METABOLISM OF GALACTOSE, FRUCTOSE & AMINO SUGARS

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Transcript of METABOLISM OF GALACTOSE, FRUCTOSE & AMINO SUGARS

Gandham.RajeevEmail:[email protected]

• Lactose, present in milk & milk products.

• Principal dietary source of galactose.

• Lactase ( β-galactosidase ) of intestinal

mucosal cells hydrolyses lactose to galactose

and glucose.

• Galactose is also produced from lysosomal

degradation of glycoproteins & glycolipids.

• Galactose is metabolised almost exclusively

by the liver and therefore galactose

tolerance test is done to assess the functional

capacity of the liver

• UDP-galactose is the active donor of

galactose during synthetic reactions

• Step: 1

• Galactokinase reaction:

• Galactose is first phosphorylated by

galactokinase to galactose -1- phosphate

• Step: 2

• Galactose -1- phosphate uridyl transferase

• This is the rate limiting enzyme.

• Galactose 1-phosphate reacts with UDP-

glucose to form UDP-galactose & glucose 1-

phosphate, in the presence of the enzyme

Galactose 1-phosphate uridyl transferase

• UDP-galactose is an active donor of galactose.

• UDP-galactose is essential for the formation of

compounds like lactose, glycosaminoglycans,

glycoproteins, cerebrosides & glycolipids.

• Step: 3

• Epimerase reaction:

• UDP-galactose can be converted to UDP-

glucose by UDP hexose 4-epimerase

• Galactose is channeled to the metabolism of

glucose.

• Galactose is not an essential nutrient since

UDP-glucose can be converted to UDP –

galactose by the enzyme UDP-hexose 4-

epimerase and requires NAD+

• Galactose is not essential in diet

• Step: 4

• Alternate pathway:

• The galactose 1-phosphate

pyrophosphorylase in liver becomes active

only after 4 or 5 years of life

• The enzyme will produce UDP-galactose

directly which can be epimerized to UDP-

glucose.

Galactose

Galactose 1-phosphate

Glucose 1-phosphate

Glucose 6-phosphate

Glycolysis Glucose

Galactitol

UDP-Glucose

UDP-Galactose

Lactose GAGSGlycolipids

Glycoproteins

NADP

ATP

ADPGalactokinase

Gala-1-Pho-Uridyl transferase

Epi

merase

MutaseSynthase

Galactose Metabolism

Disorders of galactose metabolism

• Classical galactosemia:

• Due to deficiency of enzyme galactose 1-

phosphate uridyltransferase

• Rare congenital disease in infants

• Inherited as an autosomal recessive disorder

Salient features

• Due to the block in this enzyme, galactose 1-

phosphate will accumulate in liver.

• This will inhibit galactokinase as well as

glycogen phosphorylase

• It results in hypoglycemia.

• Galactose cannot be converted to glucose

• Increased galactose level increases insulin

secretion, which lowers blood glucose level.

• Galactose metabolism is impaired leading to

increased galactose levels in circulation

(galactosemia) & urine (galactosuria)

• Bilirubin uptake is less & bilirubin conjugation

is reduced.

• Unconjugated bilirubin level is increased.

• There is enlargement of liver, jaundice &

severe mental retardation – due to

accumilation of galactose & galactose 1-

phosphate.

Galactosemia

Development of cataracts

• Causes:

• Excess of galactose in lens is reduced to galactitol

(dulcitol) by the enzyme aldose reductase

• Galactitol cannot escape from lens cells

• Osmotic effect of the sugar alcohol contributes to

injury of lens proteins & development of cataracts.

Galactokinase deficiency

• The defect in the enzyme galactokinase.

• Results in galactosemia & galactosuria

• Dulcitol or galactitol is formed.

• Absence of hepatic and renal complications.

• Development of cataracts very rare.

• Treatment:

• Removal of galactose & lactose from the diet.

Fructose metabolism

• Fructose is present in fruit juices & honey.

• Chief dietary source is sucrose.

• Sucrose is hydrolyzed in the intestine by the

enzyme sucrase.

• Fructose is absorbed by facilitated transport

and taken by portal blood to liver.

• It is mostly converted to glucose.

• Fructose is easily metabolized & a good

source of energy

• Seminal fluid is rich in fructose &

spermatozoa utilizes fructose for energy.

• In diabetics, fructose metabolism through

sorbitol pathway may account for the

development of cataract.

