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Pyruvate, oxaloacetate, acetyl-CoA as key metabolites:

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  1. Front
    Pyruvate, oxaloacetate, and acetyl-CoA
    Back
    Central crossroads metabolites that connect carbohydrate metabolism, TCA cycle, gluconeogenesis, fatty acid synthesis, fatty acid oxidation, and ketone body metabolism
  2. Front
    Why pyruvate, oxaloacetate, and acetyl-CoA are high-yield
    Back
    Knowing what each can become, what produces it, and what regulates those reactions helps answer many metabolism questions
  3. Front
    Pyruvate concept
    Back
    Major end product of glycolysis and branch point into lactate, alanine, acetyl-CoA, and oxaloacetate
  4. Front
    Oxaloacetate concept
    Back
    Key TCA intermediate and key entry point for gluconeogenesis that is also needed to combine with acetyl-CoA
  5. Front
    Acetyl-CoA concept
    Back
    Common oxidative intermediate from carbohydrates, fats, and many amino acids that enters TCA and connects to fatty acid synthesis and ketone body synthesis
  6. Front
    Major end product of aerobic glycolysis
    Back
    Pyruvate
  7. Front
    Pyruvate structure
    Back
    3-carbon α-keto acid
  8. Front
    Metabolic importance of pyruvate
    Back
    One of the most important branch points in metabolism
  9. Front
    Reaction producing pyruvate from glycolysis
    Back
    PEP → pyruvate by pyruvate kinase
  10. Front
    High-yield facts about the pyruvate kinase reaction
    Back
    It is an irreversible glycolysis step and a substrate-level phosphorylation step because ATP is formed
  11. Front
    Reaction producing pyruvate from alanine
    Back
    Alanine → pyruvate by transamination
  12. Front
    Reaction producing pyruvate from lactate
    Back
    Lactate → pyruvate by lactate dehydrogenase
  13. Front
    Importance of lactate to pyruvate conversion
    Back
    Especially important in liver during gluconeogenesis
  14. Front
    Reaction using pyruvate to make lactate
    Back
    Pyruvate → lactate
  15. Front
    Why pyruvate is reduced to lactate
    Back
    To regenerate NAD+ and allow glycolysis to continue when oxidative metabolism is limited
  16. Front
    Reaction using pyruvate to make acetyl-CoA
    Back
    Pyruvate → acetyl-CoA by pyruvate dehydrogenase complex
  17. Front
    Location of pyruvate dehydrogenase complex
    Back
    Mitochondria
  18. Front
    Role of pyruvate dehydrogenase reaction
    Back
    Links glycolysis to the TCA cycle and commits pyruvate carbon toward oxidation or lipid synthesis pathways
  19. Front
    Reaction using pyruvate to make oxaloacetate
    Back
    Pyruvate → oxaloacetate by pyruvate carboxylase
  20. Front
    Role of pyruvate carboxylase reaction
    Back
    Replenishes TCA intermediates and begins gluconeogenesis
  21. Front
    Relationship between pyruvate and alanine
    Back
    Pyruvate and alanine are interconverted by transamination
  22. Front
    Why pyruvate-alanine interconversion matters
    Back
    It is important in amino acid metabolism and alanine supply for gluconeogenesis
  23. Front
    Role of pyruvate in energy metabolism
    Back
    Produced from glucose and can enter mitochondria for further oxidation
  24. Front
    Role of pyruvate in anaerobic metabolism
    Back
    Reduced to lactate to regenerate NAD+
  25. Front
    Role of pyruvate in gluconeogenesis
    Back
    It can be carboxylated to oxaloacetate
  26. Front
    Role of pyruvate in amino acid interconversion
    Back
    Linked with alanine
  27. Front
    Pyruvate as a metabolic concept
    Back
    Major decision point in metabolism
  28. Front
    Pyruvate kinase function
    Back
