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3.) The tricarboxylic acid cycle (TCA).

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  1. Front
    TCA cycle other names
    Back
    Citric acid cycle (CAC), Krebs cycle, and tricarboxylic acid cycle (TCA)
  2. Front
    Location of the TCA cycle
    Back
    Mitochondrial matrix
  3. Front
    Main job of the TCA cycle
    Back
    Oxidize the acetyl group of acetyl-CoA to 2 CO2 while producing 3 NADH, 1 FADH2, and 1 GTP per turn
  4. Front
    Reduced cofactors produced by one turn of TCA
    Back
    3 NADH and 1 FADH2
  5. Front
    High-energy phosphate produced by one turn of TCA
    Back
    1 GTP
  6. Front
    Why the TCA cycle is a major source of ATP production
    Back
    The NADH and FADH2 it produces donate electrons to the respiratory chain
  7. Front
    Total ATP yield from oxidation of 1 acetyl-CoA according to the lecture
    Back
    10 ATP total when oxidative phosphorylation is included
  8. Front
    Why the TCA cycle works only under aerobic conditions
    Back
    NADH and FADH2 must be reoxidized by the respiratory chain, so if oxygen is lacking NADH accumulates and the cycle slows
  9. Front
    Catabolism definition
    Back
    Breakdown of fuel molecules to generate energy
  10. Front
    Common intermediate in catabolism
    Back
    Acetyl-CoA
  11. Front
    Three stages of catabolism in the lecture
    Back
    Hydrolysis of complex molecules to monomers, conversion to acetyl-CoA, and final oxidations by the Krebs cycle and respiratory chain
  12. Front
    Final common oxidative pathway for carbohydrates, fatty acids, and many amino acids
    Back
    TCA cycle
  13. Front
    High-yield convergence point of different fuels
    Back
    Different fuels enter in different ways, but they converge at acetyl-CoA
  14. Front
    Entry molecule into the TCA cycle
    Back
    Acetyl-CoA
  15. Front
    Lecture statement about compounds oxidized to CO2 and H2O
    Back
    Any organic compound oxidized to CO2 and H2O must first be transformed to acetyl-CoA
  16. Front
    Source of acetyl-CoA from glucose
    Back
    Glucose → glycolysis → pyruvate → acetyl-CoA by pyruvate dehydrogenase
  17. Front
    Source of acetyl-CoA from fatty acids
    Back
    Fatty acids undergo β-oxidation to produce acetyl-CoA, NADH, and FADH2
  18. Front
    Source of TCA inputs from amino acids
    Back
    Some amino acids are degraded to pyruvate, acetyl-CoA, or TCA intermediates
  19. Front
    Source of acetyl-CoA from ketone bodies
    Back
    Ketone bodies in extrahepatic tissues can be converted back to acetyl-CoA
  20. Front
    What the TCA cycle directly uses
    Back
    Acetyl-CoA rather than glucose or fatty acids directly
  21. Front
    Number of carbons in acetyl-CoA
    Back
    2 carbons
  22. Front
    Number of carbons in oxaloacetate (OAA)
    Back
    4 carbons
  23. Front
    Number of carbons in citrate
    Back
    6 carbons
  24. Front
    How citrate is formed
    Back
    Acetyl-CoA (2C) combines with oxaloacetate (4C) to form citrate (6C)
  25. Front
    Number of carbons released as CO2 per turn of TCA
    Back
    2 carbons
  26. Front
    Fate of oxaloacetate in the TCA cycle
    Back
    Oxaloacetate is regenerated at the end of the cycle
  27. Front
    Important carbon-tracking point in TCA
    Back
    The 2 carbons released as CO2 in one turn are not necessarily the same exact carbons that just entered from acetyl-CoA
  28. Front
    Key carbon accounting for one turn of TCA
    Back
    2 carbons enter as acetyl-CoA, 2 carbons leave as CO2, and oxaloacetate is regenerated
  29. Front
    Oxaloacetate concentration in the TCA cycle
    Back
    Very low and continuously consumed and regenerated
  30. Front
    Order of TCA intermediates
    Back
    Oxaloacetate + acetyl-CoA → citrate → isocitrate → α-ketoglutarate → succinyl-CoA → succinate → fumarate → malate → oxaloacetate
  31. Front
    Step 1 enzyme of TCA
    Back
    Citrate synthase
  32. Front
    Step 1 reaction of TCA
    Back
    Oxaloacetate + acetyl-CoA + H2O → citrate + CoA-SH
