FRUCTOSE & GALACTOSE METABOLISM

FRUCTOSE CHEMISTRY
Fructose is a reducing monosacchride Important biological monosaccharide Hexose

FRUCTOSE CHEMISTRY
Exists as a 5-member ring fructofuranose ring

FRUCTOSE CHEMISTRY
Mutarotation of fructose

WHERE IT CAN BE FOUND ?

HFCS

FRUITS

TABLE SUGAR

HONEY

ABSORPTION OF FRUCTOSE
Rate of absorption of fructose is less than that of glucose - half the rate of glucose but metabolised more rapidly than glucose 18 min vs. 43 min Absorbed from the intestinal lumen into the eneterocyte by carrier mediated passive transport (facilitated diffusion) - GLUT 5 from eneterocyte into capillaries thro GLUT 2 by facilitated diffusion

Fructose; also glucose, Intestinal Epithelial cell

Glucose

Na+

Galactose

Lumen of intestine

GLUT-5

SGLT-1

Brush border
Fructose

Glucose
Galactose

Na+

3Na+ 2K+

ATP ADP + Pi

contraluminal membrane

GLUT-2

to capillaries = facilitated diffusion = Na+-dependent co-transport

3Na+ 2K+

= Na,K-ATPase

ABSORPTION OF MONOSACCHRIDES

FRUCTOSE METABOLISM
Metabolised more rapidly than glucose twice the rate
18 min vs. 43 min Ultimately enters glycolytic pathway Converted to either glucose or glycolytic intermediates Cytosol of cells metabolised at twice the rate as glucose Promptly & mainly metabolised by liver Also by intestine, muscle and kidneys but by different route

Fructose metabolism
Some tissues convert utilise fructose as major source of energy in preference to glucose Polyol pathway Spermatozoan, lens, retina, peripheral nerves, endothelial cells

FRUCTOSE METABOLISM
Extrahepatic tissues like spermatozoa, muscle utilise fructose as a source of energy before it enters liver

 Muscle contains only hexokinase/ No glucokinase

FRUCTOSE METABOLISM IN MUSCLE

HK high Km for D-Fructose (low affinity) compared to D-glucose Hence acts only when blood levles of fructose is maintained high

FRUCTOSE METABOLISM IN MUSCLE

Glycolysis

HOCH2 O H H OH HO H

CH2 OH OH

ATP

ADP

POCH2 O H H OH HO H

CH 2OH OH

Hexokinase

-D-Fructose

Fructose-6-P

FRUCTOSE METABOLISM IN MUSCLE (cont.)

Fru 6-PO4 enters glycolytic pathway
HOCH2 O H H OH HO H CH2 OH OH ATP ADP

Glycolysis

POCH2 O H H OH HO H

CH 2OH OH

Hexokinase

-D-Fructose

Fructose-6-P

FRUCTOSE METABOLISM IN LIVER

Mainly fructokinase Little hexokinase GK - low affinity for fructose (high Km)

FRUCTOSE METABOLISM IN LIVER (cont.)

ATP dependant - Committed step FK- Low Km for D-Fructose (high affinity) FK not dependant on insulin (not inducible)

HOCH2 O H H OH HO H

CH2OH

ATP ADP

HOCH2 O H H OH HO H

CH2OP OH

Fructokinase OH (Committed Step)

-D-Fructose

Fructose-1-P

FRUCTOSE METABOLISM IN LIVER (cont.)

Fru 1- PO4 cleaved by upon by aldolase B to glceraldehyde and DHAP Glyceraldehyde converted by ATP dependent triose kinase to Gly 3-PO4 DHAP & Gly 3-PO4 enter glycolytic pathway

FRUCTOSE METABOLISM IN LIVER (cont.)

CH2 OP C O CH2 OH

Glycolysis

HOCH2 O H H OH HO H

CH 2OP OH

CH2 OP C O HO C H H C OH H C OH CH2 OH

DHAP
CHO CHOH CH2 OH

Glyceraldehyde

Fructose-1-P
Fructose-1-P Aldolase

FRUCTOSE METABOLISM IN LIVER (cont.)

