1. Metabolism of pentoses, glycogen, fructose and galactose
Jana Novotna

2. 1. The Pentose Phosphate Pathway

3. The pentose phosphate pathway (PPP): (hexose monophosphate or 6-phosphogluconate patway)
Process that generates NADPH and pentoses (5-carbon sugars).
Enzymes are located in the cytosol.
Rapidly dividing cells (bone marrow, skin, intestinal mucosa, tumors)  ribose 5-phosphate  RNA, DNA.
Other tissues  NADPH  electron donor for reductive biosynthetic reactions
fatty acids synthesis (liver, adipose tissue),
cholesterol and steroid hormones synthesis (liver, adrenal glands, gonads)
elimination of oxygen radicals effects (erythrocytes).

5. An overview:

6. Two stages:
Oxidative (irreversible)
products:
→ ribose 5-phosphate (nucleotide synthesis)
→ NADPH (fatty acid synthesis, detoxification, reduction of glutathion)
2) Nonoxidative (reversible)
conversion of ribose 5-phosphate to intermediates of glycolysis
production of ribose 5-phosphate from intermediates of glycolysis

7. 1. The oxidative phase of PPP:
Regulation:
Glucose 6-phosphate dehydrogenase
inhibition - by NADPH
induction - by insulin/gluckagon ↑

8. Some concepts
Isomers - molecules with the same molecular formula but different chemical structures (glucose and fructose)
Epimeres - differ at only one chiral center, not the anomeric carbon.
Enantiomers - chiral molecules that are mirror images of one another.
Epimers
Enantiomers

9. 2. The nonoxidative phase of PPP:

10. Pathways that require NADPH:
Detoxification
reduction of oxidized glutathione
cytochrome P450 monooxygenases
Reductive synthesis
fatty acid synthesis
fatty acid chain elongation
cholesterol synthesis
steroid hormon synthesis
neurotransmitter synthesis
deoxynucleotide synthesis

11. The role of PPP in maintenance of the erythrocyte membrane integrity:

12. Clinical correlations:
Treatment by certain drugs (i.e. sulfonamides)
people with glucose 6-phosphate dehydrogenase deficiency (7% of the world population)
increased production of free radicals
reduced protection of erythrocytes against FR
hemolysis, hemoglobinuria, hemolytic anemia

13. Summary: The pentose phosphate pathway A shunt from glycolysis
Production of NADPH (reductive syntheses, detoxifications), ribose 5-phospate
Conversion to intermediates of glycolysis
Isomerases, epimerases, transketolases, transaldolases
Glucose 6-phosphate dehydrogenase deficiency

14. 2. Metabolism of glycogen

15. Glycogen The glycogen – a storage form of glucose
Required as a ready source of energy
The liver – tremendous capacity for storing glycogen – 10% of the wet weight
Muscle – max.1 – 2% of the wet weight
Muscle and liver glycogen stores serve completely different roles:
muscle glycogen – fuel reserve for ATP synthesis
liver glycogen – glucose reserve for the maintenance of blood glucose concentration

16. source of energy in animals (liver, muscles)
Glucosyl units of α-D-glucose linked by α-1,4 and α-1,6 link (branching every 8-10 units)
source of energy in animals (liver, muscles)
highly branched structure (rapid degradation and synthesis, better solubility)
Nonreducing end
glycogenin

17. The glycogen metabolism in the muscles and the liver:
Decrease in glucose in the blood
→ glycogen degradation
→ release of glucose to the blood
Glucose 6-phosphatase (only in liver)
High ATP demand
→ glycogen degradation
→ anaerobic glycolysis

18. Glycogen metabolism - an overview:
Synthesis and degradation of glycogen:
→ different enzymes (regulation!)

19. UDP-glucose – the substrate for glycogen synthesis and UDP is released as a reaction product
glucose-1-phosphate + UTP  UDP-glucose + PPi
PPi + H2O  2 Pi
Overall: glucose-1-phosphate + UTP  UDP-glucose + 2 Pi
Cleavage of PPi is the only energy cost for glycogen synthesis (one ~P bond per glucose residue).

20. Glycogenin - (enzyme) initiates glycogen synthesis.
Glycogenin is an enzyme that catalyzes attachment of a glucose molecule to one of its own tyrosine residues. Glycogenin is a dimer, and evidence indicates that the two copies of the enzyme glucosylate one another.

