysine enter as acetyl CoA
- 66. Anabolic function Glucose, fatty acids and many amino acids can be synthesized from inter- mediates of citric acid cycle Therefore, this cycle plays an important role in interconversion of nutrients
- 67. All the intermediates of CAC can be converted into oxaloacetate Oxaloacetate is a substrates for gluco- neogenesis Therefore, glucose can be synthesized from intermediates of citric acid cycle
- 68. Some intermediates can be trans- aminated to amino acids a-Ketoglutarate can be transaminated to glutamate and oxaloacetate to aspartate Some other amino acids can be formed from these two
- 69. Fatty acids are synthesized from acetyl CoA Major source of acetyl CoA is pyruvate Acetyl CoA is formed in mitochondria but fatty acids are synthesised in cytosol Acetyl CoA cannot traverse mitochondrial membrane but citrate can
- 70. Acetyl CoA is converted into citrate in the mitochondria Citrate goes to cytosol, and is cleaved into acetyl CoA and oxaloacetate Acetyl CoA is used for fatty acid synthesis
- 71. Citrate + CoA ATP-Citrate lyase ATP ADP + Pi Acetyl CoA + Oxaloacetate
- 72. Citric acid cycle performs catabolic as well as anabolic functions Therefore, it is said to be an amphibolic pathway
- 73. Oxaloacetate Citrate cis-Aconitate Isocitrate Oxalosuccinate a-Ketoglutarate Succinyl CoA Succinate Phe, Tyr Fumarate Malate Val Propionyl CoA Fatty acids (C)2n+1 Ile Met Glutamate Gln Pro Arg His Gly, Ala, Ser, Thr, Cys, Trp, Hyp PyruvateGlucose Glycerol Acetyl CoA Fatty acids (C)2n Asn Asp Acetyl CoA Amphibolic role of CAC
- 74. Capture of energy Much of the energy is captured as ATP when these fuels are oxidized in the citric acid cycle An important functions of citric acid cycle is to capture the energy present in carbohydrates, lipids and proteins
- 75. Regulation The major function of citric acid cycle is to capture energy Availability of energy in the cell is the major regulator of the pathway In addition, some enzymes are allosteric enzymes
- 76. The allosteric enzymes are: Ca++ is the allosteric activator of all the three a-Ketoglutarate dehydrogenase Isocitrate dehydrogenase Citrate synthetase
- 77. The allosteric inhibitors are: Enzyme Inhibitor Citrate synthetase ATP and acyl CoA Isocitrate dehydrogenase ATP and NADH a-Ketoglutarate dehydrogenase NADH and succinyl CoA
- 78. Citrate synthetase ATP, acyl CoACa++ + - Isocitrate dehydrogenase ATP, NADHCa++ + + - a-Ketoglutarate dehydrogenase NADH, Succinyl CoA - Ca++
- 79. Glucose is major source of energy for brain Pyruvate formed by glycolysis is converted into acetyl CoA Glucose is oxidized by glycolysis in brain Regulation in brain The fate of acetyl CoA is its oxidation in the citric acid cycle
- 80. Rate of citric acid cycle reactions in brain depends upon the availability of acetyl CoA PDH complex is regulated by allosteric mechanism as well as covalent modification Availability of acetyl CoA depends upon pyruvate dehydrogenase (PDH) complex
- 81. The components of PDH complex are: Pyruvate dehydrogenase Dihydrolipoyl dehydrogenase Dihydrolipoyl acetyltransferase
- 82. Dihydrolipoyl acetyltransferase and dihydro- lipoyl dehydrogenase are allosteric enzymes Dihydrolipoyl dehydrogenase is allosterically inhibited by NADH Dihydrolipoyl acetyltransferase is allosterically inhibited by acetyl CoA
- 83. PDH can exist in two forms: PDH-a and PDH-b PDH-b is the phosphorylated form PDH-a is the dephosphorylated form Pyruvate dehydrogenase (PDH) is regulated by covalent modification
- 84. PDH-a is the active form; PDH-b is the inactive form PDH-b is dephosphorylated to PDH-a by PDH phosphatase PDH-a is phosphorylated to PDH-b by PDH kinase
- 85. PDHâa (active) PDHâb (inactive) ATP ADP PDH kinase PDH phosphatase Pi H2O ââ EMB-RCG
- 86. PDH kinase and PDH phosphatase are allosteric enzymes PDH phosphatase is activated by Ca++ and Mg++ PDH kinase is activated by acetyl CoA, NADH & ATP, and is inhibited by pyruvate
- 87. High concentrations of acetyl CoA, NADH and ATP convert active PDH into inactive PDH A high concentration of pyruvate has the opposite effect This, in turn, decreases the rate of citric acid cycle reactions Conversion of pyruvate into acetyl CoA is decreased
- 88. ATP PDH PDHâ NADHAcetyl CoA ï ï ï ï ï -ï ATP ADP PDH kinase Pyruvate PDH phosphatase Pi H2O Mg ++ Ca ++ Insulin (in adipose tissue) EMB-RCG â
- 89. In adipose tissue, insulin activates PDH phosphatase This increases the oxidative decarboxylation of pyruvate into acetyl CoA PDH phosphatase converts inactive PDH into active PDH