Download - 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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FRUCTOSE METABOLISM IN LIVER (cont.)
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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FRUCTOSE METABOLISM IN LIVER (cont.)
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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FRUCTOSE METABOLISM IN LIVER (cont.)
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 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 asglucose
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FRUCTOSE METABOLISM IN LIVER (cont.)
Diabetic patients can still metabolise fructose
Reason: not dependant upon insulin (notinducible)
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FRUCTOSE METABOLISM IN LIVER (cont.)
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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FRUCTOSE METABOLISM INBORN ERRORS
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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FRUCTOSE METABOLISM INBORN ERRORS
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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FRUCTOSE METABOLISM INBORN ERRORS
Symptoms & signs of Hereditary fructoseintolerance (HFI)
Failure to thrive
JaudiceHepatomrgaly & Cirrohosis of liver
liver cell failure
HypoglycemiaHypophosphatemia
Hypermagnesemia
Hyperuricemia
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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-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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ABSORPTION OF GALACTOSE
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
ABSORPTION OF GALACTOSE
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ABSORPTION OF GALACTOSE
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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GALACTOSE METABOLISM
There are no catabolic pathways tometabolize Galactose
So the strategy is to convert Galactoseinto a metabolite of glucose
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GALACTOSE METABOLISM
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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GALACTOSE METABOLISM
Almost entirely metabolised by the liver
Cytosol of hepatocyte
GALACTOSE METABOLISM
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GALACTOSE METABOLISM
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GALACTOSE METABOLISM
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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GALACTOSE METABOLISM
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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GALACTOSE METABOLISM
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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GALACTOSE METABOLISM
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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GALACTOSE METABOLISM
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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GALACTOSE METABOLISM
Step 6 - UDP-Galactose isrecycled back toUDP-Glucose by UDP Galactose 4-Epimerase (GALE)
GALACTOSE METABOLISM
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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
GALACTOSE METABOLISM
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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