21. Glycogen synthesis:
A glycogen primer - 4 attached glucose molecules to glycogenin
- not degraded
- synthesis autocatalytic glycosylation, autophosphorylation of glycogenin)
Transfer of 6-8 units
Glycogen synthase (regulation)
An energy-requiring pathway (UTP)

22. Glycogen degradation:
Chain cleavage (phosphorolysis) –glycogen phosphorylase
- to 4 units from a branch point
The debrancher enzyme - amylo-16 glukosydase (transfer of 3 units, hydrolysis of 1 glucose)
two catalytic activities – transferase + a-16-glucosydase
Glycogen phosphorylase (regulation)

23. Glycogen storage diseases:
Type
Enzyme affected
Genetics
Organ involved
Manifestations
I (Von Gierke´s disease)
Glucose 6-phosphatase
AR (1/ )
Liver
Hypoglycemia, lactate acidosis, hyperlipidemia, hyperuricemia.
Enlarged liver and kidney.
II (Pompe disease)
Lysosomal α-1,4-glucosidase AR
Organs with lysosomes
Glycogen deposits in lysosomes.
Hypotonia, cardiomegaly, cardiomyopathy (Infantile f.).
Muscle weakness (Adult f.)
III (Cori´s disease)
The debrancher enzyme
Liver, muscle, heart
Hepatomegaly, hypoglycemia
V (McArdles disease)
Muscle glycogen phosphorylase
Muscle
Exercise-induced muscular pain, cramps, muscle weakness

24. Regulation of glycogen synthase by covalent modification

25. Regulation of glycogen phosphorylase by covalent modification

26. Regulation of glycogen synthesis and degradation in the liver

27. Activation of muscle glycogen phosphorylase during exercise
Activation of muscle glycogen phosphorylase during exercise. Glycogenolysis in skeletal muscle is initiated by muscle contraction, neural impulses, and epinepherine. (1) AMP produced from the degradation of ATP during muscle contraction allosterically activates glycogen phosphorylase b (2) The neural impulses that initiate contraction release Ca2+ from sarcoplasmic reticulum. The Ca2+ binds to calmodulin, which is a modifier protein that activates phosphorylase kinase. (3) Phosphorylase kinase is also activated through phosphorylation by protein kinase A. The formation of cAMP and the resultant activation of protein kinase A are initiated by binding of epinephrine to plasma membrane receptor.

28. Clinical correlations:
Maternal malnutrition in the last trimester of pregnancy
(physiologically: glycogen formation and storage during the last 10 weeks of pregnancy by the fetus → reserve for first hours → prevention of hypoglycemia)
reduced or no glycogen reserve in the fetus
after birth → hypoglycemia, apathy, coma

29. Regulation of liver and muscle glycogen metabolism:
State
Regulators
Response
Liver
Fasting
Glucagon ↑, Insulin ↓
cAMP ↑
Glycogen degradation ↑
Glycogen synthesis ↓
Carbohydrate meal
Glu ↑, Glucagon ↓, Insulin ↑
cAMP ↓
Glycogen degradation ↓ Glycogen synthesis ↑
Exercise and stress
Adrenalin ↑
cAMP ↑, Ca2+-calmodulin ↑
Glycogen degradation ↑ Glycogen synthesis ↓
Muscle
Fasting (rest)
Insulin ↓
Glucose transport ↓
Carbohydrate meal (rest)
Insulin ↑
Glycogen synthesis ↑
Glucose transport ↑
Exercise
Epinephrine ↑
AMP ↑, Ca2+-calmodulin ↑, cAMP ↑
Glycolysis ↑

30. Summary: Glycogen metabolism
Different role of glycogen stores in the liver and muscles
Glycogen synthesis and degradation are separate pathways (regulation)
Glycogen storage diseases

31. 3. Fructose and Galactose metabolism

32. Fructose metabolism Principally in the liver (small intestine, kidney)
Essential fructosuria
Hereditary fructose intolerance
Principally in the liver (small intestine, kidney)
Aldolase B: low affinity for fructose 1-phosphate (→ accumulation of fructose 1-phosphate in the liver )

33. The polyol pathway Seminal vesicles (spermatozoa use fructose)
Accumulation of sorbitol in diabetic patients
Lens (diabetic cataract)
Muscles, nerves (periferal neuropathy)

34. Galactose metabolism:

35. Lens metabolism: Diabetic cataract :
↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol accumulation → ↑osmolarity, structural changes of proteins

36. Clinical correlations:
A newborn: failure to thrive, vomiting and diarrhea after milk
galactosemia (Galactose 1-phosphate uridylyltransferase deficiency)
genetic disease (AR, 1/60 000)
hepatomegaly, jaundice, cataracts, mental retargation, death
Management: early diagnose, elimination of galactose from the diet (artificial milk from soybean hydrolysate)

37. Summary: Fructose and Galactose metabolism
Conversion to intermediates of glycolysis
Genetic abnormalities, accumulation of intermediates, tissue damage
Accumulation of sorbitol in diabetes

38. Pictures used in the presentation:
Marks´ Basic Medical Biochemistry A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks)
Textbook of Biochemistry with Clinical Correlations, sixth edition, 2006 (T.M. Devlin)