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5.) Carbohydrate metabolism part 2

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  1. Front
    Gluconeogenesis
    Back
    Synthesis of glucose from non-carbohydrate precursors
  2. Front
    Main importance of gluconeogenesis
    Back
    Essential for maintaining blood glucose, especially during fasting and starvation
  3. Front
    Normal fasting blood glucose in the lecture
    Back
    About 4.4–5.5 mM
  4. Front
    Why gluconeogenesis is important during fasting
    Back
    It helps prevent hypoglycemia
  5. Front
    Main site of gluconeogenesis
    Back
    Liver
  6. Front
    Secondary site of gluconeogenesis
    Back
    Renal cortex or kidney
  7. Front
    Approximate contribution of gluconeogenesis by organ according to the lecture
    Back
    About 80% liver and up to 20% kidney
  8. Front
    Relationship of gluconeogenesis to glycolysis
    Back
    Gluconeogenesis is not simply glycolysis run backward
  9. Front
    Why gluconeogenesis is not the reverse of glycolysis
    Back
    Glycolysis has three irreversible steps that must be bypassed by different enzymes
  10. Front
    Why gluconeogenesis is necessary
    Back
    Some tissues need a steady supply of glucose
  11. Front
    Tissues specifically listed as needing glucose
    Back
    Erythrocytes, nerve cells or brain, and renal medulla
  12. Front
    Other reason glucose is needed besides fuel
    Back
    It is also needed as a precursor for other biosyntheses
  13. Front
    Brain glucose use in the lecture
    Back
    About 120 g/day
  14. Front
    Why RBCs especially depend on glucose
    Back
    They lack mitochondria
  15. Front
    What the liver must do during fasting
    Back
    Keep making glucose
  16. Front
    Major substrates for gluconeogenesis
    Back
    Lactate, alanine, and glycerol
  17. Front
    Lactate entry into gluconeogenesis
    Back
    Lactate is converted to pyruvate by lactate dehydrogenase
  18. Front
    Special cycle involving lactate in gluconeogenesis
    Back
    Cori cycle
  19. Front
    Alanine entry into gluconeogenesis
    Back
    Alanine is converted to pyruvate by alanine aminotransferase
  20. Front
    Glycerol entry into gluconeogenesis
    Back
    Glycerol is converted to glycerol-3-phosphate and then to dihydroxyacetone phosphate
  21. Front
    High-yield substrate entry summary for gluconeogenesis
    Back
    Lactate and alanine enter as pyruvate, whereas glycerol enters as DHAP
  22. Front
    Cellular compartments involved in gluconeogenesis
    Back
    Mitochondria and cytoplasm
  23. Front
    Why compartmentation matters in gluconeogenesis
    Back
    It is especially important for the pyruvate-to-PEP bypass and transport between compartments
  24. Front
    Location of pyruvate carboxylase
    Back
    Mitochondria
  25. Front
    Location of later gluconeogenic steps
    Back
    Many later steps occur in the cytosol
  26. Front
    Three irreversible glycolytic reactions that must be bypassed in gluconeogenesis
    Back
    Hexokinase, PFK-1, and pyruvate kinase
  27. Front
    Four unique bypass reactions of gluconeogenesis
    Back
    Pyruvate carboxylase, PEP carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase
  28. Front
    Bypass enzyme for pyruvate kinase reaction
    Back
    Pyruvate carboxylase and PEP carboxykinase
  29. Front
    Bypass enzyme for PFK-1 reaction
    Back
    Fructose-1,6-bisphosphatase
  30. Front
    Bypass enzyme for hexokinase or glucokinase reaction
    Back
    Glucose-6-phosphatase
  31. Front
    Pyruvate carboxylase reaction
    Back
    Pyruvate → oxaloacetate
  32. Front
    Cofactor requirement of pyruvate carboxylase
    Back
    Biotin-dependent
  33. Front
    Energy requirement of pyruvate carboxylase
    Back
    Requires ATP