Glyceraldehyde-3-P
CHO CHOH CH2 OP

Triose-P Isomerase Glycolysis

CH2 OH C O CH2 OP

ADP ATP
CHO CHOH CH2 OH

Glyceraldehyde Kinase NADH + H+ NADH + H NAD+ Alcohol Dehydrogenase NAD+

CH2 OH CHOH CH2 OH

Dihydroxyacetone-P (DHAP)
+

Glyceraldehyde

Glycerol-P Dehydrogenase

CH2 OH CHOH

Glycerol Kinase

CH2 OP

Glycerol

Glycerol-3-P

FRUCTOSE METABOLISM IN LIVER (cont.)

Fructose more rapidly utilised even in normal persons Reason: bottle neck steps of glycolysis namely GK and PFK steps are by passed net energy yield from fructose is same as glucose

FRUCTOSE METABOLISM IN LIVER (cont.)

Diabetic patients can still metabolise fructose

Reason : not dependant upon insulin (not inducible)

FRUCTOSE METABOLISM IN LIVER (cont.)

Not a substitute for glucose in diabetics Reason: uncontrolled phosphorylation of fructose by FK sequestration of intracellular phosphates as Fru 1 PO4 depletion of intracellular PO4s - decreased ATP production & liver cell failure excess fructose increased TGL & VLDL

FRUCTOSE METABOLISM INBORN ERRORS

1. Hereditary Frutose Intolerance (HFI) 2. Essential Fructosuria

FRUCTOSE METABOLISM INBORN ERRORS

Essential Fructosuria BENIGN condition Reason : fructose not a dietary essential Due to deficiency of FRUCTOKINASE Fructose cannot be metabolised Only abnormality excretion of fructose in urine POSITIVE BENEDICTS TEST important in diffentiating from glucose

FRUCTOSE METABOLISM INBORN ERRORS

Hereditary fructose intolerance (HFI)
Serious IEM but rare Deficiency of ALDOLASE B Autosomal Recessive disorder Manifests around 3 to 6 months of age when sugar or fruits are introduced in the diet of the infant (sucrose or fructose) Inability to metabolise fructose

FRUCTOSE METABOLISM INBORN ERRORS

Symptoms & signs of Hereditary fructose intolerance (HFI)
Failure to thrive Jaudice Hepatomrgaly & Cirrohosis of liver liver cell failure Hypoglycemia Hypophosphatemia Hypermagnesemia Hyperuricemia

FRUCTOSE METABOLISM INBORN ERRORS

Hereditary fructose intolerance (HFI)
Deficiency of the enzyme Aldolase B Accumualtion of fru 1-PO4 sequestration of PO4 as F 1-PO4 hence glycogen phosphorylae a is not activated remains inhibited Also inhibits Phospho Hexose Isomerase leads to hypoglycemia following ingestion of diet rich in fructose Liver is unable to release glucose from glycogen

GALACTOSE METABOLISM
Glactose another reducing monosacchride Hexose Important biological monosaccharide Exists as a 6-member ring - pyran ring D-Galactopyranose

GALACTOSE METABOLISM
Glucose & Galactose differ only in the orientation of the OH and H on carbon 4 (epimers)

WHERE IT CAN BE FOUND ?

Can be found in ....

CURD

MILK

WHEY

CHEESE

Galactose - where it is found ?

Major source is Lactose of Milk (Glu & Gal)

Glycolysis

CH2 OH HO O H OH H H OH H O

CH2 OH O H OH H H OH H

Glucose
HO

CH2 OH O H OH H H OH OH H

OH

-Galactosidase

Lactose

-D-Galactose

ABSORPTION OF GALACTOSE
Rate of absorption of Galactose is less than that of glucose Absorbed from the intestinal lumen into the eneterocyte by carrier mediated facilitated diffusion GluT 5 secondary active transport by SGLT -1 (Na dependent Glucose Transporter SGLT-1)

Along with sodium CO-TRANSPORT / SYMPORT

Against a concentration gradient

ABSORPTION OF GALACTOSE

Absorbed into capillaries from eneterocyte thro GLUT 2 by facilitated diffusion

Fructose; also glucose, Intestinal Epithelial cell

Glucose

Na+

Galactose

Lumen of intestine

GLUT-5

SGLT-1

Brush border
Fructose

Glucose
Galactose

Na+

3Na+ 2K+

ATP ADP + Pi

contraluminal membrane

GLUT-2

to capillaries = facilitated diffusion = Na+-dependent co-transport

3Na+ 2K+

= Na,K-ATPase

ABSORPTION OF MONOSACCHRIDES

GALACTOSE METABOLISM
There are no catabolic pathways to metabolize Galactose So the strategy is to convert Galactose into a metabolite of glucose