Fructose metabolism

• Fructose is phosphorylated to form fructose 6-

phospate, catalyzed by the enzyme

hexokinase

• Affinity of the enzyme hexokinase for

fructose is very low

Fructose Fructose -6-p Glucose-6-p

E.M pathway

ATP ADP

Hexokinase Isomerase

• Fructose is mostly phosphorylated by

fructokinase to fructose-1-phosphate

• Fructokinase is present in liver, kidney,

muscle and intestine.

• Hexokinase can also act on fructose to

produce fructose 1-phosphate.

• Fructose-1-phosphate is cleaved to

glyceraldehyde & dihydroxy acetone

phosphate (DHAP) by aldolase B

• Glyceraldehyde is phosphorylated by

triokinase to glyceraldehyde 3-phosphate,

along with DHAP enters glycolysis or

gluconeogenesis.

Fructose entering glycolysis

Fructose

Sorbitol

Fru-1-P

Glyceraldehyde

Glycerol

Glucose

Fru-6-P

DHAP

NADP NADPH+H+

ReductaseNAD+

NADH+H+DH

Glucose 6-P

Fru 1,6-BisP

Glycerol 3-P DHAP

Glyceraldehyde 3-P

PFK F-1,6 bis-P

Hexokinase

ATP

FructokinaseATP

Aldolase B

Triokinase ATP

Glycerol kinase

ATP

DH

Glycogen

NADH+H+

NAD

• It involves the conversion of glucose to

fructose via sorbitol

• Sorbitol pathway is higher in uncontrolled

diabetes

• The enzyme aldose reductase reduces glucose

to sorbitol in the presence of NADPH

• Sorbitol is then oxidized to fructose by Sorbitol

dehydrogenase and NAD+

Sorbitol pathway

• In uncontrolled diabetes, large amounts of

glucose enter the cells which are not

dependent on insulin

• The cells with increased intracellular glucose

levels in diabetes (lens, retina, nerve cells,

kidney etc) possess high activity of aldose

reductase and sufficient supply of NADPH.

• This results in a rapid & efficient conversion of

glucose to sorbitol

• The enzyme Sorbitol Dehydrogenase is either

low in activity or absent in these cells.

• Sorbitol is not converted to fructose.

• Sorbitol cannot freely pass through the cell

membrane and accumulate in the cells.

• Sorbitol-due to its hydrophilic nature-causes

osmotic effects leading to swelling of the cells.

• Pathological changes associated with

diabetes are due to accumulation of sorbitol.

• Essential fructosuria:

• Deficiency of the enzyme hepatic fructokinase.

• Fructose is not converted to fructose 1-

phosphate.

• Excretion of fructose in urine.

• Treatment: Restriction of dietary fructose

• Urine gives positive benedicts & seliwanoff’s

test

• An autosomal recessive inborn error.

• Due to defect in the enzyme aldolase-B.

• Fructose 1-phosphate, cannot be metabolised.

• Intracellular accumulation of fructose 1-

phosphate will inhibit glycogen

phosphorylase.

• Leads to accumulation of glycogen in liver &

associated with hypoglycemia

• Vomiting, loss of appetite, hepatomegaly &

jaundice.

• If liver damage progresses, death will occur.

• Fructose is excreted in urine.

• Restriction of dietary fructose.

• One or more hydroxyl groups of the

monosaccharides are replaced by amino groups

• E.g.D-glucosamine, D-galactosamine,

mannoseamine, sialic acid.

• They are present as constituents of GAG’s,

glycolipids & glycoproteins.

• Also found in some oligosaccharides &

antibiotics.

• The amino groups of amino sugars are

sometimes acetylated e.g.N-acetyl D-glucosamine

• Fructose 6-phosphate is major precursor for

glucosamine, N-acetylgalactosamine & NANA.

• N-Acetyl neuramic acid (NAN) is derivative of N-

Acetyl mannose & pyruvic acid.

• 20% of glucose is utilized for the synthesis of

amino sugars, which mostly occurs in the

connective tissues.

Glucose

Glu-6-P Fru-6-P Glucose amine-6-P

GlucoseAmine-1-P

UDP-GlucoseAmine

N-AcetylGlucoseamine-6P

N-AcetylGlucoseamine1-P

GAGS

N-Acetylmannosamine-6-P

N-acetyl neuramic acid -9-P

UDP-N-acetylglucosamine

UDP-N-acetylgalactosamineCMP-NANA

Sialic acidGangliosidesGlycoproteins

GAGS

Glucosamine

PEP

Epimerase

Epimerase

UTP

CTP

UTP

References

• Textbook of Biochemistry-U Satyanarayana

• Textbook of Biochemistry-DM Vasudevan

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