  33. Front
    Type of reaction catalyzed by citrate synthase
    Back
    Condensation
  34. Front
    Carbon change in citrate synthase reaction
    Back
    A 2-carbon acetyl group joins 4-carbon oxaloacetate to form 6-carbon citrate
  35. Front
    Physiologic reversibility of citrate synthase reaction
    Back
    Irreversible
  36. Front
    Why citrate synthase irreversibility matters
    Back
    OAA concentration is very low, which helps drive the reaction forward
  37. Front
    Structural idea of oxaloacetate
    Back
    Oxaloacetate is a dicarboxylate with a keto group
  38. Front
    Structural idea of citrate
    Back
    Citrate is a tricarboxylate
  39. Front
    Step 2 enzyme of TCA
    Back
    Aconitase
  40. Front
    Step 2 reaction of TCA
    Back
    Citrate ⇌ isocitrate
  41. Front
    Type of reaction catalyzed by aconitase
    Back
    Isomerization
  42. Front
    Main structural change in the aconitase reaction
    Back
    The OH group is moved to create a molecule that can be oxidized in the next step
  43. Front
    Why citrate is converted to isocitrate
    Back
    Citrate is a poor substrate for oxidation, and isomerization makes isocitrate able to undergo oxidative decarboxylation
  44. Front
    Step 3 enzyme of TCA
    Back
    Isocitrate dehydrogenase
  45. Front
    Step 3 reaction of TCA
    Back
    Isocitrate → α-ketoglutarate + CO2 + NADH
  46. Front
    Type of reaction in step 3
    Back
    First oxidative decarboxylation
  47. Front
    Products of isocitrate dehydrogenase reaction
    Back
    α-Ketoglutarate, CO2, and NADH
  48. Front
    Carbon count and class of α-ketoglutarate
    Back
    5-carbon α-keto acid
  49. Front
    Physiologic reversibility of isocitrate dehydrogenase reaction
    Back
    Irreversible
  50. Front
    Regulatory importance of isocitrate dehydrogenase
    Back
    It is one of the major regulatory steps of the TCA cycle
  51. Front
    Step 4 enzyme of TCA
    Back
    α-Ketoglutarate dehydrogenase complex
  52. Front
    Step 4 reaction of TCA
    Back
    α-Ketoglutarate → succinyl-CoA + CO2 + NADH
  53. Front
    Type of reaction in step 4
    Back
    Second oxidative decarboxylation
  54. Front
    Products of α-ketoglutarate dehydrogenase reaction
    Back
    Succinyl-CoA, CO2, and NADH
  55. Front
    Nature of succinyl-CoA
    Back
    High-energy thioester
  56. Front
    Physiologic reversibility of α-ketoglutarate dehydrogenase reaction
    Back
    Irreversible
  57. Front
    Mechanistic relationship of α-ketoglutarate dehydrogenase
    Back
    It has the same mechanism as pyruvate dehydrogenase
  58. Front
    Association tested for α-ketoglutarate dehydrogenase
    Back
    α-Ketoglutarate dehydrogenase resembles the pyruvate dehydrogenase complex
  59. Front
    Step 5 enzyme of TCA
    Back
    Succinyl-CoA synthetase
  60. Front
    Step 5 reaction of TCA
    Back
    Succinyl-CoA → succinate + GTP
  61. Front
    Energy source for GTP formation in step 5
    Back
    The high-energy thioester bond of succinyl-CoA
  62. Front
    Type of phosphorylation in step 5
    Back
    Substrate-level phosphorylation
  63. Front
    Only substrate-level phosphorylation step in TCA
    Back
    Succinyl-CoA synthetase reaction
  64. Front
    How GTP can be used energetically
    Back
    GTP can transfer its phosphate to ADP by GTP + ADP ⇌ GDP + ATP
  65. Front
    Step 6 enzyme of TCA
    Back
    Succinate dehydrogenase
  66. Front
    Step 6 reaction of TCA
    Back
    Succinate → fumarate + FADH2
  67. Front
    Redox event in step 6
    Back
    Succinate is oxidized and FAD is reduced to FADH2
  68. Front
    Special significance of succinate dehydrogenase
    Back
    It is also Complex II of the respiratory chain
  69. Front
    Inhibitor of succinate dehydrogenase
    Back
    Malonate
  70. Front
    Type of inhibition by malonate
    Back
    Competitive inhibition
  71. Front
    Why malonate inhibits succinate dehydrogenase
    Back
    It is a structural analog of succinate
  72. Front
    Step 7 enzyme of TCA
    Back
    Fumarase
  73. Front
