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16.5 - cholesterol derivatives, pages 45-59

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  1. Front
    Main functions of cholesterol
    Back
    Stabilizing component of biological membranes + substrate for synthesis of bile acids, steroid hormones, and vitamin D/hormone
  2. Front
    Cholesterol content of plasma membrane lipids
    Back
    Can make up up to about 30% of plasma membrane lipids
  3. Front
    Steroid nucleus of cholesterol
    Back
    Rigid four-ring steroid nucleus called perhydrocyclopentenophenanthrene
  4. Front
    Two major roles of cholesterol
    Back
    Structural role in membranes and precursor role for major biologically active compounds
  5. Front
    Major cholesterol derivatives emphasized in this section
    Back
    Bile acids/bile salts + steroid hormones
  6. Front
    Major cholesterol precursors emphasized in this section
    Back
    vitamin D
  7. Front
    Biochemical view of cholesterol
    Back
    Normal and necessary precursor molecule, not only a bad blood lipid
  8. Front
    Site of bile acid synthesis
    Back
    Liver
  9. Front
    Substrate for bile acid synthesis
    Back
    Cholesterol
  10. Front
    Key regulatory step in bile acid synthesis
    Back
    7α-hydroxylation of cholesterol
  11. Front
    Rate-limiting enzyme of bile acid synthesis
    Back
    Cholesterol 7α-hydroxylase
  12. Front
    Type of enzyme cholesterol 7α-hydroxylase
    Back
    Cytochrome P450 enzyme
  13. Front
    Reducing power required for bile acid synthesis entry step
    Back
    NADPH
  14. Front
    Regulation of bile acid synthesis
    Back
    Feedback inhibition by bile acids
  15. Front
    What does more bile acids present cause
    Back
    DECREASE in new bile acid synthesis
  16. Front
    Committed entry point into bile acid synthesis
    Back
    Cholesterol 7α-hydroxylase step
  17. Front
    Important enzyme to remember in bile acid synthesis
    Back
    7α-hydroxylase
  18. Front
    Later ring modification in bile acid synthesis
    Back
    Reduction of the double bond in the B ring
  19. Front
    Hydroxylation patterns highlighted in bile acid synthesis
    Back
    3,7,12 and 3,7
  20. Front
    Primary bile acid with 3,7,12 hydroxylation pattern
    Back
    Cholic acid
  21. Front
    Primary bile acid with 3,7 hydroxylation pattern
    Back
    Chenodeoxycholic acid
  22. Front
    Side-chain change during bile acid synthesis
    Back
    Shortening of the hydrocarbon side chain
  23. Front
    Activation step before bile salt formation
    Back
    Formation of CoA derivatives
  24. Front
    Amino acids used for bile acid conjugation
    Back
    Glycine and taurine
  25. Front
    Effect of conjugating bile acids with glycine or taurine
    Back
    Lowers the pKa of the carboxyl group → makes them better detergents in the intestine
  26. Front
    Intestinal bacterial modifications of bile salts
    Back
    Deconjugation and 7-dehydroxylation
  27. Front
    Products formed after intestinal modification of bile salts
    Back
    Secondary bile acids
  28. Front
    Secondary bile acids named on the slide
    Back
    Lithocholic acid + deoxycholic acid
  29. Front
    Fate of secondary bile acids after intestinal formation
    Back
    Return to the liver for reconjugation
  30. Front
    Overall flow of bile acid pathway
    Back
    Cholesterol → primary bile acids → conjugated bile salts → intestinal modification by bacteria → secondary bile acids formed → return to liver
  31. Front
    Why cholesterol disposal is special
    Back
    The ring structure of cholesterol cannot be metabolized to CO2 and H2O
  32. Front
    Main ways the body eliminates cholesterol
    Back
    Conversion to bile acids and bile salts + secretion of cholesterol into bile for intestinal elimination via faeces
  33. Front
    How the body gets rid of cholesterol
    Back
    Not by full oxidation, mainly by bile acid or bile salt formation and biliary secretion
  34. Front
    Repeated transition concept for cholesterol
    Back
    Same cholesterol molecule can enter different derivative pathways depending on tissue and enzyme expression
  35. Front
    Sites of steroid hormone synthesis
    Back
    Adrenal cortex, ovaries, testes, and ovarian corpus luteum
  36. Front
    First key step of steroid hormone synthesis
    Back
    Cholesterol is converted to pregnenolone
  37. Front
    Location of first key step in steroid hormone synthesis
    Back
    Mitochondria
  38. Front
    Structural change in cholesterol during pregnenolone formation
    Back
    Shortening or cleavage of the side chain on C-17 of the D ring
  39. Front
    Rate-limiting step in all steroid hormone synthesis
    Back
    Conversion of cholesterol to pregnenolone
  40. Front
    P450 side-chain cleavage enzyme name
    Back
    P450scc
