Cho Metabolism Lect 3 PDF

CHO Metabolism Lect 3 Dr. Abeer Ahmed THE HEXOSE MONOPHOSPHATE SHUNT (HMP-SHUNT)= THE PENTOSE PHOSPHATE PATHWAY  The HMP shunt is an alternative major pathway for the oxidation of glucose. ATP is neither produced nor utilized. Site: the enzymes of the pentose phosphate pathway...

CHO Metabolism Lect 3 Dr. Abeer Ahmed THE HEXOSE MONOPHOSPHATE SHUNT (HMP-SHUNT)= THE PENTOSE PHOSPHATE PATHWAY  The HMP shunt is an alternative major pathway for the oxidation of glucose. ATP is neither produced nor utilized. Site: the enzymes of the pentose phosphate pathway are found in the cytoplasm of many tissues e.g. liver, lactating mammary gland, adipose tissues, erythrocytes (RBCs) and adrenal cortex. Steps: - The reactions of HMP-shunt occur in 2 phases 1-Oxidative (irreversible) phase: - ✓ Where 3 molecules of glucose are converted into 3 molecules of ribulose-5-P with production of NADPH+H+ and 3CO2 2-non-oxidative (reversible) phase: - ✓ Where 3 molecules of ribulose-5-P are converted into 2 molecules of glucose-6-P and 1 molecule of glyceraldehyde-3-P. Importance of the pentose phosphate pathway: A. Generation of NADPH+H+ NADPH is essential for the reductive synthesis which includes: {Fatty acid synthesis, steroid synthesis, amino acid synthesis and synthesis of reduced glutathione in erythrocytes}. B. Generation of ribose residues: The ribose residues are used for nucleotide and nucleic acid synthesis (DNA & RNA). Reduced glutathione is needed for: 1. Maintenance of the normal integrity of RBCs by removal of hydrogen peroxide (H2O2), which is a toxic compound that increases cell membrane fragility by glutathione peroxidase. 2. Detoxification of many drugs and carcinogens. Regulation of HMP shunt: - Glucose-6-phosphate dehydrogenase is the key enzyme of HMP shunt. It is stimulated by insulin and NADP+ and inhibited by NADPH+H+. Favism - Favism is an inherited disease, which is manifested as red cell hemolysis. It results from deficiency of the enzyme glucose-6-phosphate dehydrogenase with consequent deficiency of NADPH+H. NADPH+H+ is required to reduce the oxidized glutathione glutathione reductase By the action of glutathione peroxidase, in the red cells, reduced glutathione will attack H2O2 (hemolysis) hydrolyzing it to H2O. Precipitating factors: Fava beans, infection, antimalarial drugs, aspirin and antibiotics as sulfonamides.  An alternative pathway for the oxidation of glucose glucose to glucorunic acid (UDP-glucuronic acid) Conjugation reactions with certain substances e.g. steroid hormones, certain drugs and bilirubin. Ascorbic acid in all animals except humans. Pentoses. No generation of ATP Site: It occurs in the cytoplasm of many tissues. GLYCOGEN METABOLISM  GLYCOGEN SYNTHESIS (GLYCOGENESIS) Glycogenesis is the process by which glycogen is synthesized from glucose It occurs in the cytoplasm of the liver and muscle.  Glycogen is the storage form of carbohydrate in animals. It is stored mainly in the liver and muscles. Liver glycogen Muscle glycogen 1- Occurs in the liver. - Occurs in muscle. 2- It constitutes up to 5% of liver weight. - Rarely exceeds 1% of total muscle weight. 3- It is concerned with storage and export of glucose for - Acts as a source of glucose for glycolysis maintenance of blood glucose during early stage of fasting. within the muscle itself. 4- Depletion occurs after 12-18 hours of fasting. - Depletion occurs after prolonged vigorous exercise. 