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9.) Metabolism of fructose and galactose. Inherited defects (fructosuria, fructose intolerance, galactosemia.

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  1. Front
    Fructose and galactose
    Back
    Dietary monosaccharides that can be converted into glycolysis intermediates
  2. Front
    How fructose and galactose enter mainstream carbohydrate metabolism
    Back
    Each uses its own pathway to be converted into intermediates of central carbohydrate metabolism
  3. Front
    Main site of fructose metabolism
    Back
    Liver
  4. Front
    Main site of high galactose metabolism
    Back
    Liver
  5. Front
    Why inherited disorders of fructose and galactose metabolism occur
    Back
    They result from deficiency of key enzymes in the entry pathways for fructose and galactose metabolism
  6. Front
    Major dietary source of fructose
    Back
    Sucrose
  7. Front
    Products of sucrose cleavage
    Back
    Glucose and fructose
  8. Front
    Other dietary sources of fructose
    Back
    Fruits, honey, and high-fructose corn syrup
  9. Front
    Fructose transport into cells
    Back
    Insulin independent
  10. Front
    Extent of fructose metabolism by hexokinase
    Back
    Only to a small extent because hexokinase has low affinity for fructose
  11. Front
    Main enzyme for efficient fructose metabolism
    Back
    Fructokinase
  12. Front
    Major tissues containing both fructokinase and aldolase B
    Back
    Liver, kidney, and small intestine
  13. Front
    First step of fructose metabolism
    Back
    Fructose is phosphorylated to fructose-1-phosphate by fructokinase
  14. Front
    Energy requirement for fructokinase reaction
    Back
    Uses ATP
  15. Front
    Main first product of liver fructose metabolism
    Back
    Fructose-1-phosphate
  16. Front
    Second step of fructose metabolism
    Back
    Fructose-1-phosphate is cleaved by aldolase B
  17. Front
    Products of aldolase B reaction in fructose metabolism
    Back
    DHAP and glyceraldehyde
  18. Front
    How DHAP from fructose metabolism enters central metabolism
    Back
    DHAP can enter glycolysis or gluconeogenesis
  19. Front
    Fate of glyceraldehyde from fructose metabolism
    Back
    It can be further metabolized into glycolytic intermediates
  20. Front
    High-yield entry point of fructose into metabolism
    Back
    Fructose enters metabolism mainly at the triose phosphate level
  21. Front
    Why fructose is metabolized rapidly in liver
    Back
    Metabolism of fructose-1-phosphate to trioses bypasses PFK-1, the major regulatory step of glycolysis
  22. Front
    High-yield regulatory point bypassed by fructose
    Back
    PFK-1
  23. Front
    Minor alternative pathway for fructose metabolism
    Back
    Hexokinase can phosphorylate fructose in some tissues
  24. Front
    Why the hexokinase pathway for fructose is minor
    Back
    Hexokinase has low affinity for fructose and is usually busy phosphorylating glucose
  25. Front
    Major versus minor pathway of fructose metabolism
    Back
    Major pathway uses fructokinase, while minor pathway uses hexokinase
  26. Front
    Essential fructosuria
    Back
    Caused by deficiency of fructokinase
  27. Front
    Biochemical defect in essential fructosuria
    Back
    Fructose cannot be efficiently converted to fructose-1-phosphate
  28. Front
    Effect of fructokinase deficiency on the major hepatic fructose pathway
    Back
    The major hepatic fructose pathway is blocked
  29. Front
    Alternative handling of fructose in essential fructosuria
    Back
    Some fructose is slowly metabolized by hexokinase in extrahepatic tissues
  30. Front
    Main laboratory finding in essential fructosuria
    Back
    Fructose in the urine
  31. Front
    Why essential fructosuria is benign
    Back
    No toxic fructose-1-phosphate accumulates
  32. Front
    Clinical picture of essential fructosuria
    Back
    Usually asymptomatic and benign with fructosuria
  33. Front
    High-yield summary of essential fructosuria
    Back
    Fructokinase deficiency causes essential fructosuria, which is benign
  34. Front
    Hereditary fructose intolerance (HFI)
    Back
    Caused by deficiency of aldolase B
  35. Front
    Metabolite that accumulates in hereditary fructose intolerance
    Back
    Fructose-1-phosphate accumulates, especially in liver
