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Lecture 13 Summary

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  1. Front
    Central map of glucose metabolism
    Back
    Early pathway maps show that glucose can be directed into glycolysis, glycogen synthesis, the pentose phosphate pathway, and biosynthetic routes such as fat and cholesterol synthesis.
  2. Front
    Glucose-6-phosphate
    Back
    G6P is the central branch-point metabolite that directs glucose carbon into multiple metabolic pathways.
  3. Front
    Glucose phosphorylation reaction
    Back
    Glucose + ATP → glucose-6-phosphate + ADP.
  4. Front
    Enzymes that phosphorylate glucose
    Back
    Hexokinase or glucokinase catalyzes phosphorylation of glucose to glucose-6-phosphate.
  5. Front
    Why glucose phosphorylation is important
    Back
    Phosphorylation traps glucose inside the cell and prepares it for further metabolism.
  6. Front
    Why G6P is trapped in the cell
    Back
    G6P cannot diffuse across the membrane because it is not a substrate for glucose transporters.
  7. Front
    Pathways entered after glucose phosphorylation
    Back
    G6P can enter glycolysis, the pentose phosphate pathway, glycogen synthesis, and other biosynthetic pathways.
  8. Front
    High-yield effect of glucose phosphorylation
    Back
    It traps glucose in the cell and commits it to further metabolism.
  9. Front
    Hexokinase I–III tissue distribution
    Back
    Hexokinase I–III is found in various tissues.
  10. Front
    Hexokinase Km
    Back
    Hexokinase has a low Km.
  11. Front
    Hexokinase activity at low glucose
    Back
    Hexokinase works well at low glucose concentrations.
  12. Front
    Hexokinase product inhibition
    Back
    Hexokinase is inhibited by glucose-6-phosphate.
  13. Front
    Physiologic role of hexokinase
    Back
    Hexokinase allows tissues to keep using glucose even when blood glucose is low.
  14. Front
    Glucokinase
    Back
    Glucokinase is hexokinase IV.
  15. Front
    Glucokinase tissue distribution
    Back
    Glucokinase is found in liver and pancreatic beta cells.
  16. Front
    Glucokinase Km
    Back
    Glucokinase has a high Km.
  17. Front
    Glucokinase product inhibition
    Back
    Glucokinase is not inhibited by glucose-6-phosphate.
  18. Front
    Glucokinase synthesis in liver
    Back
    Glucokinase synthesis in liver is insulin-dependent.
  19. Front
    Physiologic role of glucokinase in liver
    Back
    Glucokinase helps the liver process and store excess glucose in high-glucose states.
  20. Front
    Physiologic role of glucokinase in beta cells
    Back
    Glucokinase helps pancreatic beta cells sense elevated glucose.
  21. Front
    Hexokinase summary
    Back
    Hexokinase is present in most tissues, has a low Km, is active at low glucose, and is inhibited by G6P.
  22. Front
    Glucokinase summary
    Back
    Glucokinase is present in liver and beta cells, has a high Km, is active at higher glucose, and is not inhibited by G6P.
  23. Front
    Liver glucokinase regulation
    Back
    Glucokinase activity in liver is regulated by translocation between nucleus and cytoplasm, influenced by glucose and fructose metabolites.
  24. Front
    Effect of glucose on glucokinase localization
    Back
    Glucose promotes translocation of glucokinase from the nucleus.
  25. Front
    Effect of F6P on glucokinase localization
    Back
    F6P promotes translocation of glucokinase to the nucleus.
  26. Front
    Effect of fructose-1-phosphate on glucokinase localization
    Back
    Fructose-1-phosphate inhibits translocation of glucokinase to the nucleus.
  27. Front
    Meaning of glucose effect on glucokinase
    Back
    Glucose tends to keep glucokinase available for action.
  28. Front
    Meaning of F6P effect on glucokinase
    Back
    F6P tends to reduce active glucokinase.
