1.Glycogen metabolism & gluconeogenesis -Carbohydrate metabolic pathways for glucose homeostasis

2. GLYCOGEN METABOLISM 3. Liver glycogenMuscle glycogenmaintains blood glucose.supplies energy during muscle contraction. 4. Introduction Storage form of carbohydrates in animals Sites: Liver & muscleGlycogen:Functions Liver glycogen is used to maintain blood glucose. Muscle glycogen supplies energy during muscle contraction. 5. Glycogenesis It is the synthesis of glycogen from glucose. Tissue : Liver & muscle Intracellular site : Cytosol Requirements : Glycogen primer UTP, ATP Reactions :Synthesis of UDP-Glucose. Adding glucose units to glycogen primer to form linear chain of glycogen by glycogen synthase Formation of branches by branching enzyme to form glycogen. 6. 1. Synthesis of UDP-Glucose.Glucose glucokinase (liver)ATPhexokinase (muscle)ADPGlucose-6- phosphate phosphoglucomutaseGlucose-1- phosphate UDP-glucose pyrophosphorylaseUTP PPiUDP -glucose ( UDP - ) 7. Glycogen primerglycogeninGlycogen primer 8. 2. Formation linear chain of glycogen by glycogen synthaseGlycogen primer 13 UDP 13 UDPGlycogen synthase 9. 4.Formation of branches in glycogen.Branching enzyme 10. 3. Elongation of branches to form glycogen.1-6- bondElongation by glycogen synthase Formation of branches by branching enzymeGlycogen 11. GlucoseADP glucokinase (liver) ATP hexokinase (muscle) Glucose-6- phosphate phosphoglucomutase Glucose-1- phosphate UDP-glucose pyrophosphorylase PPi UTP (UDP UDP -glucose glycogenin OH Glycogen initiator synthase UDP Glycogen primer 13 UDP Glycogen synthase 13UDP Branching enzyme Elongation by glycogen synthase Formation of branches by branching enzymeGlycogen 12. Glycogenolysis It is the degradation of glycogen stored in liver and muscle to glucose. Glycogenolysis is not the reverse of the glycogenesis but is a separate pathway . Tissue : Liver & muscle Intracellular site : Cytosol Reactions : Action of glycogen phosphorylase. Action of debranching enzyme. Formation of glucose -6 - phosphate. 13. Action of glycogen phosphorylase.Glycogen PiGlycogen phosphorylase nGlucose-1 phLimit dextrin 14. Action of debranching enzyme.Limit dextrinDebranching enzyme (transferase activity)glucoseDebranching enzyme ( 1,6 glucosidase) 15. Formation of glucose -6 - phosphate. Further action of glycogen phosphorylaseGlucose-1- phosphate phosphoglucomutase glycolysismuscle Glucose-6- phosphate Glucose -6-phosphotase (liver ,kidney )Glucose 16. Glycogen Glycogen phosphorylaseLimit dextrin Debranching enzyme (transferase activity) Debranching enzyme ( 1,6 glucosidase) Further action of glycogen phosphorylaseGlucose-1- phosphateGlucose-6- phosphate Glucose 17. Regulation of glycogen metabolism 18. Glycogenesis..zzzzz!!!! 19. Glycogenolysis.!!!! 20. Regulation of glycogen metabolism Glycogenesis and gluconeogenesis are controlled by the enzymes glycogen synthase and glycogenphosphorylase. Regulation of these enzymes is accomplished by 2 mechanisms1.Covalent modification -brought about by Hormones 2. Allosteric regulation. -brought about by substrates 21. Regulation of glycogen metabolism... glycogen synthase and glycogen phosphorylase are said to be RECIPROCALLY REGULATED That is, when one enzyme is active, the other one is inactive. RECIPROCALLY REGULATION is brought about by hormones, by COVALENT MODIFICATION OF THE 2 ENZYMES. 