  34. Front
    Allosteric activator of pyruvate carboxylase
    Back
    Acetyl-CoA
  35. Front
    PEP carboxykinase reaction
    Back
    Oxaloacetate → phosphoenolpyruvate
  36. Front
    Energy requirement of PEP carboxykinase
    Back
    Uses GTP
  37. Front
    What is released in the PEPCK reaction
    Back
    CO2
  38. Front
    What happens after PEP is formed in gluconeogenesis
    Back
    PEP continues through the reversible glycolytic reactions in the gluconeogenic direction
  39. Front
    Why oxaloacetate transport matters in gluconeogenesis
    Back
    Oxaloacetate cannot cross the inner mitochondrial membrane
  40. Front
    How oxaloacetate is often transported indirectly
    Back
    It is converted to malate, transported, and then reconverted to oxaloacetate in the cytosol
  41. Front
    Additional purpose of the malate shuttle in gluconeogenesis
    Back
    It helps provide cytosolic NADH needed for gluconeogenesis
  42. Front
    Lecture detail about transport when lactate is the main substrate
    Back
    If lactate is the main substrate, PEP may be transferred to the cytoplasm instead
  43. Front
    Very high-yield oxaloacetate transport fact
    Back
    Oxaloacetate cannot cross the inner mitochondrial membrane, and the malate shuttle solves that problem
  44. Front
    Fructose-1,6-bisphosphatase reaction
    Back
    Fructose-1,6-bisphosphate → fructose-6-phosphate by hydrolysis
  45. Front
    How fructose-1,6-bisphosphatase bypasses PFK-1
    Back
    It removes phosphate by hydrolysis rather than transferring it to ADP
  46. Front
    Regulatory importance of fructose-1,6-bisphosphatase
    Back
    It is a major regulatory point of gluconeogenesis
  47. Front
    Glucose-6-phosphatase reaction
    Back
    Glucose-6-phosphate → glucose by hydrolysis
  48. Front
    Importance of glucose-6-phosphatase
    Back
    It is the final bypass step of gluconeogenesis
  49. Front
    Tissue distribution of glucose-6-phosphatase according to the lecture
    Back
    Present only in liver and renal cortex
  50. Front
    Why muscle cannot release free glucose into blood
    Back
    Muscle lacks glucose-6-phosphatase
  51. Front
    Which organs can release free glucose into blood
    Back
    Liver and kidney
  52. Front
    Basic logic of the gluconeogenic pathway
    Back
    Pyruvate → oxaloacetate → PEP → reversible glycolytic steps backward → fructose-1,6-bisphosphate → fructose-6-phosphate → glucose-6-phosphate → glucose
  53. Front
    Main gluconeogenic enzymes to know best
    Back
    Pyruvate carboxylase, PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase
  54. Front
    Major regulatory enzymes specifically called out for gluconeogenesis
    Back
    Pyruvate carboxylase and fructose-1,6-bisphosphatase
  55. Front
    Effect of acetyl-CoA on pyruvate carboxylase
    Back
    Activates pyruvate carboxylase
  56. Front
    Metabolic logic of acetyl-CoA activation of pyruvate carboxylase
    Back
    High acetyl-CoA signals abundant fuel oxidation and directs pyruvate toward oxaloacetate for gluconeogenesis
  57. Front
    Inhibitors of fructose-1,6-bisphosphatase
    Back
    AMP and fructose-2,6-bisphosphate
  58. Front
    Activator of fructose-1,6-bisphosphatase
    Back
    Citrate
  59. Front
    High-yield meaning of AMP inhibition of fructose-1,6-bisphosphatase
    Back
    Low-energy state should not favor glucose synthesis
  60. Front
    High-yield meaning of fructose-2,6-bisphosphate effect on fructose-1,6-bisphosphatase
    Back
    F2,6BP opposes gluconeogenesis and favors glycolysis
  61. Front
    High-yield meaning of citrate activation of fructose-1,6-bisphosphatase
    Back
    Citrate signals abundant carbon and energy and can favor gluconeogenesis
  62. Front
    Reciprocal regulation of glycolysis and gluconeogenesis