  29. Front
    Meaning of fructose-1-phosphate effect on glucokinase
    Back
    Fructose-1-phosphate helps keep glucokinase active in the cytoplasm.
  30. Front
    Excess fructose intake
    Back
    Long-term excess fructose intake is associated with fatty liver, increased uric acid production, and gout.
  31. Front
    Glycolysis definition
    Back
    Glycolysis is the cytosolic pathway that converts glucose to 2 pyruvate.
  32. Front
    End product of aerobic glycolysis
    Back
    Under aerobic conditions, glycolysis ends in pyruvate.
  33. Front
    End product of anaerobic glycolysis
    Back
    Under anaerobic conditions, glycolysis ends in lactate.
  34. Front
    ATP generation in glycolysis
    Back
    Glycolysis produces ATP by substrate-level phosphorylation.
  35. Front
    Additional ATP after glycolysis
    Back
    Pyruvate can be further oxidized after conversion to acetyl-CoA, indirectly yielding more ATP.
  36. Front
    Cellular location of glycolysis
    Back
    Glycolysis occurs in the cytosol.
  37. Front
    Net yield of glycolysis per glucose
    Back
    Glycolysis yields 2 ATP, 2 NADH, and 2 pyruvate per glucose.
  38. Front
    Importance of glycolysis in tissues
    Back
    Glycolysis occurs in all human tissues and is a fundamental source of metabolic energy.
  39. Front
    Tissues highly dependent on glycolysis
    Back
    Glycolysis is the main or only energy source for erythrocytes and renal medulla.
  40. Front
    Biosynthetic role of glycolysis
    Back
    Glycolysis supplies carbon skeletons for amino acid, lipid, and nucleotide synthesis.
  41. Front
    Energy investment phase of glycolysis
    Back
    The energy investment phase consumes 2 ATP.
  42. Front
    Energy generation phase of glycolysis
    Back
    The energy generation phase produces 4 ATP total and 2 NADH per glucose.
  43. Front
    Net ATP from glycolysis
    Back
    Because 2 ATP are consumed and 4 are produced, net ATP from glycolysis is 2.
  44. Front
    Glycolysis step 1
    Back
    Glucose → glucose-6-phosphate.
  45. Front
    Enzyme for glycolysis step 1
    Back
    Hexokinase or glucokinase catalyzes step 1.
  46. Front
    Energy use in glycolysis step 1
    Back
    Step 1 uses ATP.
  47. Front
    Regulation of glycolysis step 1
    Back
    Step 1 is irreversible and regulatory.
  48. Front
    Glycolysis step 2
    Back
    G6P → fructose-6-phosphate.
  49. Front
    Enzyme for glycolysis step 2
    Back
    Phosphohexose isomerase catalyzes step 2.
  50. Front
    Glycolysis step 3
    Back
    F6P → fructose-1,6-bisphosphate.
  51. Front
    Enzyme for glycolysis step 3
    Back
    PFK-1 catalyzes step 3.
  52. Front
    Energy use in glycolysis step 3
    Back
    Step 3 uses ATP.
  53. Front
    Regulation of glycolysis step 3
    Back
    Step 3 is the most important regulatory step in glycolysis.
  54. Front
    Glycolysis step 4
    Back
    F1,6BP → DHAP + glyceraldehyde-3-phosphate.
  55. Front
    Enzyme for glycolysis step 4
    Back
    Aldolase catalyzes step 4.
  56. Front
    Glycolysis step 5
    Back
    DHAP ↔ glyceraldehyde-3-phosphate.
  57. Front
    Enzyme for glycolysis step 5
    Back
    Triose phosphate isomerase catalyzes step 5.
  58. Front
    Consequence after triose phosphate isomerase step
    Back
    All downstream glycolytic reactions occur twice per glucose.
  59. Front
    Glycolysis step 6
    Back
    Glyceraldehyde-3-phosphate → 1,3-bisphosphoglycerate.
