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

17-19

after dietary fructose consumption

low blood glucose level

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 liverGenerated fructose 1-P stimulates pyruvate kinase.

Hypertriglyceridemia

improper substitute of glucose for diabete patient

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 phosphorylasestimulates 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 + ATPADP + Pi + “energy provided by electron transport chain” ATPNet: Pi + fructose fructose 1-PThe ATP levels fall precipitously inside cells.Cells cannot perform normal work functions.

•Deficiency of fructose 1,6-bisphophatase causes similar effect.

Galactose metabolism

Galactose can enter glycolysis and gluconeogenesis

Phosphorylation of galactose by galactokinase: Galactose 1-PUDP-galactose is an epimer of UDP-glucoserecyclereversible: internal sources for other biosynthesis

Galactosemia

Deficiency of galactose 1-P uridyl transferaseAccumulation of galactose (cataract) or galactose 1-P (damage to liver)

17-20

Recycle

17-23Polyol pathway

Galactose Galactitol no reaction

Other pathways

Pentose phosphate pathway

Produces ribose 5-P and NADPHOxidative branch: irreversible, high [NADPH]/[NADP+] NADPH is a stronger reductant than NADH in cells.

Non-oxidative branch: irreversible

17-21

Oxidative branch of pentose phosphate pathway

3 glucose 6-P + 6 NADP+

2 fructose 6-P + glyceraldehyde 3-P+ 6 NADPH + 6H + + 3 CO2

17-22Non-oxidative branch of pentose phosphate pathway

Thiamine pyrophosphate

17-21

Oxidative branch of pentose P pathway

3 glucose 6-P + 6 NADP+

2 fructose 6-P + glyceraldehyde 3-P+ 6 NADPH + 6H + + 3 CO2

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 NADPHGenerating ribose 5-P from oxidative branch, reverse reaction in Non-oxidative branchUsed in muscle , where glucose 6-P dehydrogenase level is low and nucleotides are stored.

2. Need both ribose 5-P and NADPHPredominantly oxidative branch and phosphate pentose isomerase reaction.

3. need NADPH more than ribose 5-PGenerating fructose 5-P and glyceraldehyde 3-P by both branchesChanged to glucose 6-P through gluconeogenesisThus, theoretically all glucose can be converted to CO2 and NADPH.

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 gland and 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

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 glutathioneMany anti-malarial drugs, etc.-Plasmodium requires the reducing power of NADPH for their life cycle.-Favism -Viral hepatitis, pneumonia, and typhoid fever

Glu

Gly

Cys

Box 17-1,2,3

-Glu Cys SH + Gly

-Glu SH Cys Gly

-Glu Cys S Gly

-Glu S Cys Gly

-Glu 2 Cys SH + Gly

H2O2

-Glu Cys S Gly

-Glu S Cys + 2 H2O Gly

-Glu 2 Cys SH + Gly

NADP+

-Glu Cys S Gly

-Glu S Cys + NADPH + H+

Gly

Glutathione

peroxidase

Glutathione

reductase

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

17-24

Synthesis of amino sugars

17-25

essential pentosuria

Uronic acid pathway