  41. Front
    Alternative name for P450scc
    Back
    Desmolase
  42. Front
    Gene name for P450 side-chain cleavage enzyme
    Back
    CYP11A1
  43. Front
    Universal first committed step in steroidogenesis
    Back
    Cholesterol to pregnenolone via CYP11A1 in mitochondria
  44. Front
    Carbon number of glucocorticoids
    Back
    21 carbons
  45. Front
    Carbon number of mineralocorticoids
    Back
    21 carbons
  46. Front
    Carbon number of androgens
    Back
    19 carbons
  47. Front
    Carbon number of estrogens
    Back
    18 carbons
  48. Front
    Mitochondrial P450 system components for steroidogenesis
    Back
    Cytochrome P450, adrenodoxin, and adrenodoxin reductase
  49. Front
    Electron donor for mitochondrial steroidogenic P450 system
    Back
    NADPH
  50. Front
    Electron flow in mitochondrial steroidogenic P450 system
    Back
    NADPH → adrenodoxin reductase → adrenodoxin → cytochrome P450 (CYP11A1)
  51. Front
    Role of adrenodoxin reductase
    Back
    Transfers electrons from NADPH to adrenodoxin
  52. Front
    Role of adrenodoxin
    Back
    Transfers electrons to cytochrome P450
  53. Front
    Key distinction of steroidogenic P450 system
    Back
    Mitochondrial system rather than the broad ER detoxification-type P450 system
  54. Front
    Chemistry of steroid biosynthesis after pregnenolone formation
    Back
    Hydroxylation, oxygenation, and oxidative modification reactions
  55. Front
    Enzymes catalyzing hydroxylation and oxygenation in steroid biosynthesis
    Back
    Mixed-function oxygenases
  56. Front
    Requirements for mixed-function oxygenases in steroid biosynthesis
    Back
    NADPH, O2, and mitochondrial cytochrome P450
  57. Front
    General biochemical principle of P450 oxygenation
    Back
    One oxygen atom is inserted into the substrate and the other is reduced to water via NADPH as reducing equivalents
  58. Front
    Clinical significance of steroid hormone synthesis enzymes
    Back
    Defects in steroidogenic enzymes cause disease
  59. Front
    Effect of defects in steroid hormone biosynthesis enzymes
    Back
    Alter production of glucocorticoids, mineralocorticoids, and sex steroids
  60. Front
    Transport protein for vitamin D and 25-OH D
    Back
    Vitamin D-binding protein (DBP)
  61. Front
    Skin precursor of vitamin D derived from cholesterol
    Back
    7-dehydrocholesterol
  62. Front
    UVB wavelength range highlighted for vitamin D formation
    Back
    295 to 300 nm
  63. Front
    Effect of UVB light on 7-dehydrocholesterol in skin
    Back
    Converts it into vitamin D precursor forms or pre-vitamin D
  64. Front
    Key ACTIVATION PATHWAY enzyme in vitamin D pathway
    Back
    1α-hydroxylase
  65. Front
    Gene name for vitamin D 1α-hydroxylase
    Back
    CYP27B1
  66. Front
    Active hormone produced by 1α-hydroxylase
    Back
    1,25-(OH)2D
  67. Front
    Key INACTIVE PATHWAY enzyme in vitamin D pathway
    Back
    24-hydroxylase
  68. Front
    Gene name for vitamin D 24-hydroxylase
    Back
    CYP24A1
  69. Front
    Two general types of cytochrome P450 systems
    Back
    Highly specific single-substrate systems and broad-specificity systems
  70. Front
    Example of highly specific P450 systems
    Back
    Steroid hormone and eicosanoid synthesis
  71. Front
    Example of broad-specificity P450 systems
    Back
    Hydroxylation of xenobiotics in phase I detoxification
  72. Front
    Cellular locations of cytochrome P450 enzymes
    Back
    ER and mitochondria
  73. Front
    General reaction catalyzed by cytochrome P450
    Back
    Hydroxylation of RH → R-OH
  74. Front
    How cytochrome P450 enzymes uses molecular oxygen
    Back
    One oxygen atom incorporated from O₂ into the substrate, and the other oxygen atom becomes H₂O
  75. Front
    Electron donors used by cytochrome P450
    Back
    NADPH or NADH
  76. Front
    How electrons reach cytochrome P450
    Back
    Usually through electron transfer proteins
  77. Front
    P450 enzymes as a class
    Back
    Monooxygenases
  78. Front
    Major functional styles of P450 enzymes
    Back
    Narrow or specific biosynthetic enzymes and broad detoxification enzymes
  79. Front
    P450 enzymes narrow/specific functions
    Back
    biosynthesis
  80. Front
    P450 enzymes broad/general functions
    Back
    detox
  81. Front
    Common role of mitochondrial P450s
    Back
    Steroid-related biosynthesis
  82. Front
    Common role of ER P450s
    Back
    Drug and xenobiotic metabolism, with some roles in lipid pathways
  83. Front
    Key point about steroid hormone synthesis
    Back
    Steroid hormone synthesis uses mitochondrial P450 machinery
  84. Front
    Location emphasized for steroidogenic P450 enzymes
    Back
    Mitochondrial system
  85. Front
    CYP1, CYP2, CYP3 family functions
    Back