  36. Front
    Effect of fructose-1-phosphate accumulation on phosphate and ATP in HFI
    Back
    Fructose-1-phosphate traps phosphate, causing decreased Pi and decreased ATP
  37. Front
    Major consequences of fructose-1-phosphate accumulation in HFI
    Back
    Hypoglycemia and damage to liver and kidneys
  38. Front
    Additional metabolic effect of low ATP in HFI
    Back
    Low ATP impairs gluconeogenesis
  39. Front
    Additional metabolic effect of low Pi in HFI
    Back
    Low Pi inhibits glycogenolysis
  40. Front
    Possible additional biochemical consequence in HFI
    Back
    AMP degradation can lead to hyperuricemia
  41. Front
    Core mechanism of hereditary fructose intolerance
    Back
    Fructose-1-phosphate traps phosphate, ATP falls, and hepatic glucose production fails
  42. Front
    Mechanism of hypoglycemia in HFI
    Back
    Fructose-1-phosphate accumulation lowers Pi and ATP, which decreases gluconeogenesis and impairs glycogenolysis
  43. Front
    Main steps leading to hypoglycemia in HFI
    Back
    Fructose-1-phosphate accumulates, Pi falls, ATP falls, gluconeogenesis decreases, glycogenolysis is impaired, and hypoglycemia results
  44. Front
    Typical timing of hereditary fructose intolerance symptoms
    Back
    Symptoms begin when an infant starts ingesting fructose or sucrose, often after weaning from milk
  45. Front
    Major clinical findings in hereditary fructose intolerance
    Back
    Vomiting, hypoglycemia, liver damage, and kidney damage
  46. Front
    Severe untreated consequence of hereditary fructose intolerance
    Back
    Liver failure and possible death
  47. Front
    Treatment of hereditary fructose intolerance
    Back
    Remove fructose and sucrose from the diet
  48. Front
    High-yield summary of hereditary fructose intolerance
    Back
    Aldolase B deficiency causes hereditary fructose intolerance, which is severe
  49. Front
    Essential fructosuria versus hereditary fructose intolerance
    Back
    Essential fructosuria is fructokinase deficiency with no toxic accumulation and benign fructosuria, whereas HFI is aldolase B deficiency with fructose-1-phosphate accumulation, hypoglycemia, and liver or kidney damage
  50. Front
    Major dietary source of galactose
    Back
    Lactose
  51. Front
    Composition of lactose
    Back
    Galactose and glucose
  52. Front
    Galactose transport into cells
    Back
    Insulin independent
  53. Front
    Core sequence of galactose metabolism
    Back
    Galactose → galactose-1-phosphate → glucose-1-phosphate + UDP-galactose → UDP-glucose
  54. Front
    First step of galactose metabolism
    Back
    Galactose is phosphorylated to galactose-1-phosphate by galactokinase
  55. Front
    Tissues with high galactokinase activity
    Back
    Liver and other tissues
  56. Front
    Second step of galactose metabolism
    Back
    Galactose-1-phosphate reacts with UDP-glucose to form glucose-1-phosphate and UDP-galactose
  57. Front
    Enzyme for galactose-1-phosphate to glucose-1-phosphate conversion
    Back
    Galactose-1-phosphate uridylyltransferase (GALT)
  58. Front
    Third step of galactose metabolism
    Back
    UDP-galactose is converted to UDP-glucose
  59. Front
    Enzyme converting UDP-galactose to UDP-glucose
    Back
    UDP-hexose 4-epimerase
  60. Front
    How galactose enters mainstream metabolism
    Back
    Glucose-1-phosphate is converted to glucose-6-phosphate, which can enter glycolysis or glycogen metabolism
  61. Front
    Why UDP-galactose is important
    Back
    It is both an intermediate in galactose metabolism and a donor for synthesis of glycolipids, glycoproteins, and lactose
  62. Front
    Biosynthetic uses of UDP-galactose
    Back
    Synthesis of glycolipids, glycoproteins, and lactose in the mammary gland
  63. Front
    Metabolic role of galactose
    Back
    Galactose is both an energy substrate and a building block for glycoconjugates
  64. Front
    Classic galactosemia
    Back
    Caused by deficiency of galactose-1-phosphate uridylyltransferase (GALT)
  65. Front
    Metabolites that accumulate in classic galactosemia
    Back
    Galactose-1-phosphate accumulates and galactose increases in blood and tissues
  66. Front
    Alternative pathway for excess galactose in classic galactosemia
    Back
    Excess galactose is reduced by aldose reductase to galactitol
