Fructose Metabolism Fructose can enter glycolysis and gluconeogenesis.

1. Fructose Metabolism • Fructose can enter glycolysis and gluconeogenesis. • Glucose is a main metabolic fuel in most organisms. • Other sugars convert to glycolytic intermediates. • Fructose metabolism is faster than glucose in blood. • Hexokinase can phosphorylate fructose: • Fructose + ATP Fructose 6-P + ADP • Km for fructose >> Km for glucose, thus important only if [frucose] is high. • Most of fructose metabolized to fructose 1-P by fructokinase. • Fructose + ATP Fructose 6-P + ADP • Adolase B cleaves the molecule of fructose into two 3-Carbon compounds. • dihydroxyaceton-P + glycealdehyde glycogenesis/gluconeogenesis

2. after dietary fructose consumption low blood glucose level 17-19

3. Excess fructose is toxic. • Accumulation of fructose 1-P causes damage to liver. • fructosekinase > aldolase B in activity • Metabolism of (fructose by fructokinase) >> (glucokinase for glucose) in liver • Generated fructose 1-P stimulates pyruvate kinase. • Hypertriglyceridemia  improper substitute of glucose for diabete patient

4. Disorder of fructose metabolism • Essential fructosuria: deficiency of fructokinase • Hereditary fructose intolerance: deficiency of aldolase B • -Accumulation of fructose 1-P: • inhibits aldolase, phosphohexose isomerase and glycogen phosphorylase • stimulates glucokinase • -Tying up Pi in the form of fructose 1-P makes it impossible for liver mitochondria to generate ATP by oxidative phosphorylation. • fructose + ATP  fructose 1-P + ATP • ADP + Pi + “energy provided by electron transport chain”  ATP • Net: Pi + fructose  fructose 1-P • The ATP levels fall precipitously inside cells. • Cells cannot perform normal work functions. • Deficiency of fructose 1,6-bisphophatase causes similar effect.

5. Galactose metabolism Galactose can enter glycolysis and gluconeogenesis Phosphorylation of galactose by galactokinase: Galactose 1-P UDP-galactose is an epimer of UDP-glucose recycle reversible: internal sources for other biosynthesis Galactosemia Deficiency of galactose 1-P uridyl transferase Accumulation of galactose (cataract) or galactose 1-P (damage to liver)

6. Recycle 17-20

7. Galactose Galactitol no reaction Polyol pathway 17-23

8. Other pathways Pentose phosphate pathway Produces ribose 5-P and NADPH Oxidative branch: irreversible, high [NADPH]/[NADP+] NADPH is a stronger reductant than NADH in cells. Non-oxidative branch: irreversible

9. 3 glucose 6-P + 6 NADP+ 2 fructose 6-P + glyceraldehyde 3-P + 6 NADPH + 6H + + 3 CO2 Oxidative branch of pentose phosphate pathway 17-21

10. 17-22 Non-oxidative branch of pentose phosphate pathway

12. Thiamine pyrophosphate

14. 3 glucose 6-P + 6 NADP+ 2 fructose 6-P + glyceraldehyde 3-P + 6 NADPH + 6H + + 3 CO2 Oxidative branch of pentose P pathway 17-21

15. Use of oxidative and nonoxidative branches is dependent on need of NADPH and ribose 5-P in cells 1. When cells need ribose 5-P more than NADPH Generating ribose 5-P from oxidative branch, reverse reaction in Non-oxidative branch Used in muscle , where glucose 6-P dehydrogenase level is low and nucleotides are stored. 2. Need both ribose 5-P and NADPH Predominantly oxidative branch and phosphate pentose isomerase reaction. 3. need NADPH more than ribose 5-P Generating fructose 5-P and glyceraldehyde 3-P by both branches Changed to glucose 6-P through gluconeogenesis Thus, theoretically all glucose can be converted to CO2 and NADPH.

16. Activity of pentose phosphate pathway • The cell keeps the ratio of [NADPH]/[NADP+] at above 100 to favor reductive biosynthesis. • In some tissues such as adrenal cortex, lactating mammary glandand liver, where fatty acid and cholesterol synthesis are rapid, as much as 30% of glucose is metabolized by the pentose phosphate shunt. (weak in brain and muscle) • NADPH as an antioxidant: important to tissues exposed to high oxygen pressure such as the cornea • Oxidative branch produces NADPH, The first step in oxidative branch is oxidation of glucose 6-P via glucose 6-P dehydrogenase

17. Deficiency of glucose 6-P causes hemolytic anemia. • The pentose phosphate pathway supplies the RBC with NADPH to maintain the reduced state of glutathione. • -Oxidation of glucose 6-P via glucose 6-P dehydrogenase to produce NADPH. • The inability to maintain reduced glutathione in RBCs leads to increased accumulation of peroxides, predominantly H2O2, that in turn results in a weakening of the cell wall and concomitant hemolysis. • The pentose phosphate pathway in erythrocytes is essentially the only pathway for these cells to produce NADPH. Any defect in the production of NADPH could, therefore, have profound effects on erythrocyte survival. • Oxidant drugs: increase the oxidation of glutathione • Many anti-malarial drugs, etc. • Plasmodium requires the reducing power of NADPH for their life cycle. • Favism • Viral hepatitis, pneumonia, and typhoid fever

18. a b Glu g Cys a a Gly

19. g-Glu  Cys SH +  Gly g-Glu  SH Cys  Gly g-Glu  Cys S   Gly g-Glu  S Cys  Gly g-Glu  2 Cys SH +  Gly g-Glu  Cys S   Gly g-Glu  S Cys + 2 H2O  Gly H2O2 Glutathione peroxidase g-Glu  Cys S   Gly g-Glu  S Cys + NADPH + H+  Gly g-Glu  2 Cys SH +  Gly NADP+ Glutathione reductase Box 17-1,2,3

20. Fructose is a major sugar in semen • Advantage over bacteria • Polyol pathway is present in the seminal vesicles for fructose synthesis for seminal fluid (energy source for spermatozoa) • Amino sugar synthesis from glucose (표 17-3 참고) • Essential pentosuria

21. Synthesis of amino sugars 17-24

22. essential pentosuria Uronic acid pathway 17-25