  60. Front
    Key product of glycolysis step 6
    Back
    Step 6 produces NADH.
  61. Front
    Glycolysis step 7
    Back
    1,3-bisphosphoglycerate → 3-phosphoglycerate.
  62. Front
    Key product of glycolysis step 7
    Back
    Step 7 produces ATP by substrate-level phosphorylation.
  63. Front
    Glycolysis steps 8–9
    Back
    3-phosphoglycerate is converted to 2-phosphoglycerate and then to phosphoenolpyruvate.
  64. Front
    Glycolysis step 10
    Back
    PEP → pyruvate.
  65. Front
    Enzyme for glycolysis step 10
    Back
    Pyruvate kinase catalyzes step 10.
  66. Front
    Key product of glycolysis step 10
    Back
    Step 10 produces ATP by substrate-level phosphorylation.
  67. Front
    Regulation of glycolysis step 10
    Back
    Step 10 is irreversible and regulatory.
  68. Front
    Three irreversible glycolytic steps
    Back
    Hexokinase or glucokinase, PFK-1, and pyruvate kinase.
  69. Front
    Most important control point in glycolysis
    Back
    PFK-1 is the most important regulatory step.
  70. Front
    RBC-specific glycolytic side pathway
    Back
    In erythrocytes, 1,3-BPG can be diverted to 2,3-bisphosphoglycerate.
  71. Front
    2,3-BPG pathway specificity
    Back
    The 2,3-BPG shunt is specific to RBCs.
  72. Front
    Function of 2,3-BPG
    Back
    2,3-BPG binds hemoglobin.
  73. Front
    Why NAD+ matters in glycolysis
    Back
    Glycolysis requires NAD+ at the glyceraldehyde-3-phosphate dehydrogenase step.
  74. Front
    Effect of failure to regenerate NAD+
    Back
    If NAD+ is not regenerated, glycolysis slows or stops.
  75. Front
    Determinants of pyruvate fate
    Back
    The fate of pyruvate depends on NAD+ availability for glyceraldehyde-3-phosphate dehydrogenase and on how NADH is reoxidized.
  76. Front
    Aerobic glycolysis and NADH
    Back
    Under aerobic conditions, NADH is reoxidized through mitochondrial pathways.
  77. Front
    Aerobic fate of pyruvate
    Back
    Pyruvate can become acetyl-CoA and enter further oxidative metabolism.
  78. Front
    Anaerobic glycolysis conditions
    Back
    Anaerobic glycolysis occurs during oxygen deficiency and in erythrocytes.
  79. Front
    Anaerobic fate of pyruvate
    Back
    Pyruvate is reduced to lactate.
  80. Front
    Enzyme regenerating NAD+ in anaerobic glycolysis
    Back
    Lactate dehydrogenase reoxidizes NADH to NAD+.
  81. Front
    High-yield role of lactate formation
    Back
    Lactate formation regenerates NAD+ during anaerobic glycolysis.
  82. Front
    Pyruvate fates shown in the lecture
    Back
    Pyruvate can be converted to lactate, acetyl-CoA, oxaloacetate, or ethanol in yeast.
  83. Front
    Human pyruvate fate: lactate
    Back
    Pyruvate is converted to lactate under anaerobic conditions and in RBCs to regenerate NAD+.
  84. Front
    Human pyruvate fate: acetyl-CoA
    Back
    Pyruvate is converted to acetyl-CoA for aerobic oxidative metabolism.
  85. Front
    Human pyruvate fate: oxaloacetate
    Back
    Pyruvate can be converted to oxaloacetate.
  86. Front
    Why cytosolic NADH needs shuttles
    Back
    Cytosolic NADH cannot directly donate electrons to the respiratory chain because there are no NAD(H) translocases in the inner mitochondrial membrane.
  87. Front
    Main glycerol-phosphate shuttle tissues
    Back
    The glycerol-phosphate shuttle is the main shuttle in most tissues.