22. COVALENT MODIFICATION OF THE 2 ENZYMES -Addition or removal of a group (phosphate group) makes the enzyme either active or inactive.glycogen phosphorylase is active in PHOSPHORYLATED Form. (inactive in dephoshorylated form) glycogen synthase is active in DEPHOSPHORYLATED Form. (inactive in dephoshorylated form) 23. Hormonal regulation -mainly by 3 hormones; 1. epinephrine in fasting state2.glucagon3. insulin-In fed state 24. Regulation of glycogen degradation by c AMPDuring fasting condition and muscle contraction Glucagon,Epinehrine,Ca++c AMP Via protein kinase and phosphorylase kinaseGlycogen phosphorylase b (dephosphorylated Inactive)Glycogen phosphorylase a (phosphorylated active)Glycogenolysis 25. Regulation of glycogen formation by c AMPDuring fasting condition and muscle contraction Glucagon,Epinehrine,Ca++c AMP Via protein kinase and phosphorylase kinaseGlycogen synthase a (dephosphorylated active)Glycogen synthase b (phosphorylated inactive)Glycogenesis stopped 26. Regulation of glycogen formation by insulinDuring fed state and in resting muscle insulinphosphatase PO4Glycogen synthase b (phosphorylated inactive)Glycogen synthase a (dephosphorylated active)Glycogenesis++ 27. Regulation of glycogen degradation by insulinDuring fed state and in resting muscle insulinphosphatase PO4Glycogen phosphorylase a (phosphorylated active)Glycogen phosphorylase b (dephosphorylated inactive)Glycogenolysis stopped 28. Allosteric regulation. Glucose 6-po4, and ATP are allostearic modulators. They activate Glycogen synthase Inhibit glycogen phoshorylase 29. Allosteric regulation Glucose 6-po4, and ATP are allostearic modulators.activate Glycogen synthaseglycogenesisInhibit glycogen phoshorylaseglycogenolysis This Occurs in fed state 30. Allosteric regulation. Fed state.liverGlycogenGlycogen phosphorylaseGlycogen synthaseGlucose-6glucose Glucose-6ATPphosphate Glucose-1-phosphate phosphateFasting state.liver Glycogen phosphorylaseGlycogenGlucose-1-phosphateGlycogen synthase 31. Resting state. GlycogenmuscleGlycogen phosphorylaseGlycogen synthaseGlucose-6ATP Glucose-6phosphate Glucose-1-phosphate phosphateMuscle contractionmuscleGlycogenGlycogen phosphorylasecalcium AMPGlucose-1-phosphateGlycogen synthase 32. Glycogen storage disordersThese are a group of genetic disease that result from a defect in an enzyme required for glycogen synthesis or degradation . The enzymes defect may be either generalized (affecting all tissues) or tissue-specific (liver, muscle, kidney, intestine, myocardium) They result in either formation of glycogen that has an abnormal structure or the accumulation of excessive amounts of normal glycogen in specific tissues. 33. Glycogen storage disorders Type NameDeficient enzymeFeaturesIVon gierkes diseaseGlucose- 6phosphataseHepatomegaly, fasting hypoglycemia, lactic acidosis, hyperuricemiaIIPompes diseaseLysosomal maltaseAccumulation of glycogen in lysosomes of liver, heart, muscle. Death before 2yrs 34. III Limit dextrinosis/ Coris diseaseDebranching enzymeIV Amylopectinosis/ Branching Andersons enzyme diseaseAccumulation of highly branched polysaccharide-limit dextrin. Fasting hypoglycemia ,hepatomegaly Accumulation of glycogen with few branches .mild hypoglycemia hepato splenomegaly 35. VMcArdles Muscle disease phosphorylaseIIAccumulation of glycogen in muscles. Exercise intolerance 36. Gluconeogenesis 37. Gluconeogenesis Definition The synthesis of glucose from non carbohydrate substrates. Substrates lactate Glycerol Glucogenic amino acids Propionate Sites: Liver (90%) kidney (10%) Sub cellular sites: Partly mitochondrial & partly cytosolic 38. Significance of gluconeogenesis 1.Maintenance of blood glucose,when glycogen stores are depleted. -Tissues such as brain , RBC , require a continous supply of glucose as a source of energy . Liver glycogen meets these needs for 12-18 hrs .As the glycogen stores starts depleting, gluconeogenesis ensures continous supply of glucose to tissues . 2. removes the products of metabolism eg; lactate produced in the muscle , propionate and glycerol. 39. Death from alcohol overdose is due to hypoglycemia due to reduced gluconeogenesis!!! 