Glycogen metabolism


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Glycogen metabolism

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  3. 3. GLUCONEOGENESIS  synthesis of glucose from noncarbohydrate precursors during longer periods of starvation  a very important pathway since the brain depends on glucose as its primary fuel (120g of the 160g daily need for glucose) and RBCs use only glucose as fuel  amount of glucose in body fluids is 20g and the amount that can be derived from glycogen is 190g  major noncarbohydrate sources are lactate, amino acids, and glycerol
  4. 4.  noncarbohydrate sources need to be first converted to either pyruvate, oxaloacetate or dihydroxyacetone phosphate (DHAP) to be converted to glucose  major site is the liver with small amount taking place in the kidneys  gluconeogenesis in the liver and kidneys helps maintain the glucose demands of the brain and muscles by increasing blood glucose levels  little occurs in the brain, skeletal muscle or heart muscle  not a reversal of glycolysis
  5. 5. NONCARBOHYDRATE SOURCES  Pyruvate is converted to glucose in the gluconeogenetic pathway  Lactate is formed by active skeletal muscle when glycolytic rate exceeds oxidative rate; becomes glucose by first converting it to pyruvate  Amino acids are derived from dietary proteins and internal protein breakdown during starvation; becomes glucose by converting them first to either pyruvate or oxaloacetate  Glycerol is derived from the hydrolysis of triacylglycerols (TAG) or triglycerides; becomes glucose by conversion first to dihydroxyacetone phosphate (DHAP)
  6. 6. IRREVERSIBLE STEPS of GLYCOLYSIS  Causes of most of the decrease in free energy in glycolysis  Bypassed steps during gluconeogenesis  Steps catalyzed by the enzymes  Hexokinase (glucose + ATP  G-6-P + ADP)  Phosphofructokinase (F-6-P + ATP  F-1,6-BP + ADP)  Pyruvate kinase (PEP + ADP  Pyruvate + ATP)
  7. 7. NEW STEPS in GLUCOSE FORMATION from PYRUVATE via GLUCONEOGENESIS  PEP is formed from pyruvate by way of oxaloacetate Pyruvate carboxylase  Pyruvate + CO2 + ATP + HOH ------------ oxaloacetate + ADP + Pi + 2H+ PEP carboxykinase  Oxaloacetate + GTP ------------- PEP + GDP + CO2  F-6-P is formed from F-1,6-BP by hydrolysis of the phosphate ester at carbon 1, an exergonic hydrolysis Fructose-1,6-bisphosphatase  Fructose-1,6-bisphosphate + HOH -------------- fructose-6-phosphate + Pi  Glucose is formed by hydrolysis of G-6-P Glucose-6-phosphatase  Glucose-6-phosphate + HOH ------------- glucose + Pi
  8. 8. RECIPROCAL REGULATION OF GLYCOLYSIS & GLUCONEOGENESIS Glucose GLUCONEOGENESIS F-2,6-BP + F-2,6-BP - Fructose-6-phosphate AMP + PFK F-1,6-BPase AMP - ATP - Citrate + Fructose-1,6-bisphosphate Citrate - Several steps ADP - H+ - PEP PEP F-1,6-BP + carboxykinase PK Oxaloacetate ATP - Pyruvate Pyruvate AcetylCoA + Alanine - carboxylase ADP -
  9. 9. GLYCOGEN  Readily mobilized storage form of glucose  very large, branched polymer of glucose residues linked via α-1,4 (straight) and α- 1,6 glycosidic bonds  branching occurs for every 10th glucose residue of the open helical polymer  not as reduced as fatty acids are and consequently not as energy-rich  serves as buffer to maintain blood sugar levels  Released glucose from glycogen can provide energy anaerobically unlike fatty acids
  10. 10.  Two major sites of glycogen storage are the liver (10% by weight) and skeletal muscles (2% by weight)  In the liver, its synthesis and degradation are regulated to maintain normal blood glucose  in the muscles, its synthesis and degradation is intended to meet the energy needs of the muscle itself  present in the cytosol as granules (10-40nm)
  11. 11. GLYCOGENOLYSIS  Consists of three steps 1. release of glucose-1-phosphate from from the nonreducing ends of glycogen (phosphorolysis) 2. remodeling of glycogen substrate to permit further degradation with a transferase and α-1,6 glucosidase 3. conversion of glucose-1-phosphate to glucose-6-phosphate for further metabolism
  12. 12. Fates of Glucose-6-Phosphate  Initial substrate for glycolysis  Can be processed by the pentose phosphate pathway to NADPH and ribose derivatives  Can be converted to free glucose in the liver, intestine and kidneys for release into the blood stream
  13. 13. Glycogen Glycogen n-1 Glycogen phosphorylase Glucose-1-phosphate Phosphoglucomutase Glucose-6-phosphate Muscle,Brain Glycolysis Glucose-6-phosphatase PPP Liver Pyruvate Glucose Ribose + NADPH Lactate CO2 + HOH Blood for use by other tissues
  14. 14. GLYCOGENESIS  Regulated by a complex system and requires a primer, glycogenin  Requires an activated form of glucose, the Uridine diphosphate glucose (UDP- glucose) formed from UTP and glucose-1- phosphate  UDP-glucose is added to the nonreducing end of glycogen using glycogen synthase, the key regulatory enzyme in glycogen synthesis  Glycogen is then remodeled for continued synthesis
  15. 15. GLYCOGEN BREAKDOWN & SYNTHESIS ARE RECIPROCALLY REGULATED Glycogen breakdown Glycogen synthesis Epinephrine Adenylate cyclase Adenylate cyclase ATP cAMP Protein kinase A Protein kinase A Phosphorylase kinase Phosphorylase kinase Glycogen synthase a Glycogen synthase b Phosphorylase b Phosphorylase a PINK – inactive GREEN - active
  16. 16. GLYCOGEN STORAGE DISEASE TYPE DEFECTIVE ORGAN AFFECTED GLYCOGEN IN CLINICAL FEATURES ENZYME AFFECTED ORGAN I (Von Gierke) Glucose-6- Liver & kidney Increased amount; Hepatomegaly, failure to thrive, phosphatase normal structure hypoglycemia, ketosis, hyperuricemia, hyperlipidemia II (Pompe dse) α-1,4 glucosidase All organs Massive increase in Cardiorespiratory failure causes amount; normal death usually before age 2 structure III (Cori dse) Amylo-1,6- Muscle & liver Increased amount; Like type 1 but milder glucosidase short outer branches (debranching) IV (Andersen Branching enzyme Liver & spleen Normal amount; very Progressive cirrhosis of the liver; dse) (α-1,4 & 1,6) long outer branches liver failure causes death before age 2 V (McArdle dse) Phosphorylase muscle Moderately Limited ability to perform increased amount; strenuous exercise because of normal structure painful muscle cramps. Otherwise patient is normal or well-developed. VI (Hers dse) Phosphorylase liver Increased amount Like type 1 but milder VII Phosphofructokina muscle Increased amount; Like type V se normal structure VIII Phosphorylase liver Increased amount; Mild liver enlargement. Mild kinase normal structure hypoglycemia
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