  67. Front
    Metabolite causing cataracts in galactose disorders
    Back
    Galactitol
  68. Front
    Site of galactitol accumulation causing cataracts
    Back
    Lens
  69. Front
    Mechanism of cataract formation in galactosemia
    Back
    Excess galactose is reduced to galactitol, which accumulates in the lens and causes osmotic damage
  70. Front
    Lecture findings in classic galactosemia
    Back
    Increased galactose-1-phosphate in tissues, mental retardation in nerve cells, cirrhosis in liver, and galactitol in lens causing cataracts
  71. Front
    Core exam features of classic galactosemia
    Back
    Cataracts, liver damage, neurologic or brain damage, and accumulation of galactose-1-phosphate
  72. Front
    Treatment of classic galactosemia
    Back
    Remove galactose and lactose from the diet
  73. Front
    Galactokinase deficiency versus classic galactosemia
    Back
    Galactokinase deficiency can cause cataracts, but classic galactosemia is the more severe disorder caused by GALT deficiency
  74. Front
    High-yield identity of classic galactosemia
    Back
    Classic galactosemia is due to GALT deficiency
  75. Front
    Fructose metabolism summary
    Back
    Fructose is metabolized mainly in liver by fructokinase to fructose-1-phosphate, then by aldolase B to DHAP and glyceraldehyde, entering metabolism as triose phosphates
  76. Front
    Galactose metabolism summary
    Back
    Galactose is metabolized by galactokinase to galactose-1-phosphate, by GALT to glucose-1-phosphate plus UDP-galactose, and by epimerase to UDP-glucose, entering metabolism through glucose-1-phosphate or glucose-6-phosphate
  77. Front
    Fructose versus galactose entry into metabolism
    Back
    Fructose enters as triose phosphates, whereas galactose enters through glucose-1-phosphate and glucose-6-phosphate
  78. Front
    Inherited defects of fructose and galactose metabolism summary
    Back
    Essential fructosuria is fructokinase deficiency and benign, hereditary fructose intolerance is aldolase B deficiency with fructose-1-phosphate accumulation and hypoglycemia, and classic galactosemia is GALT deficiency with galactose-1-phosphate accumulation and cataracts
  79. Front
    High-yield fructose enzyme pair in liver
    Back
    Fructokinase and aldolase B
  80. Front
    High-yield fructose metabolism distinction
    Back
    Fructose bypasses PFK-1
  81. Front
    High-yield summary of essential fructosuria
    Back
    Essential fructosuria is caused by fructokinase deficiency and is benign
  82. Front
    High-yield summary of hereditary fructose intolerance
    Back
    Hereditary fructose intolerance is caused by aldolase B deficiency and leads to fructose-1-phosphate accumulation
  83. Front
    Why HFI causes hypoglycemia
    Back
    Fructose-1-phosphate lowers Pi and ATP and impairs gluconeogenesis and glycogenolysis
  84. Front
    High-yield galactose pathway sequence
    Back
    Galactose enters metabolism via galactose-1-phosphate, UDP-galactose, and glucose-1-phosphate
  85. Front
    High-yield cause of classic galactosemia
    Back
    Classic galactosemia is caused by GALT deficiency
  86. Front
    High-yield cause of cataracts in galactose disorders
    Back
    Galactitol accumulation in the lens
  87. Front
    Cheat-sheet fructose metabolism
    Back
    Fructose → fructose-1-phosphate by fructokinase → DHAP + glyceraldehyde by aldolase B
  88. Front
    Main site of fructose metabolism in the cheat sheet
    Back
    Liver
  89. Front
    Minor fructose pathway in the cheat sheet
    Back
    Small minor pathway through hexokinase
  90. Front
    Cheat-sheet fructose disorders
    Back
    Essential fructosuria is fructokinase deficiency and benign, whereas hereditary fructose intolerance is aldolase B deficiency with fructose-1-phosphate accumulation, hypoglycemia, liver or kidney damage, and need to remove fructose and sucrose
  91. Front
    Cheat-sheet galactose metabolism
    Back
    Galactose → galactose-1-phosphate by galactokinase → glucose-1-phosphate + UDP-galactose by GALT → UDP-glucose by epimerase
  92. Front
    Cheat-sheet galactose disorder
    Back
    Classic galactosemia is GALT deficiency with increased galactose-1-phosphate, galactitol in lens causing cataracts, liver and brain damage, and need to remove galactose and lactose

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