  88. Front
    Main malate-aspartate shuttle tissues
    Back
    The malate-aspartate shuttle is important in heart, liver, and kidneys.
  89. Front
    Why glycolytic ATP yield varies
    Back
    The ATP yield of cytosolic NADH depends on which shuttle system is used.
  90. Front
    Pyruvate dehydrogenase reaction
    Back
    Pyruvate undergoes oxidative decarboxylation to form acetyl-CoA.
  91. Front
    Location of pyruvate dehydrogenase complex
    Back
    The pyruvate dehydrogenase complex is located in the mitochondrial matrix.
  92. Front
    Importance of pyruvate dehydrogenase
    Back
    It is the major source of acetyl-CoA and the bridge from glycolysis to acetyl-CoA production and further oxidation.
  93. Front
    Irreversibility of pyruvate dehydrogenase
    Back
    PDH is irreversible in animal cells.
  94. Front
    Consequence of PDH irreversibility
    Back
    Carbon reaching acetyl-CoA through PDH cannot directly return to glucose by this route.
  95. Front
    PDH cofactors
    Back
    The five cofactors are TPP, lipoate, CoA, FAD, and NAD+.
  96. Front
    PDH vitamin relationship
    Back
    The PDH complex uses 5 coenzymes derived from 4 vitamins.
  97. Front
    Thiamine deficiency and pyruvate utilization
    Back
    In thiamine deficiency, normal utilization of pyruvate is impossible.
  98. Front
    Tissue especially affected by thiamine deficiency
    Back
    Nervous tissue is especially affected.
  99. Front
    PDH mechanism outline
    Back
    The PDH mechanism includes decarboxylation, oxidation, transesterification, regeneration of lipoate, and regeneration of FAD.
  100. Front
    PDH as a multienzyme complex
    Back
    PDH is a multienzyme complex that channels intermediates efficiently.
  101. Front
    Advantage of multienzyme complex organization
    Back
    Intermediates do not dissociate from the complex, which increases reaction rate.
  102. Front
    Why PDH is tightly regulated
    Back
    Conversion of pyruvate to acetyl-CoA is absolutely irreversible in animal cells.
  103. Front
    Allosteric inhibitors of PDH
    Back
    PDH is inhibited by NADH and acetyl-CoA.
  104. Front
    Covalent regulation of PDH
    Back
    Phosphorylation by a specific protein kinase inhibits PDH.
  105. Front
    Activators of PDH kinase
    Back
    PDH kinase is activated by ATP, NADH, and acetyl-CoA.
  106. Front
    Effect of phosphoprotein phosphatase on PDH
    Back
    Phosphoprotein phosphatase reverses PDH inhibition.
  107. Front
    Activator of PDH phosphatase
    Back
    Ca2+ activates the phosphoprotein phosphatase that reactivates PDH.
  108. Front
    PDH phosphorylation state and activity
    Back
    Phosphorylated PDH is OFF; dephosphorylated PDH is ON.
  109. Front
    Aerobic glycolysis products
    Back
    Aerobic glycolysis of 1 glucose yields 2 ATP, 2 NADH, and 2 pyruvate.
  110. Front
    Complete oxidation of glucose ATP yield
    Back
    Complete oxidation of 1 glucose yields 30–32 ATP depending on the shuttle system.
  111. Front
    Anaerobic glycolysis products
    Back
    Anaerobic glycolysis of 1 glucose yields 2 ATP and 2 lactate.
  112. Front
    Relative ATP yield of anaerobic glycolysis
    Back
    Anaerobic glycolysis provides about 15 times less ATP per glucose than complete aerobic oxidation.
  113. Front
    Tissues where anaerobic glycolysis is especially important
    Back
    Anaerobic glycolysis is especially important in erythrocytes, kidney medulla, eye lens, and skeletal muscle.