    Controls pyruvate formation from PEP
  29. Front
    Pyruvate kinase activator
    Back
    Fructose-1,6-bisphosphate
  30. Front
    Pyruvate kinase inhibitor
    Back
    ATP
  31. Front
    Effect of liver PKA phosphorylation on pyruvate kinase
    Back
    Inactivates pyruvate kinase
  32. Front
    PDH function
    Back
    Controls conversion of pyruvate to acetyl-CoA
  33. Front
    Conditions favoring PDH activity
    Back
    High substrate supply and high ADP
  34. Front
    Effect of high acetyl-CoA on PDH
    Back
    Inhibits PDH
  35. Front
    Pyruvate carboxylase function
    Back
    Controls conversion of pyruvate to oxaloacetate
  36. Front
    Pyruvate carboxylase activator
    Back
    Acetyl-CoA
  37. Front
    Pyruvate carboxylase location
    Back
    Mitochondrial
  38. Front
    Pyruvate carboxylase cofactor requirement
    Back
    Biotin-dependent
  39. Front
    Very high-yield effect of high acetyl-CoA on pyruvate fate
    Back
    High acetyl-CoA pushes pyruvate toward oxaloacetate rather than PDH
  40. Front
    Oxaloacetate structure
    Back
    4-carbon dicarboxylic keto acid
  41. Front
    Metabolic importance of oxaloacetate
    Back
    Key intermediate of the TCA cycle
  42. Front
    Other major roles of oxaloacetate
    Back
    Essential for gluconeogenesis and for transport of acetyl units out of mitochondria as citrate
  43. Front
    Reaction producing oxaloacetate in TCA
    Back
    Malate → oxaloacetate by malate dehydrogenase
  44. Front
    Most important OAA-producing reaction
    Back
    Pyruvate → oxaloacetate by pyruvate carboxylase
  45. Front
    Reaction producing cytosolic OAA in gluconeogenesis
    Back
    Cytosolic malate → oxaloacetate after malate transport out of mitochondria
  46. Front
    Major reaction using oxaloacetate in TCA
    Back
    OAA + acetyl-CoA → citrate by citrate synthase
  47. Front
    Major reaction using oxaloacetate in gluconeogenesis
    Back
    OAA → PEP by PEP carboxykinase
  48. Front
    Reaction using OAA for transport and redox balancing
    Back
    OAA → malate
  49. Front
    Why OAA combines with acetyl-CoA to form citrate for export
    Back
    To move acetyl units into the cytosol for fatty acid synthesis because acetyl-CoA cannot cross the inner mitochondrial membrane
  50. Front
    Role of OAA in the TCA cycle
    Back
    Accepts the 2-carbon acetyl group from acetyl-CoA
  51. Front
    Why OAA is required for effective TCA entry of acetyl-CoA
    Back
    Without OAA, acetyl-CoA cannot enter the cycle effectively
  52. Front
    Role of OAA in gluconeogenesis
    Back
    It is the immediate product of pyruvate carboxylase and leads toward PEP and then glucose synthesis
  53. Front
    Role of OAA in anaplerosis
    Back
    Replenishes TCA intermediates
  54. Front
    Why anaplerotic OAA is important
    Back
    It is especially important when TCA intermediates are drawn off for biosynthesis
  55. Front
    Role of OAA in the citrate shuttle
    Back
    OAA combines with acetyl-CoA to make citrate, which can leave mitochondria and be cleaved in the cytosol into acetyl-CoA and OAA for fatty acid synthesis
  56. Front
    Major regulator of OAA production
    Back
    Pyruvate carboxylase
  57. Front
    Effect of acetyl-CoA on OAA production
    Back
    Activates pyruvate carboxylase and promotes OAA formation
  58. Front
    Why OAA availability is a major metabolic control point
    Back
    Low OAA slows TCA cycle, limits citrate formation from acetyl-CoA, and pushes acetyl-CoA toward ketogenesis in liver
  59. Front
    Effect of active gluconeogenesis on OAA fate
    Back
    OAA is more likely to be pulled toward glucose production
  60. Front
    Very high-yield consequence of low OAA
    Back
