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16.3 - Synthesis of Cholesterol

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  1. Front
    Core idea of cholesterol
    Back
    Cholesterol is a membrane lipid and a precursor for many molecules.
  2. Front
    Big picture of cholesterol metabolism
    Back
    The liver makes cholesterol, it is transported in lipoproteins, and about 150 mg per day is synthesized.
  3. Front
    Core concept of cholesterol distribution
    Back
    Cholesterol is synthesized mainly in the liver and distributed to tissues.
  4. Front
    Function of cholesterol in membranes
    Back
    Cholesterol contributes to membrane structure and can make up to 30 percent of membrane lipids.
  5. Front
    Molecules derived from cholesterol
    Back
    Bile acids, steroid hormones, and vitamin D.
  6. Front
    Structure of cholesterol
    Back
    Four fused rings forming a rigid structure.
  7. Front
    Core concept of cholesterol function
    Back
    Cholesterol is both a structural molecule and a precursor molecule.
  8. Front
    Location of cholesterol synthesis
    Back
    Cytosol and smooth ER.
  9. Front
    Major organs that synthesize cholesterol
    Back
    Liver, intestine, adrenal cortex, and gonads.
  10. Front
    Most important organ for cholesterol synthesis
    Back
    Liver.
  11. Front
    Starting molecule for cholesterol synthesis
    Back
    Acetyl-CoA.
  12. Front
    Energy requirements for cholesterol synthesis
    Back
    18 acetyl-CoA, 36 ATP, and 16 NADPH.
  13. Front
    Rate-limiting enzyme of cholesterol synthesis
    Back
    HMG-CoA reductase.
  14. Front
    Core concept of cholesterol synthesis
    Back
    Cholesterol synthesis is energetically expensive and tightly regulated.
  15. Front
    Problem of acetyl-CoA location in cholesterol synthesis
    Back
    Acetyl-CoA is made in mitochondria but cholesterol synthesis occurs in the cytosol.
  16. Front
    Solution for moving acetyl-CoA to the cytosol
    Back
    Citrate shuttle.
  17. Front
    First step of citrate shuttle
    Back
    Acetyl-CoA plus oxaloacetate forms citrate in mitochondria.
  18. Front
    Second step of citrate shuttle
    Back
    Citrate moves from mitochondria to cytosol.
  19. Front
    Third step of citrate shuttle
    Back
    Citrate is cleaved in the cytosol to acetyl-CoA and oxaloacetate.
  20. Front
    Core concept of acetyl-CoA transport
    Back
    Citrate transports acetyl-CoA to the cytosol.
  21. Front
    Stage 1 of cholesterol synthesis
    Back
    Acetoacetyl-CoA (2 Acetyl-CoAs + 1 Acetyl-CoA) is converted to mevalonate (2C) - condensation
  22. Front
    What enzyme controls step 1?
    Back
    HMG-CoA reductase (HMGR)
  23. Front
    What cofactors are required for step 1?
    Back
    2 NADPH
  24. Front
    What is the intermediate for step 1?
    Back
    HMG-CoA
  25. Front
    Stage 2 of cholesterol synthesis
    Back
    Mevalonate is converted to activated isoprenoids (5C) - phosphorylation + decarboxylation
  26. Front
    What enzymes control step 2?
    Back
    Mevalonate kinase, Phosphomevalonate kinase, Mevaolate-5-diphosphate decarboxylase
  27. Front
    What cofactors are required for step 2?
    Back
    3 ATP for phosphorylations
  28. Front
    Stage 3 of cholesterol synthesis
    Back
    Isoprenes are converted to squalene (30C) - condensation
  29. Front
    What enzymes control step 3?
    Back
    Geranyl transferase & Squalene synthase
  30. Front
    What cofactors are required for step 3?
    Back
    NADPH
  31. Front
    Stage 4 of cholesterol synthesis
    Back
    Squalene is cyclized to cholesterol with four rings (27C).
  32. Front
    What enzymes control step 4?
    Back
    Squalene monooxygenase & Lanosterol cyclase
  33. Front
    What cofactors are required for step 4?
    Back
    O2 + NADPH for oxygenation & reduction
  34. Front
    What is the intermediate for step 4?
    Back
    Lanosterol - the 1st steroid formed
  35. Front
    Core concept of cholesterol synthesis stages
    Back
    Cholesterol is built stepwise from 2-carbon units to 5-carbon units to a 30-carbon linear intermediate to a ringed structure.
  36. Front
    Key reaction of stage 1
    Back
    HMG-CoA is converted to mevalonate.
  37. Front
    Enzyme for HMG-CoA to mevalonate
    Back
    HMG-CoA reductase.
  38. Front
    Importance of HMG-CoA reductase
    Back
    It controls the whole cholesterol synthesis pathway.
  39. Front
    Core concept of stage 1
    Back
    This is the most important control point in cholesterol synthesis.
  40. Front
    Key idea of stage 2
    Back
    Mevalonate is converted to 5-carbon isoprene units.
  41. Front
    Energy use in stage 2
    Back
    3 ATP are used per isoprene unit formed.
  42. Front
    Core concept of stage 2
    Back
    Small 5-carbon building blocks are formed.