    Step 7 reaction of TCA
    Back
    Fumarate → malate
  74. Front
    Type of reaction catalyzed by fumarase
    Back
    Hydration
  75. Front
    Structural change in step 7
    Back
    Water is added across the double bond of fumarate to form malate
  76. Front
    Step 8 enzyme of TCA
    Back
    Malate dehydrogenase
  77. Front
    Step 8 reaction of TCA
    Back
    Malate → oxaloacetate + NADH
  78. Front
    Redox event in step 8
    Back
    Malate is oxidized and NAD+ is reduced to NADH
  79. Front
    Importance of malate dehydrogenase reaction
    Back
    Regenerates oxaloacetate for the next turn of the cycle
  80. Front
    Why the malate dehydrogenase reaction proceeds in the cycle
    Back
    OAA concentration is extremely low and OAA is quickly consumed in the citrate synthase reaction, pulling the pathway forward
  81. Front
    Three irreversible reactions of the TCA cycle
    Back
    Citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase
  82. Front
    Why irreversible TCA reactions matter
    Back
    They determine direction of flow and are the main points of regulation
  83. Front
    Products per acetyl-CoA in one turn of TCA
    Back
    2 CO2, 3 NADH, 1 FADH2, and 1 GTP
  84. Front
    ATP equivalent of 3 NADH in TCA
    Back
    7.5 ATP
  85. Front
    ATP equivalent of 1 FADH2 in TCA
    Back
    1.5 ATP
  86. Front
    ATP equivalent of 1 GTP in TCA
    Back
    1 ATP
  87. Front
    Total ATP equivalent per acetyl-CoA in TCA
    Back
    10 ATP
  88. Front
    Overall TCA reaction
    Back
    Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2 H2O → 2 CO2 + 3 NADH + 3 H+ + FADH2 + GTP + CoA-SH
  89. Front
    Big-picture regulation of the TCA cycle
    Back
    Substrate availability and respiratory control
  90. Front
    Important substrates affecting TCA rate
    Back
    Acetyl-CoA, oxaloacetate, NAD+, and FAD
  91. Front
    How ADP indirectly promotes TCA
    Back
    ATP demand drives oxidative phosphorylation, which regenerates NAD+ and FAD
  92. Front
    Very high-yield dependence of TCA entry
    Back
    The TCA cycle depends on availability of oxaloacetate
  93. Front
    Consequence of low oxaloacetate
    Back
    Acetyl-CoA cannot enter the TCA cycle efficiently
  94. Front
    Fasting and ketogenesis link to TCA
    Back
    In prolonged fasting, liver β-oxidation produces abundant acetyl-CoA, but if OAA is low acetyl-CoA is diverted to ketone body synthesis instead of entering TCA efficiently
  95. Front
    Respiratory control effect on TCA
    Back
    If the respiratory chain is slow, NADH accumulates and TCA dehydrogenase reactions slow because they need NAD+
  96. Front
    Effect of a high NADH/NAD+ ratio on TCA
    Back
    It inhibits TCA dehydrogenase reactions and slows the cycle
  97. Front
    Effect of high ATP and low ADP on TCA
    Back
    The cycle slows because cellular energy demand is low
  98. Front
    High-yield respiratory control summary for TCA
    Back
    High NADH inhibits TCA, high ATP inhibits TCA, and low oxygen inhibits TCA indirectly because NADH cannot be reoxidized
  99. Front
    Effect of anaerobic conditions on the Krebs cycle
    Back
    Anaerobic conditions inhibit the Krebs cycle because NADH accumulates and NAD+ levels drop
  100. Front
    Citrate synthase regulation
    Back
    Regulated step that is inhibited when energy is high and is especially sensitive to OAA availability
  101. Front
    Isocitrate dehydrogenase regulation
    Back
    Major control point inhibited by high ATP and high NADH and favored by low ATP or higher ADP
  102. Front
    α-Ketoglutarate dehydrogenase regulation
    Back
    Major control point inhibited by high NADH and generally slowed when energy is abundant
  103. Front
    Main regulated enzymes of the TCA cycle
    Back
    Citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase
  104. Front
    Why the main regulated TCA enzymes are those three
    Back
    They are the irreversible steps
  105. Front
    Amphibolic nature of the TCA cycle
    Back
    The TCA cycle functions in both catabolism and anabolism