    Acetyl-CoA cannot be efficiently converted to citrate
  61. Front
    Integrated consequence of low OAA on metabolism
    Back
    TCA cycle slows, acetyl-CoA accumulates, accumulated acetyl-CoA inhibits PDH, and pyruvate may accumulate and be diverted to lactate
  62. Front
    Acetyl-CoA structure
    Back
    2-carbon activated acetyl group linked to coenzyme A
  63. Front
    Major sources of acetyl-CoA
    Back
    Breakdown of carbohydrates, fatty acids, and many amino acids
  64. Front
    Metabolic importance of acetyl-CoA
    Back
    Central molecule of catabolism that also feeds major anabolic pathways
  65. Front
    Reaction producing acetyl-CoA from pyruvate
    Back
    Pyruvate → acetyl-CoA by PDH
  66. Front
    Reaction producing acetyl-CoA from fatty acids
    Back
    β-oxidation of fatty acids
  67. Front
    Reaction producing acetyl-CoA from ketone bodies
    Back
    Ketone body utilization in extrahepatic tissues
  68. Front
    Reaction producing acetyl-CoA from amino acids
    Back
    Catabolism of certain amino acids
  69. Front
    Major reaction using acetyl-CoA for TCA entry
    Back
    Acetyl-CoA + OAA → citrate
  70. Front
    Reaction using acetyl-CoA for ketone body formation
    Back
    Acetyl-CoA → ketone bodies in liver mitochondria during fasting or high fatty acid oxidation states
  71. Front
    How acetyl-CoA contributes to fatty acid synthesis
    Back
    It first exits mitochondria as citrate and is then converted back to cytosolic acetyl-CoA
  72. Front
    Reaction converting acetyl-CoA to malonyl-CoA
    Back
    Acetyl-CoA → malonyl-CoA by acetyl-CoA carboxylase
  73. Front
    Why acetyl-CoA carboxylase is high yield
    Back
    It catalyzes the committed regulatory step of fatty acid synthesis
  74. Front
    Role of acetyl-CoA in cholesterol synthesis
    Back
    Cytosolic acetyl-CoA is used for cholesterol synthesis
  75. Front
    Major take-home role of acetyl-CoA in catabolism
    Back
    Final common oxidative intermediate on which fuels converge before final oxidation
  76. Front
    Role of acetyl-CoA in the TCA cycle
    Back
    Donates 2 carbons by condensing with OAA
  77. Front
    Role of cytosolic acetyl-CoA in biosynthesis
    Back
    Used for fatty acid synthesis and cholesterol synthesis
  78. Front
    Regulatory role of acetyl-CoA
    Back
    Acts as a signal molecule that activates pyruvate carboxylase and inhibits pyruvate flow into PDH at course-level logic
  79. Front
    Role of acetyl-CoA in fasting liver
    Back
    Excess acetyl-CoA can be diverted to ketone body synthesis
  80. Front
    PDH as a regulator of acetyl-CoA formation
    Back
    Controls formation of acetyl-CoA from pyruvate
  81. Front
    Effect of high acetyl-CoA on PDH activity
    Back
    Inhibits PDH
  82. Front
    Conditions favoring PDH activity in acetyl-CoA production
    Back
    When substrate and ADP are high and products are being used
  83. Front
    ACC function
    Back
    Controls conversion of acetyl-CoA to malonyl-CoA
  84. Front
    Allosteric activator of ACC
    Back
    Citrate
  85. Front
    Allosteric inhibitor of ACC
    Back
    Palmitoyl-CoA
  86. Front
    Effect of insulin on ACC
    Back
    Dephosphorylation and activation of ACC
  87. Front
    Effect of glucagon on ACC
    Back
    Phosphorylation and inactivation of ACC
  88. Front
    Effect of adrenaline on ACC
    Back
    Phosphorylation and inactivation of ACC
  89. Front
    Effect of AMPK on ACC
    Back
    Phosphorylation and inactivation of ACC
  90. Front
    Effect of insulin on lipogenic enzyme expression
    Back
    Increases expression of citrate lyase, malic enzyme, ACC1, and fatty acid synthase
  91. Front
    Effect of malonyl-CoA on CPT I
    Back
