1. Metabolism of pentoses, glycogen, fructose and galactose Alice Skoumalová

2. 1. The Pentose Phosphate Pathway

3. An overview:

4. The pentose phosphate pathway (PPP):  occurs in the cytosol  in all cells  Two stages: 1)Oxidative (irreversible) Products: → Ribulose 5-phosphate (nucleotide synthesis) → NADPH (fatty acid synthesis, detoxification, reduction of glutathion) 2)Nonoxidative (reversible) Conversion of Ribulose 5-phosphate to intermediates of glycolysis Production of Ribulose 5-phosphate from intermediates of glycolysis

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

6. 2. The nonoxidative phase of PPP:

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

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

9. Pathways that require NADPH: Detoxification Reduction of oxidized glutathione Cytochrome P450 monooxygenases Reductive synthesis Fatty acid synthesis Fatty acid chain elongation Cholesterol synthesis Neurotransmitter synthesis Deoxynucleotide synthesis Superoxide synthesis

10. 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

11. 2. Metabolism of glycogen

12. Glycogen  α-D-Glucose, 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

13. The role of glycogen in muscles and 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

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

15. Glycogen synthesis:  A glycogen primer - not degraded - synthesis (autophosphorylation of glycogenin)  Transfer of 6-8 units  Glycogen synthase (regulation)  An energy-requiring pathway (UTP)

16. Glycogen degradation:  Chain cleavage (phosphorolysis) - to 4 units from a branch point - The debrancher enzyme (transfer of 3 units, hydrolysis of 1 glucose)  Glycogen phosphorylase (regulation)

17. TypeEnzyme affectedGeneticsOrgan involved Manifestations I (Von Gierke´s disease) Glucose 6- phosphatase AR (1/200 000) LiverHypoglycemia, lactate acidosis, hyperlipidemia, hyperuricemia. Enlarged liver and kidney. II (Pompe disease) Lysosomal α-1,4- glucosidase AROrgans with lysosomes Glycogen deposits in lysosomes. Hypotonia, cardiomegaly, cardiomyopathy (Infantile f.). Muscle weakness (Adult f.) III (Cori´s disease) The debrancher enzyme ARLiver, muscle, heart Hepatomegaly, hypoglycemia V (McArdles disease) Muscle glycogen phosphorylase ARMuscleExercise-induced muscular pain, cramps, muscle weakness Glycogen storage diseases:

18. 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

19. StateRegulatorsResponse Liver FastingGlucagon ↑, Insulin ↓ cAMP ↑ Glycogen degradation ↑ Glycogen synthesis ↓ Carbohydrate mealGlu ↑, Glucagon ↓, Insulin ↑ cAMP ↓ Glycogen degradation ↓ Glycogen synthesis ↑ Exercise and stressAdrenalin ↑ cAMP ↑, Ca 2+ -calmodulin ↑ Glycogen degradation ↑ Glycogen synthesis ↓ Muscle Fasting (rest)Insulin ↓Glycogen synthesis ↓ Glucose transport ↓ Carbohydrate meal (rest)Insulin ↑Glycogen synthesis ↑ Glucose transport ↑ ExerciseEpinephrine ↑ AMP ↑, Ca 2+ -calmodulin ↑, cAMP ↑ Glycogen synthesis ↓ Glycogen degradation ↑ Glycolysis ↑ Regulation of liver and muscle glycogen metabolism:

20. Regulation of glycogenolysis in the liver by glucagon: cAMP → protein kinase A: 1. inactivates glycogen synthase 2. activates glycogen phosphorylase

21. Regulation of glycogenolysis in muscle:

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

23. 3. Fructose and Galactose metabolism

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

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

26. Galactose metabolism:

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

28. 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)

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

30. 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)