  106. Front
    Why the TCA cycle is catabolic
    Back
    It oxidizes acetyl-CoA for energy production
  107. Front
    Why the TCA cycle is anabolic/amphibolic
    Back
    Its intermediates are withdrawn for biosynthesis
  108. Front
    Biosynthetic products linked to TCA intermediates in the lecture
    Back
    Fatty acids, steroids, amino acids such as Asp and Asn, and pyrimidine nucleotides
  109. Front
    Why anaplerotic reactions are needed
    Back
    If TCA intermediates are removed for biosynthesis, they must be replenished or the cycle will slow or stop
  110. Front
    Lecture statement about biosynthetic withdrawal of TCA intermediates
    Back
    Removal of Krebs cycle intermediates for biosyntheses decreases the level of OAA
  111. Front
    Anaplerotic reactions
    Back
    Reactions that replenish TCA intermediates
  112. Front
    Meaning of anaplerotic
    Back
    Replenishing or filling up
  113. Front
    Most important anaplerotic reaction
    Back
    Pyruvate carboxylase reaction
  114. Front
    Pyruvate carboxylase reaction
    Back
    Pyruvate + CO2 + ATP → oxaloacetate
  115. Front
    Location of pyruvate carboxylase
    Back
    Mitochondria
  116. Front
    Cofactor requirement of pyruvate carboxylase
    Back
    Biotin-dependent
  117. Front
    Allosteric activator of pyruvate carboxylase
    Back
    Acetyl-CoA
  118. Front
    Logic of pyruvate carboxylase activation by acetyl-CoA
    Back
    If acetyl-CoA is high, more OAA is needed to combine with it, so acetyl-CoA activates pyruvate carboxylase
  119. Front
    Other conceptual anaplerotic sources
    Back
    Amino acids can replenish TCA intermediates, and propionyl-CoA can contribute to succinyl-CoA
  120. Front
    Main anaplerotic answer for exams
    Back
    Pyruvate → oxaloacetate by pyruvate carboxylase
  121. Front
    Oxaloacetate structural identity
    Back
    4C dicarboxylate keto acid
  122. Front
    Citrate structural identity
    Back
    6C tricarboxylate
  123. Front
    Isocitrate structural identity
    Back
    6C isomer of citrate
  124. Front
    α-Ketoglutarate structural identity
    Back
    5C α-keto dicarboxylate
  125. Front
    Succinyl-CoA structural identity
    Back
    4C thioester
  126. Front
    Succinate structural identity
    Back
    4C dicarboxylate
  127. Front
    Fumarate structural identity
    Back
    4C trans double bond dicarboxylate
  128. Front
    Malate structural identity
    Back
    4C hydroxy dicarboxylate
  129. Front
    Kinds of reactions across the TCA cycle
    Back
    Condensation, isomerization, oxidation plus decarboxylation, oxidation plus decarboxylation, substrate-level phosphorylation, oxidation, hydration, and oxidation
  130. Front
    Irreversible steps exam table
    Back
    Citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase
  131. Front
    Products per acetyl-CoA exam table
    Back
    3 NADH, 1 FADH2, 1 GTP, 2 CO2, and 10 ATP total equivalent
  132. Front
    Regulation exam table
    Back
    Substrate availability, high NADH inhibits, high ATP inhibits, and low oxygen inhibits indirectly
  133. Front
    Most important anaplerotic reaction exam table
    Back
    Pyruvate carboxylase: pyruvate → oxaloacetate, biotin-dependent, activated by acetyl-CoA
  134. Front
    High-yield location of TCA
    Back
    Mitochondrial matrix
  135. Front
    Why TCA is aerobic in practice
    Back
    O2 is not a direct substrate, but NADH and FADH2 must be reoxidized by the ETC
  136. Front
    Common entry point for oxidation of carbohydrates, fats, and many amino acids
    Back
    Acetyl-CoA
  137. Front
    High-yield amphibolic concept
    Back
    TCA is amphibolic because its intermediates are also used for biosynthesis
  138. Front
    High-yield consequence of low OAA
    Back
    If OAA is low, acetyl-CoA cannot be used efficiently in TCA
  139. Front
    High-yield fasting consequence in liver
    Back
    During fasting, abundant acetyl-CoA from β-oxidation may exceed OAA availability and push toward ketogenesis

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