Lecture 7 by Prof.Dr.Munaf S. Daoud
Galactose , Lactose & Fructose
Metabolism
Objectives:
● Describe the metabolism of Gal,Frc and
synthesis of Lac
● Determine the deleterious effect of
excess Glc, Frc & Lac ingestion in some
conditions
● List some Inborn Errors of Gal,Frc & Lac
metabolism
Galactose ( Gal)
● It is important in cerebrocytes , brain &
cartilage and also + Glc forms the disaccharide
lactose in mammary glands.
● Reactions:
▪ Gal + ATP by
galactokinase
→ Gal1-P
▪ Gal1-P + UDP-Glc by
Gal1-P
Uridyltransferase
(
Gal1PUT
) →
Glc1-P + UDP-Gal
▪ UDP-Gal by
4-Epimerase
↔ UDP-Glc
☻Genetic defect; Deficiency of :
galactokinase
– Galactosemia & Galactosuria
Gal1PUT
– Classical Galactosemia
4- epimerase
- Galactosemia
Galactosemia – an Inborn error of CHO ( Gal)
↑ Gal(blood) → ↑ Gal diffusion into Eye lens
& by H
2
Reductase
→ Galacitol
(impermeable) &
accumulate in lens → ↑
osmotic pressure & H
2
O retention
(
swelling) → Myopia ( damage of lens
tissues → Cataracts.
Case: a male infant exhibits difficulty to feed,
diarrhea , vomiting & failure to thrive
( grow). At 5 days of age, exhibits
mild jaundice & enlarged liver
(Hepatomegaly).
●Gal is necessary for Lac formation in Mammary
gland.
UDP-Gal + Glc by
Lac Synthetase
[
Gal
transferase
(Protein A ) + Cofactor
α-Lactalbumin
(Protein B)] → Lactose.
Protein B (
α- Lactalbumin
) occurs in the last 3
months of pregnancy (Trimester 7,8,9 months)
and after birth when progesterone level is
decreased . Prior to & during pregnancy
( absence of protein B) the mammary gland
synthesize:
UDP-Gal +
N-AcetylGlcN(Acetylglucosamine
)→
N-Acetyllactosamine
Progesterone inhibits the synthesis of Protein B
and after birth Prog. Levels ↓ significantly
leading to ↑ synthesis of Prolactin leading to
↑ α- Lactalbumin .
● UDP-Gal is also used in synthesis of
Glycolipids,Glycoprotein &
Glycosaminoglycans(GAGs).
☺How can Glc synthesize Lactose?
Glc→ Glc6-P → Glc1-P → UDP-Glc→
UDP-
Gal + Glc → Lactose
Lactose (Gal + Glc)
source: milk ( synthesized in mammary gland)
● Lactase ( B-galactosidase ) found in
intestine hydrolyse it into Gal+Glc to be
transported by portal circulation to liver.
☻Genetic defect: Deficiency of Lactase
called Alactasia
→
Lactose Intolerance
.
Abnormally lactose move to Large Intestine
to be broken down by Bacteria into H
2
, 3-C
& 2-C metabolites and CO
2
causing Bloating
( flatulance),Diarrhea & Dehydration. H
2
can
be measured in the breath .
This case occurs in Infants, milk which is their
primary food is not tolerable & lactose-free formula is
used instead ( soya milk ).
In adults , the condition is less serious & is treated
by avoiding milk & its products.
Fructose ( Frc ) metabolism
source: sucrose,fruits,honey
● Reactions:
▪ Frc.+ATP
by fructokinase
→Frc1-P+ADP
▪Frc1-P
by Aldolase B
→DHAP+Glyceraldehyde
▪ DHAP
by isomerase
→ Glycerald.3-P ( link
with Glycolysis)
▪
Glyceraldehyde
activated by kinase
→
Glyceraldehyde 3-P
or
reduced to glycerol
( link with glycolysis &
gluconeogenesis )
or
oxidized to glycerate
( in serine synthesis )
●
Fructokinase
( liver,kidney,intestine) ,
specific for Frc. , not affected by feeding-
fasting cycles nor by insulin levels ( which
may explain why it is cleared from blood of
Diabetic patients at a normal rate ).
●
Aldolase B
( cleavage enzyme) found
predominantly in liver.
☻ Genetic defect; Deficiency of
Fructokinase
→
Essential Fructosuria
Aldolase B
→
HereditaryFrc.Intolerance(HFI)
▪ In Essential Fructosuria
, Frc. is accumulated &
in
HFI
, Frc1P is accumulated.
● Diets high in Sucrose or High-Frc Syrup
( HFS) used in manufactured foods & beverages
→ ↑ Frc & Glc entering the liver.
Frc undergoes more rapid glycolysis
( fructolysis) in the liver than Glc , because it
bypass the regulatory step catalyzed by PFK-1
allowing Frc to flood the pathways & lead to
enhanced fatty acid synthesis, ↑ esterification of
fatty acids & ↑ VLDL secretion → ↑ Triglyceride (
i.e.TAG) &
then ↑ LDL-cholesterol.
This is not happening in other tissues
( Muscles & Adipose) because Glc inhibits
phosphorylation of Frc .
●
HFI
occurs in Infants after ablactation breast
feeding stop ) & food ( sucrose ) intake associated
with Deficiency of the enzyme
fructose
1,6bisPhosphatase (Frc1,6bisPase)
lead to Frc1P & Frc1,6bisP accumulation in liver.
Glycolysis is normal.These two compounds will
allosterically inhibit liver Glycogen phosphorylase,
despite the presence of high Glycogen reserves.
This inhibition causes
Frc-induced Hypoglycemia
& liver enlargement ( Hepatomegaly).
● Frc also causes
Sequestration of phosphate
(Pi)
.
↑ Frc ingestion → ↑ ATP utilization for
phosphorylation → ↓ [ ATP] and ↓[ Pi] available
to participate in other essential metabolic
reactions &
↑ [ ADP ]. The depletion of ATP &
repletion of ADP cause ;
↑ levels of Purine nitrogenous base (Adenine)
and → ↑ Uric acid formation causing
Hyperuricemia & Gout
.
● In case of
hyperglycemia
(e.g.
Uncontrolled DM)
large amounts of Glc enter different tissue cells .
Glc is utilized for E production by Glycolysis ; But
when Glc is in excess, utilization differs according
to the tissue:
1- Liver, Seminal vesicles, Ovaries & Sperm cells
Excess Glc + NADPH
by Aldose Reductase
→
Sorbitol + NADP
Sorbitol + NAD
by Sorbitol Dehydrogenase
→ Frc + NADH
This pathway of Glc conversion to Frc by way of
Sorbitol is called Polyol pathway .
2- Kidney , Nerve ,Eye ( Lens & Retina) cells
Sorbitol is trapped inside the cells because
its Dehydrogenase
is low or absent . It
accumulates causing strong Osmotic effects
(H
2
O move into the cells causing H
2
O retention)
resulting in Swelling. Some pathologic alterations
associated with
Diabetes mellitus
can
be attributed to this phenomenon i.e.
Nephropathy , Neuropathy & Retinopathy
.