    Drug and steroid metabolism
  86. Front
    CYP4 family function
    Back
    Arachidonic acid and fatty acid metabolism
  87. Front
    CYP5 family function
    Back
    Thromboxane A2 synthesis
  88. Front
    CYP7 family function
    Back
    Bile acid synthesis
  89. Front
    CYP8 family function
    Back
    Various functions
  90. Front
    CYP11 family function
    Back
    Steroid biosynthesis
  91. Front
    CYP17 family function
    Back
    Steroid biosynthesis
  92. Front
    CYP19 family function
    Back
    Estrogen aromatase
  93. Front
    CYP51 family function
    Back
    Cholesterol biosynthesis
  94. Front
    What the CYP family table shows
    Back
    Different CYP families are specialized for different pathways
  95. Front
    Lecture-relevant CYP families from the table
    Back
    CYP7 for bile acids, CYP11/CYP17/CYP19 for steroid hormones, CYP51 for cholesterol biosynthesis, CYP5 for thromboxane synthesis, and CYP4 for fatty acid or arachidonic acid metabolism
  96. Front
    Major significance of CYP1, CYP2, and CYP3 families
    Back
    Large role in drug metabolism
  97. Front
    Processes involving the cytochrome P450 superfamily
    Back
    Cholesterol synthesis, bile acid synthesis, steroid hormone synthesis, eicosanoid metabolism, and drug or xenobiotic metabolism
  98. Front
    Key step in bile acid synthesis
    Back
    Conversion of cholesterol to 7-hydroxycholesterol
  99. Front
    Enzyme for cholesterol to 7-hydroxycholesterol conversion
    Back
    7-hydroxylase of the P450 family
  100. Front
    Effect of excess bile salts or bile acids on bile acid synthesis
    Back
    Inhibits the pathway
  101. Front
    Later steps in bile acid synthesis summary
    Back
    Hydroxylation, reduction, and shortening of the side chain
  102. Front
    Primary bile acids or salts after biosynthetic modifications
    Back
    Products formed from cholesterol before intestinal modification and conjugated with glycine or taurine
  103. Front
    Conjugation partners for primary bile acids
    Back
    Glycine or taurine
  104. Front
    Intestinal reactions undergone by secondary bile acids according to the slide
    Back
    Deconjugation and dehydroxylation
  105. Front
    Percent of bile acids returning to the liver
    Back
    About 95%
  106. Front
    Name of the cycle in which bile acids return to the liver
    Back
    Enterohepatic cycling
  107. Front
    Key stage in steroid hormone synthesis summarized on page 59
    Back
    Conversion of cholesterol to pregnenolone
  108. Front
    Carbon count of pregnenolone
    Back
    21 carbons
  109. Front
    Immediate product use of pregnenolone
    Back
    Used to form progesterone
  110. Front
    Branch point logic of progesterone in steroidogenesis
    Back
    Depending on enzyme expression, progesterone becomes precursor for mineralocorticoids, glucocorticoids, or sex hormones
  111. Front
    What determines which steroid hormone is produced in an endocrine cell
    Back
    Which enzymes the tissue expresses
  112. Front
    Precursor for vitamin D synthesis from cholesterol
    Back
    7-dehydrocholesterol
  113. Front
    Skin event in vitamin D synthesis
    Back
    UV radiation converts 7-dehydrocholesterol to pre-vitamin D
  114. Front
    First hydroxylation site after skin step in vitamin D synthesis
    Back
    Position 25 in the liver
  115. Front
    Second hydroxylation site after skin step in vitamin D synthesis
    Back
    Position 1 in the kidney
  116. Front
    Active hormone form of vitamin D
    Back
    1,25-dihydroxycholecalciferol
  117. Front
    Alternative name for 1,25-dihydroxycholecalciferol
    Back
    Calcitriol
  118. Front
    Major function of calcitriol
    Back
    Calcium-phosphate homeostasis
  119. Front
    Requirements for Vitamin D activation
    Back
    Vitamin D becomes hormonally active ONLY after 2 hydroxylations after UV radiation in skin step
  120. Front
    Main catalytic activity of P450 family enzymes
    Back
    Hydroxylation or monooxygenase reactions
  121. Front
    Substrates and cofactors used by P450 family
    Back
    Molecular oxygen and NADPH or NADH
  122. Front
    Products of a typical P450 reaction
    Back
    Hydroxylated substrate plus water
  123. Front
    Location and specificity of ER P450 system
    Back
    Endoplasmic reticulum with broad substrate specificity, exemplified by detoxification
  124. Front
    Location and specificity of mitochondrial P450 system
    Back
    Mitochondria with narrow substrate specificity, exemplified by steroid hormone synthesis
  125. Front
    Integrated take-home message of cholesterol derivatives
    Back
    Cholesterol is converted into bile acids, steroid hormones, and vitamin D through oxidative modifications largely catalyzed by cytochrome P450 systems

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