1. Fructose and galactose metabolism Uronic acid pathway
Dr.Soumitra Chakravarty MD

2. Learning objectives:
List the key enzymes of Galactose and Fructose metabolism
Differentiate the clinical features and the enzyme deficiency in essential Fructosuria and hereditary fructose intolerance
Differentiate the clinical features and enzyme deficiency in non classical and classical Galactosemia
Briefly describe lactose intolerance and its clinical manifestations
Describe the pathogenesis of Diabetes Mellitus and its complications.

3. URONIC ACID PATHWAY SYNTHESIZES URONIC ACID
URONIC ACID IS REQUIRED FOR :-
A. Synthesis of GAGs  Synthesis of Glycoproteins and Proteoglycans
B. Conjugation of Bilirubin and Drugs

5. Features of Fructose metabolism
Fructose enters glycolysis either as fructose 6-po4 or fructose 1-po4.
Phosphorylation by Hexokinase or fructokinase
Fructokinase found in liver, kidney and small intestine
Hexokinase in skeletal muscle and most organs

6. Features of Fructose metabolism
Entry of fructose into the cells is – not dependent on insulin.
Phosphorylation to fructose -1- phosphate by enzyme fructokinase in liver.
Is not dependent on amount of fructose in plasma
Is not dependent on insulin.
In extra hepatic tissues: glucose competes with fructose for hexokinase.

7. Fructose metabolism
Muscle which contains only hexokinase  phosphorylates fructose to F6P which is a direct glycolytic intermediate.
Hepatic fructose is phosphorylated on C-1 by fructokinase yielding fructose-1-phosphate.

8. Differences between enzymes of Glycolysis
Hexokinase
Glucokinase
Fructokinase
Substrate
All Hexoses
Glucose
Fructose
Location
All tissues
Liver
Affinity
High affinity
(Glucose> Fructose)
Low affinity
High affinity for FRUCTOSE
Velocity of reaction
Slow
Fast
Phosphorylation POSITION
6-PO4
1-PO4
Bypass rate limiting step (PFK-1) No
Yes
Regulation by insulin
Not regulated
Regulated

9. Uric acid
SLOWER
FASTER

10. Aldolase A , B and C.
Aldolase B is present in liver, kidney and small intestine converts fructose 1-P into DHAP and glyceraldehyde.
Aldolase A is a glycolytic enzyme in all other tissues.
Aldolase C is present in Brainsimilar to aldolase A

11. Kinetics of metabolism
Rate of fructose metabolism > rate of glycolysis since fructokinase/Aldolase B bypasses PFK-1 – the rate limiting step of glycolysis.
Elevated levels of dietary fructose 
increased rate of lipogenesis( fatty acid and triglyceride synthesis) in liver as a result of Acetyl CoA and glycerol-3-PO4 accumulation formed by the more rapid fructose metabolism .
Remember – Sucrose contains glucose + fructose !!

12. Role of FRUCTOSE in body
PROVIDES ENERGY
SEMINAL PLASMA – ENERGY REQUIRED FOR MOBILITY OF SPERMATOZOA
Secreted by Seminal Vesicle

13. Disorders of fructose metabolism
ATP
Fructokinase
Essential Fructosuria
def
ADP
Fructose-1-Po4
Aldolase B
Hereditary Fructose intolerance
def
Glyceraldehyde
Dihydroxyacetone phosphate

14. Essential fructosuria
Fructokinase deficiency:
Autosomal recessive – benign condition
Excretion of fructose in urine [ no other abnormality]
Wrong diagnosis of Diabetes mellitus
Treatment  Avoid fructose .

15. Hereditary Fructose intolerance
Deficiency of aldolase B
Accumulation of fructose-1- phosphate
Deficiency of phosphates in cells.
Liver failure
Hypoglycemia
Hyperuricemia
Liver failure – glycogen accumulation.