5-Glucagon (anti-insulin) stimulates glycogenolysis. - No effect  Figure showing steps of glycogenesis Pathway 1. Formation of UDP - glucose (UDP-G); a) Glycogen primer (protein- glycogenin) UDP - glucose residues are added and linked by α1-4 linkage b) Glycogen synthase (key regulatory) enzyme catalyzes formation α 1-4 glucosidic bond c) Branching enzyme: transfers about 6 glucose units of the elongated chain to a neighboring chain forming α1-6 glucosidic bond Steps: - 1. Formation of UDP - glucose (UDP-G); 2. Formation of glycogen from UDP - G units needs: a) Glycogen primer A protein called glycogenin where UDP - glucose residues are added up to 11 molecules of glucose linked by α1-4 linkage with the release of UDP. b) Glycogen synthase enzyme The key regulatory enzyme of glycogenesis. It elongates the primer up to 11 glucose units. It catalyzes the formation of α 1-4 glucosidic bond between C1 of the activated glucose of UDP-G and C4 of a terminal glucose c) Branching enzyme: - It transfers about 6 glucose units of the elongated chain to a neighboring chain forming α1-6 glucosidic bond forming a branch point in the molecule which is elongated by glycogen synthase. Figure showing glycogen synthesis.  GLYCOGENOLYSIS Glycogenolysis is the process of degradation of glycogen. It occurs in the cytoplasm of cells (liver and muscles).  Figure (12) showing glycogen degradation 1- Phosphorylase enzyme: key regulatory enzyme, acts on branches containing more than 4 glucose units and breaks down α l - 4 glycosidic bonds by phosphorylysis giving G-1-P 2- Glucan transferase enzyme: it transfers 3 glucose units to another branch, leaving the last one which is linked by α 1 - 6 linkage. 3- Debranching enzyme: removes the last glucose units that is attached by α 1 - 6 linkage by hydrolysis 4- G-1-P is converted to G-6-P by phosphoglucomutase. Figure showing steps of glycogenolysis Fate of glucose -6- phosphate: - ✓ In liver: - The liver contains glucose - 6 - phosphatase so it converts g - 6 - p into glucose that is released to the blood. ✓ In muscle: - It contains no glucose - 6 - phosphatase, so muscle glycogenolysis ends with G-6-P which can’t leave the muscle and pass to glycolysis. Regulation of glycogenesis and glycogenolysis There is a coordinated regulation of glycogenesis and glycogenolysis i.e. conditions stimulating glycogenesis inhibit glycogenolysis and vice versa. The key regulatory enzymes include: - covalent modifications: 1- Glycogen synthase: - present in 2 forms: a. Active dephosphorylated form (glycogen synthase a). b. Inactive phosphorylated form (glycogen synthase b). 2- Phosphorylase: - present in 2 forms: a. Active phosphorylated form (phosphorylase a). b. Inactive dephosphorylated form (phosphorylase b)  Regulation of glycogenesis DURING FASTING 1- LOW blood glucose causing release of epinephrine in muscle and liver and glucagon in liver 2- These hormones activate cAMP dependent protein kinase 3- cAMP dependent protein kinase causing a) Phosphorylation and inactivation of glycogen synthase inhibiting glycogenesis. b) Phosphorylation and activation of phosphorylase kinase that phosphorylates and activates phosphorylase enzymes inducing glycogenolysis. AFTER MEAL Regulation of glycogenolysis 1 Increased Blood glucose level stimulates insulin secretion 2- Stimulating phosphodiesterase enzyme which breaks down cAMP → no stimulation of protein kinase (no phosphorylation) 3- Stimulation of phosphatase enzyme which removes the phosphate group from enzymes. a) Stimulation of glycogenesis b) Inhibition of glycogenolysis c) Which decreases blood glucose DURING FASTING AFTER MEAL LOW blood glucose causing release of epinephrine in Increased Blood glucose level stimulates insulin muscle and liver and glucagon in liver secretion These hormones activate cAMP dependent protein Stimulation of phosphodiesterase enzyme which kinase breaks down cAMP → no stimulation of protein kinase cAMP dependent protein kinase causing Stimulation of phosphatase enzyme which removes a) Phosphorylation and inactivation of glycogen the synthase inhibiting glycogenesis. phosphate group from enzymes. b) Phosphorylation and activation of phosphorylase a) Stimulation of glycogenesis kinase that phosphorylates and activates phosphorylase b) Inhibition of glycogenolysis enzymes, activating glycogenolysis. which decreases blood glucose