    Back
    The same signals that activate glycolysis usually inhibit gluconeogenesis, and vice versa
  63. Front
    Classic example of reciprocal regulation
    Back
    PFK-1 is activated by AMP and F2,6BP, whereas fructose-1,6-bisphosphatase is inhibited by AMP and F2,6BP
  64. Front
    PFK-2/FBP-2
    Back
    Bifunctional enzyme that regulates fructose-2,6-bisphosphate levels
  65. Front
    PFK-2 domain function
    Back
    Makes fructose-2,6-bisphosphate from fructose-6-phosphate
  66. Front
    FBP-2 domain function
    Back
    Breaks down fructose-2,6-bisphosphate
  67. Front
    Role of fructose-2,6-bisphosphate
    Back
    It is mainly a regulatory molecule rather than a glycolytic intermediate for carbon flow
  68. Front
    Effect of fructose-2,6-bisphosphate on PFK-1
    Back
    Activates PFK-1
  69. Front
    Effect of fructose-2,6-bisphosphate on fructose-1,6-bisphosphatase
    Back
    Inhibits fructose-1,6-bisphosphatase
  70. Front
    Overall effect of more fructose-2,6-bisphosphate
    Back
    More glycolysis and less gluconeogenesis
  71. Front
    Overall effect of less fructose-2,6-bisphosphate
    Back
    Less glycolysis and more gluconeogenesis
  72. Front
    Effect of high glucagon or low insulin on liver cAMP
    Back
    Increases cAMP
  73. Front
    Effect of cAMP on protein kinase A
    Back
    Activates PKA
  74. Front
    Effect of PKA on hepatic PFK-2/FBP-2
    Back
    Phosphorylates the bifunctional enzyme
  75. Front
    Effect of phosphorylation on hepatic PFK-2 domain
    Back
    Inactivates the PFK-2 domain
  76. Front
    Effect of phosphorylation on hepatic FBP-2 domain
    Back
    Activates the FBP-2 domain
  77. Front
    Effect of glucagon signaling on fructose-2,6-bisphosphate
    Back
    Decreases F2,6BP
  78. Front
    Effect of decreased fructose-2,6-bisphosphate on PFK-1
    Back
    Less activation of PFK-1
  79. Front
    Effect of decreased fructose-2,6-bisphosphate on fructose-1,6-bisphosphatase
    Back
    Less inhibition of fructose-1,6-bisphosphatase
  80. Front
    Overall effect of glucagon in liver
    Back
    Glycolysis decreases and gluconeogenesis increases
  81. Front
    Effect of insulin in liver on PFK-2/FBP-2
    Back
    Promotes dephosphorylation of the bifunctional enzyme
  82. Front
    Effect of dephosphorylation on hepatic PFK-2 activity
    Back
    Favors PFK-2 activity
  83. Front
    Effect of insulin on fructose-2,6-bisphosphate
    Back
    Increases F2,6BP
  84. Front
    Effect of increased fructose-2,6-bisphosphate on PFK-1
    Back
    Activates PFK-1
  85. Front
    Effect of increased fructose-2,6-bisphosphate on fructose-1,6-bisphosphatase
    Back
    Inhibits fructose-1,6-bisphosphatase
  86. Front
    Overall effect of insulin in liver
    Back
    Glycolysis increases and gluconeogenesis decreases
  87. Front
    Hormone comparison for high glucagon
    Back
    cAMP ↑, PKA ↑, bifunctional enzyme phosphorylated, PFK-2 off, FBP-2 on, F2,6BP ↓, glycolysis ↓, gluconeogenesis ↑
  88. Front
    Hormone comparison for high insulin
    Back
    Dephosphorylation, PFK-2 on, FBP-2 off, F2,6BP ↑, glycolysis ↑, gluconeogenesis ↓
  89. Front
    Energy cost of gluconeogenesis from 2 pyruvate to 1 glucose
    Back
    6 ATP equivalents and 2 NADH
  90. Front
    ATP cost from pyruvate carboxylase in gluconeogenesis
    Back
    2 ATP total
  91. Front
    GTP cost from PEPCK in gluconeogenesis
    Back
    2 GTP total or 2 ATP equivalents
  92. Front
    ATP cost from phosphoglycerate kinase in gluconeogenesis
    Back
    2 ATP total
  93. Front
    Total ATP equivalent cost of gluconeogenesis
    Back
    6 ATP equivalents
  94. Front
    Additional reducing power required for gluconeogenesis
    Back
    2 NADH
  95. Front
    High-yield energy fact about gluconeogenesis
    Back
