fructosse metabolism for class

8/13/2019 Fructosse Metabolism for Class

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FRUCTOSE & GALACTOSE

METABOLISM


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FRUCTOSE CHEMISTRY

Fructose is a reducing monosacchrideImportant biological monosaccharide

Hexose
http://upload.wikimedia.org/wikipedia/commons/6/67/Beta-D-Fructofuranose.svg


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FRUCTOSE CHEMISTRY

Exists as a 5-member ring fructofuranosering
http://upload.wikimedia.org/wikipedia/commons/6/67/Beta-D-Fructofuranose.svg


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FRUCTOSE CHEMISTRY

Mutarotation of fructose


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WHERE IT CAN BE FOUND ?

HFCS

HONEY

FRUITS

TABLE SUGAR


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ABSORPTION OF FRUCTOSE

Rate of absorption of fructose is less than that ofglucose - 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


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to capillaries

ABSORPTION OF MONOSACCHRIDES

Lumen ofintestine

Intestinal

Epithelial cell

Fructose;also glucose,

Glucose GalactoseNa+

2K+

3Na+ ATPADP + Pi

= facilitated diffusion= Na+-dependent co-transport

= Na,K-ATPase

contra luminal membrane

GLUT-5

Brush border

SGLT-1

Fructose

GLUT-2

Na+2K+

3Na+

GlucoseGalactose


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FRUCTOSE METABOLISM

Metabolised more rapidly than glucosetwice the rate

18 min vs. 43 min

Ultimately enters glycolytic pathway

Converted to either glucose or glycolytic intermediates

Cytosolof cellsmetabolised at twice the rate as glucose

Promptly & mainly metabolised by liver

Also by intestine, muscle and kidneys but by different

route


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Fructosemetabolism Some tissues convert utilise fructose as

major source of energy in preference toglucose

Polyol pathway

Spermatozoan, lens, retina, peripheralnerves, endothelial cells


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FRUCTOSE METABOLISM

Extrahepatic tissues like spermatozoa,muscle utilise fructose as a source of energy

before it enters liver


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FRUCTOSE METABOLISM IN MUSCLE

Muscle contains onlyhexokinase/ No glucokinase

HK high Km for D-Fructose(low affinity) compared toD-glucose

Hence acts only when bloodlevles of fructose is

maintained high


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FRUCTOSE METABOLISM IN MUSCLE

O

HO

HOCH2

H

OH H

CH2OH

OHH

ATP ADP

O

HO

POCH2

H

OH H

CH2OH

OHHHexokinase

-D-Fructose

Glycolysis

Fructose-6-P


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FRUCTOSE METABOLISM IN MUSCLE (cont.)

O

HO

HOCH2

H

OH H

CH2OH

OHH

ATP ADP

O

HO

POCH2

H

OH H

CH2OH

OHHHexokinase

-D-Fructose

Glycolysis

Fructose-6-P

Fru 6-PO4enters

glycolytic pathway


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FRUCTOSE METABOLISM IN LIVER

Mainly fructokinase

Little hexokinase

GK - low affinity forfructose (high Km)


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FRUCTOSE METABOLISM IN LIVER (cont.)

ATP dependant - Committed step

FK- Low Km for D-Fructose (high affinity)

FK not dependant on insulin (not inducible)

O

HO

HOCH2

H

OH H

CH2OH

OHH

ATP ADPO

HO

HOCH2

H

OH H

CH2OP

OHHFructokinase

-D-Fructose

(Committed Step)

Fructose-1-P


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Fru 1- PO4 cleaved by upon by aldolase B toglceraldehyde and DHAP

Glyceraldehyde converted by ATPdependent triose kinaseto Gly 3-PO4

DHAP & Gly 3-PO4enter glycolytic pathway


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CH2OPC

CC

CCH2OH

O

HHOOHH

H OH

Glycolysis

CHO

CHOHCH2OH

Glyceraldehyde

O

HO

HOCH2

H

OH H

CH2OP

OHH

DHAP

CH2OP

CCH2OH

O

Fructose-1-P

Fructose-1-P Aldolase


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CHO

CHOH

CH2OH

ATP

ADP

CHO

CHOH

CH2OP

NAD+

CH2OH

CHOH

CH2OH

NAD+

CH2OH

C

CH2OP

O

CH2OH

CHOH

CH2OP

Glyceraldehyde

Glyceraldehyde Kinase

Glyceraldehyde-3-P

Glycolysis

AlcoholDehydrogenase

NADH + H+

Glycerol

GlycerolKinase

Glycerol-3-P

Dihydroxyacetone-P(DHAP)

NADH + H+

Glycerol-PDehydrogenase

Triose-PIsomerase


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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 asglucose


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Diabetic patients can still metabolise fructose

Reason: not dependant upon insulin (notinducible)


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Not a substitute for glucose in diabetics

Reason: uncontrolled phosphorylation of

fructose by FKsequestration of intracellular phosphates asFru 1 PO4

depletion of intracellular PO4s - decreasedATP production & liver cell failure

excess fructose increased TGL & VLDL


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FRUCTOSE METABOLISM INBORN ERRORS

1. Hereditary Frutose Intolerance (HFI)

2. Essential Fructosuria
http://www.bu.edu/aldolase/HFI/hfiinfo/index.html


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Essential Fructosuria

BENIGNcondition

Reason : fructose not a dietary essential

Due to deficiency of FRUCTOKINASE

Fructose cannot be metabolised

Only abnormality excretion of fructose in urinePOSITIVE BENEDICTS TESTimportant indiffentiating from glucose