  114. Front
    HIF-1 effect under hypoxia
    Back
    Under hypoxia, HIF-1 activates transcription of glycolytic enzyme genes.
  115. Front
    Blood lactate increases with
    Back
    Blood lactate rises with effort, large quantities of alcohol, hypoxia, carbon monoxide poisoning, respiratory chain defects, and Krebs cycle enzyme defects.
  116. Front
    Lactic acidosis definition
    Back
    Lactic acidosis is defined as lactate concentration greater than 5 mM.
  117. Front
    Key allosterically regulated glycolytic enzymes
    Back
    Hexokinase, PFK-1, and pyruvate kinase.
  118. Front
    Meaning of allosteric regulation
    Back
    Fast, easily reversible control by small molecules binding at an allosteric site, causing conformational change and altered activity.
  119. Front
    Common pattern in allosteric inhibition
    Back
    The inhibitor is often a product of the pathway.
  120. Front
    PFK-1 and energy state
    Back
    PFK-1 responds strongly to cellular energy state, especially ATP versus AMP.
  121. Front
    Effect of high ATP on PFK-1
    Back
    High ATP signals abundant energy and slows glycolysis.
  122. Front
    Effect of high AMP on PFK-1
    Back
    High AMP signals low energy and accelerates glycolysis.
  123. Front
    Adenylate kinase reaction
    Back
    ADP + ADP → ATP + AMP.
  124. Front
    Importance of adenylate kinase in working muscle
    Back
    In working muscle, rising ADP generates AMP, which becomes a strong low-energy signal for glycolysis.
  125. Front
    Fructose-2,6-bisphosphate
    Back
    F-2,6-BP is not an intermediate of glycolysis.
  126. Front
    Role of F-2,6-BP in liver
    Back
    In liver, F-2,6-BP is an allosteric activator of PFK-1.
  127. Front
    Metabolic effect of F-2,6-BP
    Back
    F-2,6-BP enhances glycolysis.
  128. Front
    Relationship of F-2,6-BP to ATP inhibition
    Back
    F-2,6-BP can oppose the inhibitory effects of ATP on PFK-1.
  129. Front
    Enzyme producing F-2,6-BP
    Back
    PFK-2 produces fructose-2,6-bisphosphate.
  130. Front
    Enzyme degrading F-2,6-BP
    Back
    FBPase-2 converts fructose-2,6-bisphosphate to F6P.
  131. Front
    Effect of F-2,6-BP on gluconeogenesis
    Back
    F-2,6-BP inhibits FBPase-1 and suppresses gluconeogenesis.
  132. Front
    Main regulator of F-2,6-BP level
    Back
    The insulin/glucagon ratio controls the level of F-2,6-BP.
  133. Front
    Overall role of F-2,6-BP in liver
    Back
    F-2,6-BP shifts liver metabolism toward glycolysis ON and gluconeogenesis OFF.
  134. Front
    PFK-2/FBPase-2
    Back
    The PFK-2/FBPase-2 system is a bifunctional regulatory enzyme that controls F-2,6-BP concentration.
  135. Front
    High-yield glycolysis activation chain
    Back
    PFK-2 ↑ → F-2,6-BP ↑ → PFK-1 activated → glycolysis ↑.
  136. Front
    High-yield gluconeogenesis inhibition chain
    Back
    F-2,6-BP ↑ → FBPase-1 inhibited → gluconeogenesis ↓.
  137. Front
    Hormonal control by covalent modification
    Back
    Hormonal signals regulate metabolism through protein kinase and protein phosphatase activity, which alter enzyme phosphorylation state.
  138. Front
    Effect of insulin/glucagon ratio on enzymes
    Back
    Changes in the insulin/glucagon ratio change the level of phosphorylation and therefore the activity of key metabolic enzymes.
  139. Front
    General rule for catabolic enzymes
    Back
    Catabolic enzymes are generally activated by phosphorylation and inhibited by dephosphorylation.

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