Fructose

1

C

C

CH2OH

H OHC

OHH C

HHO

O

CH2OH

D-Fructose

Sucrose(Table Sugar)

O-a-D-Glucopyranosyl-(1—> 2)-b-D-Fructofuranoside

OO

CH2OH

HHO

H

HOOH

H

H

OH

H HOCH2

H

OH H

H

CH2OHO

Synthesis of Fructose in the Polyol Pathway

• The polyol pathway is named for the first step of the pathway in which sugars are reduced to the sugar alcohol by the enzyme aldose reductase Glucose is reduced to the sugar alcohol sorbitol, and sorbitol is then oxidized to fructose.

Fructose Metabolism

• Monosaccharide • approximately 50 g/day • sources= sucrose, in many fruits, in honey, in high-

fructose corn syrup (55% fructose/45% glucose), which is used to sweeten soft drinks and many foods.

• Entry of fructose into cells is not insulin-dependent unlike that of glucose

• in contrast to glucose, fructose does not promote the secretion of insulin.

metabolism of fructoseprincipally = liver , lesser extent in = small intestinal mucosa and proximal renal tubule,

b/c these tissues have both fructokinase and aldolase B. Aldolase isoforms: aldolases A, B, C, and fetal aldolase. all of these aldolase isoforms can

cleave fructose 1,6-bisphosphate, the intermediate of glycolysis.only aldolase B can also cleave fructose 1-phosphate. Aldolase A, present in muscle and

most other tissues, aldolase C, present in brain, have almost no ability to cleave fructose 1-phosphate. Fetal aldolase, present in the liver before birth, is similar to aldolase C. Aldolase B is the rate-limiting enzyme of fructose metabolism, although it is not a rate-

limiting enzyme of glycolysis. It has a much lower affinity for fructose l-phosphate than fructose 1,6-bisphosphate.

after ingesting a high dose of fructose, normal individuals accumulate fructose 1-phosphate in the liver while it is slowly converted to glycolytic intermediates.

Individuals with hereditary fructose intolerance (a deficiency of aldolase B) accumulate much higher amounts of fructose 1-phosphate in their livers. Other tissues also have the capacity to metabolize fructose but do so much more slowly.

The hexokinase isoforms present in muscle, adipose tissue, and other tissues can convert fructose to fructose 6-phosphate, but react so much more efficiently with glucose. As a result, fructose phosphorylation is very slow in the presence of physiologic levels of intracellular glucose and glucose 6-phosphate.

LIVER

Fructose > rapid glycolysis in the liver than glucose b/C passes phosphofructokinase(PFK). fructose is phosphorylated by FK in the liver, leading to enhanced fatty acid synthesis, increased esterification of fatty acids, and increased VLDL secretion, which may raise serum triacylglycerols and ultimately raise LDL cholesterol.IN EXTRAHEPATIC , ADIPOSE TISSUE & MUSCLESHexokinase catalyzes most hexoses including fructoseGlucose inhibits fructose phosphorylation

at weaning, Fructose 1-phosphate accumulates,a drop in the level of inorganic phosphate (Pi) and, therefore, of ATP. As ATP falls, AMP rises. In the absence of Pi, AMP is degraded,causing ↑ uric acid. The decreased availability of hepatic ATP affects gluconeogenesis (causing hypoglycemia with vomiting), and protein synthesis (causing a decrease in blood clotting factors and other essential proteins). Diagnosis = fructose in the urine, or RFLP test

Galactose Metabolism

Lactose Metabolism(Dairy Products)

Glycolysis

O

O

CH2OH

HHO

HOH

H

H

OH

H

O

CH2OH

H

OH

H

H

OH

H

OH

O

CH2OH

HHO

HOH

H

H

OH

OH

H

Lactose

Glucose

-D-Galactose

-Galactosidase

Glycolytic Enzymes are specific and do not recognize

galactose!

Need Epimerization

OCH2OH

HHO

HOH

H

H

OH

H

OH

OCH2OH

HH

HOOH

H

H

OH

H

OH

GlucoseGalactose

Epimerization

Phosphorylation of Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

OH

ATP ADP

O

CH2OH

HOH

HOH

H

H

OH

H

OPO3=Galactokinase

Galactose Galactose-1-P

Activation of Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

OPO3=

O

CH2OH

HH

OHOH

H

H

OH

H

O P O

O

O–

P O

O–

O

Uridine

O

CH2OH

HOH

HOH

H

H

OH

H

O P O

O

O–

P O

O–

O

Uridine

UMP

Galactose-1-P

Galactose-1-PUridylyl Transferase

UDP-Glucose

Glucose-1-P

UDP-Galactose

Glucose-6-P

Phosphoglucomutase

Glycolysis

Epimerization of UDP-Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

O P UMP

O

O–

[NAD+]O

CH2OH

HH

OHOH

H

H

OH

H

O P UMP

O

O–

UDP-Galactose-4-Epimerase

UDP-GlucoseUDP-Galactose

Why UDP-Galactose?

GlycoproteinsGlycolipids

(Require UDP-Galactose)

Formation of Glucose-1-P

O

CH2OH

HH

OHOH

H

H

OH

H

O P UMP

O

O–

PPi UTPO

CH2OH

HH

OHOH

H

H

OH

H

O P O–

O

O–

UDP-GlucosePyrophosphorylase

UDP-Glucose Glucose-1-P

Formation of Glucose-6-P

O

CH2OH

HH

OHOH

H

H

OH

H

O P O–

O

O–

O

CH2OPO32–

HH

OHOH

H

H

OH

H

OHPhosphoglucomutase

Glucose-6-PGlucose-1-P

Glucose-6-P ——> Glycolysis

Galactosemia(Mental Retardation and Death)

TreatmentGalactose-free diet

(reversal of all symptoms except mental retardation)

Cataracts

C

C

C

OHH

OH

HHO

C HHO

C OHH

CH2OH

CH2OH

C

C

OHH

HHO

C HHO

C OHH

CH2OH

NAD(P)H NAD(P)+

Galactose Galactitol

Galactose metabolism & abnormalities

• Classical galactosemia = a deficiency of galactose 1-phosphate uridylyltransferase.

• galactose 1-phosphate accumulates in tissues, and galactose is elevated in the blood and urine.

• This differs from the rarer deficiency of galactokinase (nonclassical galactosemia), in which galactosemia and galactosuria occur but galactose 1-phosphate is not formed.

• Both enzyme defects result in cataracts from galactitol formation by aldose reductase in the polyol pathway

• One of the most serious problems of classical galactosemia is an irreversible mental retardation.

• Realizing this problem, begin immediate dietary therapy. • measures galactose 1-phosphate uridylyltransferase in

erythrocytes.