    Gluconeogenesis is energy-expensive
  96. Front
    Source of energy for gluconeogenesis according to the lecture
    Back
    Oxidation of fatty acids
  97. Front
    Why fatty acid oxidation is important in fasting gluconeogenesis
    Back
    Fasting increases fatty acid oxidation, raising ATP and acetyl-CoA to support hepatic gluconeogenesis
  98. Front
    Cori cycle
    Back
    Glucose-lactate cycle linking anaerobic glycolysis in muscle or RBCs with gluconeogenesis in liver
  99. Front
    What happens in the Cori cycle in muscle and RBCs
    Back
    Glucose is converted to lactate by anaerobic glycolysis
  100. Front
    What happens to lactate in the Cori cycle
    Back
    Lactate travels to the liver
  101. Front
    What the liver does with lactate in the Cori cycle
    Back
    Liver converts lactate back to glucose by gluconeogenesis
  102. Front
    What happens to the glucose made in the Cori cycle
    Back
    It returns to muscle and RBCs
  103. Front
    Energy relationship in the Cori cycle
    Back
    Muscle or RBC glycolysis gives 2 ATP, whereas liver gluconeogenesis uses 6 ATP
  104. Front
    Source of extra energy in the Cori cycle
    Back
    Fatty acid oxidation
  105. Front
    Very high-yield distinction about gluconeogenesis
    Back
    Gluconeogenesis is not the reverse of glycolysis because glycolysis has irreversible steps
  106. Front
    Very high-yield list of the four unique gluconeogenic reactions
    Back
    Pyruvate carboxylase, PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase
  107. Front
    Very high-yield facts about pyruvate carboxylase
    Back
    Mitochondrial, biotin-dependent, and activated by acetyl-CoA
  108. Front
    Very high-yield facts about fructose-1,6-bisphosphatase
    Back
    Inhibited by AMP, inhibited by F2,6BP, and activated by citrate
  109. Front
    Very high-yield facts about glucose-6-phosphatase
    Back
    Present in liver and renal cortex and important for releasing free glucose into blood
  110. Front
    Very high-yield facts about fructose-2,6-bisphosphate
    Back
    Activates PFK-1 and inhibits fructose-1,6-bisphosphatase
  111. Front
    Very high-yield effect of glucagon on fructose-2,6-bisphosphate
    Back
    Glucagon lowers F2,6BP, causing glycolysis to decrease and gluconeogenesis to increase
  112. Front
    Very high-yield effect of insulin on fructose-2,6-bisphosphate
    Back
    Insulin raises F2,6BP, causing glycolysis to increase and gluconeogenesis to decrease
  113. Front
    Cheat-sheet main purpose of gluconeogenesis
    Back
    Make glucose during fasting from non-carbohydrate precursors mainly in liver and also kidney
  114. Front
    Cheat-sheet major substrates for gluconeogenesis
    Back
    Lactate, alanine, and glycerol
  115. Front
    Cheat-sheet four bypass enzymes of gluconeogenesis
    Back
    Pyruvate carboxylase, PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase
  116. Front
    Cheat-sheet pyruvate carboxylase facts
    Back
    Mitochondrial, biotin-dependent, and activated by acetyl-CoA
  117. Front
    Cheat-sheet fructose-1,6-bisphosphatase regulation
    Back
    Inhibited by AMP, inhibited by F2,6BP, and activated by citrate
  118. Front
    Cheat-sheet role of PFK-2/FBP-2
    Back
    Controls F2,6BP, which activates PFK-1 and inhibits fructose-1,6-bisphosphatase
  119. Front
    Cheat-sheet glucagon effect
    Back
    Phosphorylation leads to F2,6BP decrease, glycolysis decrease, and gluconeogenesis increase
  120. Front
    Cheat-sheet insulin effect
    Back
    Dephosphorylation leads to F2,6BP increase, glycolysis increase, and gluconeogenesis decrease
  121. Front
    Cheat-sheet energy cost of gluconeogenesis
    Back
    For 1 glucose from 2 pyruvate, 6 ATP equivalents and 2 NADH are required

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