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Hereditary fructose intolerance (HFI)

Serious IEM but rare Deficiency ofALDOLASE B

Autosomal Recessive disorder

Manifests around 3 to 6 months of age

when sugar or fruits are introduced in thediet of the infant (sucrose or fructose)

Inability to metabolise fructose


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Symptoms & signs of Hereditary fructoseintolerance (HFI)

Failure to thrive

JaudiceHepatomrgaly & Cirrohosis of liver

liver cell failure

HypoglycemiaHypophosphatemia

Hypermagnesemia

Hyperuricemia


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Hereditary fructose intolerance (HFI)Deficiency of the enzyme Aldolase B

Accumualtion of fru 1-PO4

sequestration of PO4 as F 1-PO4hence glycogen phosphorylae a is notactivated remains inhibited Also inhibits

Phospho Hexose Isomeraseleads to hypoglycemia following ingestionof diet rich in fructose

Liver is unable to release glucose from

glycogen


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GALACTOSE METABOLISMGlactose another reducing monosacchride

Hexose

Important biological monosaccharide

Exists as a 6-member ring - pyran ring

D-Galactopyranose


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GALACTOSE METABOLISM

Glucose & Galactose differ only in the orientationof the OH and H on carbon 4 (epimers)


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WHERE IT CAN BE FOUND ?

Can be found in ....

MILK

CHEESE

CURD

WHEY


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Galactose - where it is found ?

Major source is Lactose of Milk (Glu & Gal)

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

ABSORPTION OF GALACTOSE


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Rate of absorption of Galactose is less thanthat of glucose

Absorbed from the intestinal lumen into theeneterocyte by carrier mediatedfacilitateddiffusion GluT 5secondary active transport by SGLT -1

(Na dependent Glucose Transporter SGLT-1)

Along with sodium CO-TRANSPORT/ SYMPORT

Against a concentration gradient



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Absorbed into capillaries from eneterocyte

thro GLUT 2 by facilitated diffusion


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to capillaries

ABSORPTION OF MONOSACCHRIDES

Lumen ofintestine

Intestinal

Epithelial cell

Fructose;also glucose,

Glucose GalactoseNa+

2K+

3Na+ ATPADP + Pi

= facilitated diffusion= Na+-dependent co-transport

= Na,K-ATPase

contra luminal membrane

GLUT-5

Brush border

SGLT-1

Fructose

GLUT-2

Na+2K+

3Na+

GlucoseGalactose


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There are no catabolic pathways tometabolize Galactose

So the strategy is to convert Galactoseinto a metabolite of glucose


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Glycolytic Enzymes are specific and do notrecognize galactose !!!

Need EpimerizationO

CH2OH

HHO

H OH

H

H

OH

H

OH

O

CH2OH

HH

HO OH

H

H

OH

H

OH

GlucoseGalactose

Epimerization


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Almost entirely metabolised by the liver

Cytosol of hepatocyte



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Step 1- PhosphorylationofGalactose

O

CH2OH

HOH

H OH

H

H

OH

H

OH

ATP ADP

O

CH2OH

HOH

H OH

H

H

OH

H

OPO3=Galactokinase

Galactose Galactose-1-P


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Step 2- Activation of Galactose to UDPGalactose by UDP glucose

O

CH2OH

HOH

HOH

H

H

OH

H

OPO3=

O

CH2OH

H

H

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


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Step 3- 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


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Step 4 - Formation of Glucose-1-P

O

CH2OH

H

H

OH

OH

H

H

OH

H

O P UMP

O

O

PPi UTP

O

CH2OH

H

H

OH

OH

H

H

OH

H

O P O

O

O

UDP-GlucosePyrophosphorylase

UDP-Glucose Glucose-1-P


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Step 5 - 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


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Step 6 - UDP-Galactose isrecycled back toUDP-Glucose by UDP Galactose 4-Epimerase (GALE)



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GALACTOSE METABOLISM INBORN ERRORS

Galactosemia

SERIOUS condition

Autosomal Recessive

1 : 80, 000 births

G l ct s p th


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Galactose pathway


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Inborn Errors Of GalactoseMetabolism - Galactosemia

3 FORMS1. Classical Seroius

2. Milder form

3. Rarer formDue to deficiency of enzymes in the conversionof gal to Glu

Gal 1-PO4 Uridyl transferase (GALT) Classical Galactosemia 95% of patients

Galactokinase(GALK) Mild 5 %

UridylDiphosphate Galactose 4-Epimerase(GALE) - Milder& very rare



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GALACTOSE METABOLISM INBORN ERRORS

Symptoms & signs of Classical galactosemiaDeficiency of GALTVery early symptoms- milk contains lactoseAccumulation of Gal 1 PO4Inhibits GALK & Glycogen PhosphorylaseAccumulation of Galactose leading

to galactosemiaGal reduced to galactitol (dulcitol)Cataractosmotic effectGets deposited in renal tubules


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SYMPTOMS & SIGNS OF CLASSICALGALACTOSEMIA (cont.)

Very early symptoms-Failure to thrive , JaudiceCongenital cataract

Vomiting & Diarrhea LethargyMental retardation,Hepatomegaly Hypoglycemiainhibition ofGlycogen PhosphorylasebyGalactose 1 PO4Aminoaciduria & renalfailure


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TREATMENT

Early identificationRemoval of galactose source

from dietLactose free milk formulasup to minimum 5 years Gal 1PO4 pyrophosphorylase gets

activeSymptoms recedebut MR residual

Lactose synthesis in


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Lactose synthesis inlactating mammary gland

fructosse metabolism for class

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