16. Hypoglycemia
Inhibition of glycogen phosphorylase. +
Depletion of ATP also hampers Gluconeogenesis
Depletion of ATP.AMP rises and in absence of inorganic Pi , AMP is destroyedHyperuricemia
(because the end product of purine catabolism is Uric acid )

17. Clinical features :- Acute ingestion – vomiting, nausea etc.
Prolonged fructose ingestion in infants leads to poor feeding, vomiting, hepatomegaly, jaundice, hemorrhage, proximal‐renal‐tubule syndrome (fanconi like syndrome)
Note :- Don’t confuse facconi’s syndrome with Fanconi’s anaemia !!

18. Conversion of glucose to fructose
Aldose reductase – lens, retina, kidney cells, Schwann cells, placenta, cells of ovaries and seminal vesicles.
Aldose reductase
Sorbitol dehydrogenase
No sorbitol
dehydrogenase

19. Compliations due to increased glucose:
Hyperglycemia (as in diabetes) results in elevated levels of intracellular glucose in lens, nerve, kidney.
This leads to water retention in these tissues due to osmotic effects of sorbitol swelling, cataract, peripheral neuropathy and vascular problems  nephropathy and retinopathy as complications of diabetes

20. Some consequences of the formation of AGEs
Harpe29th ed
Some consequences of the formation of AGEs

21. Metabolism of galactose

22. Functions of Galactose in Body
Energy Converted to Glucose
Synthesis of Lactose
Synthesis of Glycosaminoglycans Glycoproteins and Proteoglycans

23. Harper 29th Galactose Glycogen Glucose 1P Galactose 1p Glucose 1P

24. Galactose Galactose 1 P UDP Glc UDP Gal Glucose 1 P Glucose 6 P
GALACTOKINASE
Galactose 1 P
UDP Glc
UDP Gal
GALACTOSE 1 P URIDYL TRANSFERASE
Glucose 1 P
Glucose 6 P
Glucose

25. Galactokinase deficiency
Galactose 1-phosphate uridyl transferase deficiency
UDP-galactose 4 epimerase deficiency.

26. UDP -Galactose UDP-galactose is required for biosynthesis of: Lactose
Glycoproteins
Glycosaminoglycans
Glycolipids

27. Non Classical Galactosemia
Deficiency of enzyme Galactokinase
Autosomal recessive
Less severe compared to classic type.
Early onset of cataract in first few months of life.

28. Classical Galactosemia
Galactose 1-phosphate uridyltransferase deficiency (GALT) deficiency
Galactosemia, Galactosuria, vomiting, Diarrhoea, jaundice, cataract formation
Liver damage- cirrhosis and brain damage - mental retardation
Accumulation would inhibit the production of the second messenger inositol in the signalling system and hence causing a mental retardation.

29. Lippincott’s

30. Galactitol
Liver Damage and Cirrhosis due to accumulation of Gal-1P
Gal-1P gets deposited in Renal tubules

31. Lactose intolerance Deficiency of Lactase enzyme in the GUT.
Loose stools after consuming milk.
Seen mostly with new born or adults.
Unabsorbed lactose enters colon.
Broken by bacteria – produce gas
Unabsorbed lactose – causes osmotic diarrhoea.
Stool acidity test -
Intestinal biopsy -
Breath test – hydrogen and methane

32. A newborn vomits after each feeding of milk based formula and does not gain weight. Biochemical testing reveals a severe def of Galactose-1-phosphate uridyl transferase. If this condition goes untreated, which of the following is the likely outcome for this patient?
Benign disease except for cataract formation
Chronic emphysema appearing in early adulthood
Chronic renal failure appearing in adolescence
Mental retardation and later death in infancy
Gastrointestinal symptoms that remit with puberty

33. A 4-month-old infant is brought to emergency clinic by the parents in an unconscious state. The mother complains that the child has had repeated attacks of unconsciousness, especially in the night, in the past few months. On examination, the child had massive Hepatomegaly. Biochemical tests revealed that the blood glucose level was 40mg/dL. The lactate and triglyceride and uric acid levels in circulation were increased. Urine did not contain any reducing sugar. The developmental milestones of the child were normal; however, the weight gain of the infant was poor. Administration of glucagon failed to increase the blood glucose level. What is the most probable biochemical defect?
Von Gierke disease
Classical Galactosemia
Hereditary fructose intolerance
Essential Fructosuria
Medium chain acyl Co-A dehydrogenase deficiency