GALACTOSE METABOLISM
Glycolytic Enzymes are specific and do not recognize galactose !!! Need Epimerization
CH 2OH HO H H OH H O H OH H OH Epimerization CH 2OH H HO H OH H O H OH H OH

Galactose

Glucose

GALACTOSE METABOLISM
Almost entirely metabolised by the liver Cytosol of hepatocyte

GALACTOSE METABOLISM

GALACTOSE METABOLISM
Step 1- Phosphorylation of Galactose

CH2 OH OH H O H OH H H OH H OH

ATP

ADP
OH

CH2 OH O H OH H H OH H OPO3
=

Galactokinase

Galactose

Galactose-1-P

GALACTOSE METABOLISM
Step 2- Activation of Galactose to UDP Galactose by UDP glucose
CH2 OH H OH O H OH H H OH H O O P O O O P O O Uridine

Glycolysis

Glucose-6-P Phosphoglucomutase
CH2 OH OH O H OH H H OH H O O P O O P O

UDP-Glucose
CH2 OH OH H O H OH H H OH H OPO3 =

Glucose-1-P

UMP
O O Uridine

Galactose-1-P Uridylyl Transferase

Galactose-1-P

UDP-Galactose

GALACTOSE METABOLISM
Step 3- Epimerization of UDP-Galactose
CH2 OH OH H O H OH H H OH H O O P UMP O CH2 OH

[NAD ] UDP-Galactose4-Epimerase

H OH

O H OH H H OH

H O O P UMP O

UDP-Galactose

UDP-Glucose

GALACTOSE METABOLISM
Step 4 - Formation of Glucose-1-P
CH2 OH H OH O H OH H H OH H O O P UMP O

PPi

UTP
H

CH2 OH O H OH H H OH H O O P O O

UDP-Glucose Pyrophosphorylase

OH

UDP-Glucose

Glucose-1-P

GALACTOSE METABOLISM
Step 5 - Formation of Glucose-6-P
CH2 OH H OH O H OH H H OH H O O P O O H CH2 OPO3 2 O H OH H H OH H OH

Phosphoglucomutase

OH

Glucose-1-P

Glucose-6-P

Glucose-6-P

Glycolysis

GALACTOSE METABOLISM

Step 6 - UDP-Galactose is recycled back to UDP-Glucose by UDP Galactose 4Epimerase (GALE)

GALACTOSE METABOLISM INBORN ERRORS

Galactosemia SERIOUS condition Autosomal Recessive 1 : 80, 000 births

Galactose pathway

Inborn Errors Of Galactose Metabolism - Galactosemia

3 FORMS 1. Classical Seroius 2. Milder form 3. Rarer form Due to deficiency of enzymes in the conversion of gal to Glu Gal 1-PO4 Uridyl transferase (GALT) Classical Galactosemia 95% of patients Galactokinase (GALK) Mild 5 % Uridyl Diphosphate Galactose 4-Epimerase (GALE) - Milder & very rare

GALACTOSE METABOLISM INBORN ERRORS

Symptoms & signs of Classical galactosemia
Deficiency of GALT Very early symptoms - milk contains lactose Accumulation of Gal 1 PO4 Inhibits GALK & Glycogen Phosphorylase Accumulation of Galactose leading to galactosemia Gal reduced to galactitol (dulcitol) Cataract osmotic effect Gets deposited in renal tubules

SYMPTOMS & SIGNS OF CLASSICAL GALACTOSEMIA (cont.)

Very early symptoms Failure to thrive , Jaudice Congenital cataract Vomiting & Diarrhea Lethargy Mental retardation,Hepatomegaly Hypoglycemia inhibition of Glycogen Phosphorylase by Galactose 1 PO4 Aminoaciduria & renalfailure

TREATMENT
Early identification Removal of galactose source from diet Lactose free milk formulas up to minimum 5 years Gal 1 PO4 pyrophosphorylase gets active Symptoms recede but MR residual

Lactose synthesis in lactating mammary gland