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

Transcription

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).

4 Two stages: 1) Oxidative (irreversible) products: 2) Nonoxidative (reversible) ribose 5-phosphate (nucleotide synthesis) NADPH (fatty acid synthesis, detoxification, reduction of glutathion) conversion of ribose 5-phosphate to intermediates of glycolysis production of ribose 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 An overview:

8 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

9 The role of PPP in maintenance of the erythrocyte membrane integrity:

10 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

11 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

12 2. Metabolism of glycogen

13 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

14 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

15 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

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

17 UDP-glucose the substrate for glycogen synthesis and UDP is released as a reaction product glucose-1-phosphate + UTP UDP-glucose + PPi PPi + H 2 O 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).

18 Glycogenin - (enzyme) initiates glycogen synthesis.

19 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)

20 Glycogen degradation: Chain cleavage (phosphorolysis) glycogen phosphorylase - to 4 units from a branch point -The debrancher enzyme - amylo-16 glukosydase (transfer of 3 units, hydrolysis of 1 glucose) -two catalytic activities transferase + α-16- glucosydase Glycogen phosphorylase (regulation)

21 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 AR Liver, muscle, heart Hepatomegaly, hypoglycemia V (McArdles disease) Muscle glycogen phosphorylase AR Muscle Exercise-induced muscular pain, cramps, muscle weakness

22 Regulation of glycogen synthase by covalent modification

23 Regulation of glycogen phosphorylase by covalent modification

24 Activation of muscle glycogen phosphorylase during exercise

25 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

26 Regulation of liver and muscle glycogen metabolism: State Liver Fasting Carbohydrate meal Exercise and stress Muscle Fasting (rest) Carbohydrate meal (rest) Exercise Regulators Glucagon, Insulin camp Glu, Glucagon, Insulin camp Adrenalin camp, Ca 2+ -calmodulin Insulin Insulin Epinephrine AMP, Ca 2+ -calmodulin, camp Response Glycogen degradation Glycogen synthesis Glycogen degradation Glycogen synthesis Glycogen degradation Glycogen synthesis Glycogen synthesis Glucose transport Glycogen synthesis Glucose transport Glycogen synthesis Glycogen degradation Glycolysis

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

28 3. Fructose and Galactose metabolism

29 Fructose metabolism 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 )

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

31 Galactose metabolism:

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

33 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)

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

35 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)