  43. Front
    Process of stage 3
    Back
    6 isoprene units combine to form squalene with 30 carbons.
  44. Front
    Carbon number of squalene
    Back
    30 carbons.
  45. Front
    Core concept of stage 3
    Back
    A long linear molecule is built from isoprene units.
  46. Front
    Process of stage 4
    Back
    Squalene undergoes cyclization to form cholesterol.
  47. Front
    Irreversibility of cholesterol
    Back
    Cholesterol cannot be converted back to acetyl-CoA.
  48. Front
    Core concept of stage 4
    Back
    Cholesterol synthesis is irreversible.
  49. Front
    Three levels of cholesterol synthesis regulation
    Back
    Covalent modification, gene expression, and protein degradation.
  50. Front
    What are the forms of covalent modification in cholesterol synthesis regulation?
    Back
    Phosphorylation and Dephosphorylation
  51. Front
    Active form of HMG-CoA reductase
    Back
    Dephosphorylated form.
  52. Front
    Hormone that activates HMG-CoA reductase
    Back
    Insulin.
  53. Front
    Inactive form of HMG-CoA reductase
    Back
    Phosphorylated form.
  54. Front
    Enzymes or signals that inactivate HMG-CoA reductase
    Back
    AMPK and glucagon.
  55. Front
    Effect of low cholesterol on enzyme synthesis
    Back
    Low cholesterol = INCREASE HMG-CoA reductase synthesis.
  56. Front
    Effect of high cholesterol on enzyme synthesis
    Back
    High cholesterol = DECREASE HMG-CoA reductase synthesis.
  57. Front
    Transcriptional regulator of cholesterol synthesis
    Back
    SREBP-SCAP gene.
  58. Front
    Effect of high cholesterol on HMG-CoA reductase protein degradation
    Back
    High cholesterol promotes destruction of the enzyme.
  59. Front
    Core concept of cholesterol regulation
    Back
    High cholesterol shuts off cholesterol synthesis.
  60. Front
    Step 1 of final cholesterol summary
    Back
    Glucose is converted to acetyl-CoA in mitochondria.
  61. Front
    Step 2 of final cholesterol summary
    Back
    Citrate transports acetyl-CoA to the cytosol.
  62. Front
    Step 3 of final cholesterol summary
    Back
    Acetyl-CoA is converted to HMG-CoA and then to mevalonate.
  63. Front
    Step 4 of final cholesterol summary
    Back
    Mevalonate is converted to isoprenes.
  64. Front
    Step 5 of final cholesterol summary
    Back
    Isoprenes are converted to squalene.
  65. Front
    Step 6 of final cholesterol summary
    Back
    Squalene is converted to cholesterol.
  66. Front
    Regulation summary of HMG-CoA reductase
    Back
    HMG-CoA reductase is the key enzyme, activated by insulin and inhibited by increased cholesterol and AMPK.
  67. Front
    Final core idea of section 16.3
    Back
    Cholesterol is synthesized from acetyl-CoA through mevalonate, with HMG-CoA reductase as the key regulatory step.
  68. Front
    Cheat sheet: location of cholesterol synthesis
    Back
    Cytosol and ER.
  69. Front
    Cheat sheet: starting molecule of cholesterol synthesis
    Back
    Acetyl-CoA.
  70. Front
    Cheat sheet: key intermediate of cholesterol synthesis
    Back
    Mevalonate.
  71. Front
    Cheat sheet: key enzyme of cholesterol synthesis
    Back
    HMG-CoA reductase.
  72. Front
    Cheat sheet: stage 1 of cholesterol synthesis
    Back
    Acetyl-CoA to mevalonate.
  73. Front
    Cheat sheet: stage 2 of cholesterol synthesis
    Back
    Mevalonate to isoprenes.
  74. Front
    Cheat sheet: stage 3 of cholesterol synthesis
    Back
    Isoprenes to squalene.
  75. Front
    Cheat sheet: stage 4 of cholesterol synthesis
    Back
    Squalene to cholesterol.
  76. Front
    Cheat sheet: insulin effect on cholesterol synthesis
    Back
    Insulin turns synthesis on.
  77. Front
    Cheat sheet: glucagon and AMPK effect on cholesterol synthesis
    Back
    Glucagon and AMPK turn synthesis off.
  78. Front
    Cheat sheet: cholesterol effect on its own synthesis
    Back
    Cholesterol causes feedback inhibition.
  79. Front
    Rate-limiting enzyme in cholesterol synthesis
    Back
    HMG-CoA reductase.
  80. Front
    Molecule that transports acetyl-CoA to cytosol
    Back
    Citrate.
  81. Front
    30-carbon intermediate in cholesterol synthesis
    Back
    Squalene.
  82. Front
    Effect of low ATP on cholesterol synthesis
    Back
    Low ATP activates AMPK, which inhibits HMG-CoA reductase and decreases cholesterol synthesis.
  83. Front
    Why cholesterol synthesis is irreversible
    Back
    Because cholesterol cannot be converted back to acetyl-CoA.

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