    Inhibits CPT I
  92. Front
    Why malonyl-CoA inhibition of CPT I is important
    Back
    When fatty acid synthesis is on, fatty acid oxidation is suppressed
  93. Front
    Major integrated relationship between pyruvate, acetyl-CoA, and OAA
    Back
    Pyruvate to acetyl-CoA and pyruvate to OAA are competing major fates, and high acetyl-CoA favors pyruvate carboxylase and pushes pyruvate to OAA
  94. Front
    Major integrated relationship between acetyl-CoA and OAA
    Back
    Acetyl-CoA needs OAA to enter the TCA cycle, so if OAA is low acetyl-CoA builds up
  95. Front
    Major integrated relationship involving citrate export
    Back
    When mitochondrial citrate is high, citrate exits to the cytosol and is cleaved into acetyl-CoA and OAA for fatty acid synthesis
  96. Front
    Major integrated relationship involving citrate and ACC
    Back
    High citrate activates ACC and favors fatty acid synthesis
  97. Front
    Clean pyruvate summary
    Back
    Major sources are glycolysis, lactate, and alanine; major fates are lactate, alanine, acetyl-CoA, and OAA; key regulation is by pyruvate kinase, PDH, and pyruvate carboxylase
  98. Front
    Clean oxaloacetate summary
    Back
    Major sources are pyruvate carboxylase and malate dehydrogenase; major fates are citrate formation with acetyl-CoA, PEP in gluconeogenesis, and malate; its availability controls TCA entry of acetyl-CoA
  99. Front
    Clean acetyl-CoA summary
    Back
    Major sources are PDH, β-oxidation, amino acid catabolism, and ketone body utilization; major fates are TCA cycle, fatty acid synthesis via citrate shuttle, cholesterol synthesis, ketone body synthesis, and malonyl-CoA formation; key regulation involves PDH and ACC
  100. Front
    Super high-yield pyruvate fact
    Back
    Pyruvate is the branch point at the end of glycolysis
  101. Front
    Super high-yield pyruvate carboxylase fact
    Back
    Pyruvate carboxylase is activated by acetyl-CoA
  102. Front
    Super high-yield oxaloacetate transport fact
    Back
    Oxaloacetate cannot cross the inner mitochondrial membrane directly
  103. Front
    Super high-yield acetyl-CoA transport fact
    Back
    Acetyl-CoA cannot cross the inner mitochondrial membrane directly and exits as citrate
  104. Front
    Super high-yield TCA entry fact
    Back
    Acetyl-CoA requires OAA to enter the TCA cycle
  105. Front
    Super high-yield consequence of low OAA
    Back
    Low OAA can cause acetyl-CoA accumulation and reduce TCA flux
  106. Front
    Super high-yield ACC regulation fact
    Back
    Citrate activates ACC, while palmitoyl-CoA inhibits ACC
  107. Front
    Super high-yield malonyl-CoA fact
    Back
    Malonyl-CoA inhibits CPT I, linking fatty acid synthesis to inhibition of fatty acid oxidation
  108. Front
    Cheat-sheet pyruvate
    Back
    Sources: glycolysis, lactate, alanine; fates: lactate, alanine, acetyl-CoA, OAA; key regulation: pyruvate kinase, PDH, pyruvate carboxylase
  109. Front
    Cheat-sheet oxaloacetate
    Back
    Sources: pyruvate carboxylase, malate; fates: citrate, PEP, malate; key role: TCA entry partner for acetyl-CoA and gluconeogenesis intermediate
  110. Front
    Cheat-sheet acetyl-CoA
    Back
    Sources: PDH, β-oxidation, amino acids; fates: TCA cycle, fatty acids, cholesterol, ketone bodies, malonyl-CoA; key role: common oxidative intermediate and major biosynthetic precursor
  111. Front
    Cheat-sheet key regulatory facts
    Back
    Acetyl-CoA activates pyruvate carboxylase, high acetyl-CoA inhibits PDH, citrate activates ACC, palmitoyl-CoA inhibits ACC, malonyl-CoA inhibits CPT I, and insulin activates ACC while glucagon, adrenaline, and AMPK inhibit ACC

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