40. Characteristics Glycolysis and gluconeogenesis share the same pathway but in opposite direction.Gluconeogenesis utilizes all the seven enzymes of glycolysis catalyzing reversible reactionsGluconeogenesis also utilizes four special enzymes (the so called key enzymes of gluconeogenesis) for catalyzing the reversal of the three irreversible reactions of glycolysis 41. Glucose- 6- phosphatase is only present in liver and kidney but not in the muscle. Thus muscle cannot provide blood glucose by gluconeogenesis. 42. Reactions of gluconeogenesis 1. Carboxylation of pyruvate to oxaloacetate 2. Transport of oxaloacetate to cytosol 3. Decarboxylation of cytosolic oxaloacetate to phospho enol pyruvate (PEP). 4. Dephosphorylation of fructose -1,6bisphosphate to fructose-6- phosphate 5. Dephosphorylation of glucose -6phosphate to glucose 43. 1. Carboxylation of pyruvate to oxaloacetate mitochondria PyruvateATP+CO2biotin, Pyruvate carboxylase ADP+Pi mg2+oxaloacetateCytoplasm 44. 2. Transport of oxaloacetate to cytosol OxaloacetatePyruvateMalate dehydrogenaseoxaloacetate NADHMalate dehydrogenasemalate malateNAD+CytoplasmMalate shuttle 45. 3. Decarboxylation of cytosolic oxaloacetate to phospho enol pyruvate (PEP). Phospho enol pyruvate GDP+CO2 Phospho enol pyruvate carboxy kinase GTP PyruvateOxaloacetateoxaloacetate malate malateCytoplasm 46. 4. formation of fructose -1,6-bisphosphate by reversal of glycolysis Fructose-1,6-bisphosphate Glyceraldehyde 3- phosphateDihydroxy acetone phosphate 1,3-bisphosphoglycerateCytoplasm3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate oxaloacetate malatePyruvate oxaloacetate malate 47. 4. Dephosphorylation of fructose -1,6-bisphosphate to fructose-6- phosphate Fructose -6- phosphate H2 O Fructose- 1,6-bisphosphatase PiFructose-1,6-bisphosphate Glyceraldehyde 3- phosphateDihydroxy acetone phosphate 1,3-bisphosphoglycerateCytoplasm3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate oxaloacetate malatePyruvate oxaloacetate malate 48. 5. Dephosphorylation of glucose -6-phosphate to glucose Glucose- 6- phosphatase is only present in liver and glucose- 6-phosphatase kidney but not in the muscle. Thus muscle glucose-6- phosphate cannot provide blood glucose by gluconeogenesis. Fructose -6- phosphateglucoseFructose-1,6-bisphosphate Glyceraldehyde 3- phosphateCytoplasmDihydroxy acetone phosphate1,3-bisphosphoglycerate 3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate oxaloacetate malatePyruvate oxaloacetate malate 49. Key enzymes of gluconeogenesis4 glucose glucose- 6-phosphatase glucose-6- phosphate 3 Fructose -6- phosphate Fructose-1,6-bisphosphatase Fructose-1,6-bisphosphate Glyceraldehyde 3- phosphate CytoplasmDihydroxy acetone phosphate1,3-bisphosphoglycerate 3-phosphoglycerate 2-phosphoglyceratePyruvatephosphoenolpyruvate Phosphoenolpyruvatecarboxy kinase2Pyruvate carboxylase1 oxaloacetateoxaloacetate malate malate1 50. Substrates lactate Glycerol Glucogenic amino acids glycine Phenyl alanine alanine Tyrosine serine isoleucine Threonine cysteine valine methionine Arginine Glutamic acid Histidine Aspartic acid Propionate 51. Lactate glucose glucose- 6-phosphatase glucose-6- phosphate Fructose -6- phosphateLactate NADHLactate dehydrogenaseCytoplasmoxaloacetate malatePyruvate oxaloacetatemalateNAD+ 52. Coris cycle Cycle that operates between liver and muscle, for efficient utilization of lactatemuscleliverglucoseglucose gluconeogenesis pyruvate NADHLDHglycolysisbloodpyruvate + NAD Lactate dehydrogenaseNADH+H+lactatelactateNADH+H+ 53. Significance Of Coris Cycle Lactate accumulation causes muscle cramps during strenuous muscular exercise Coris cycle prevents such excessive accumulation of lactate and ensures efficient reutilization of lactate by the body. 54. GlucoseGlycerolGlucose-6 phosphatase Glucose -6- phosphate Fructose -6- phosphate Fructose- 1,6-bisphosphataseFructose-1,6-bisphosphate Glyceraldehyde 3- phosphateDihydroxy acetone phosphateGlycerol 55. Glucogenic amino acids glucose glucose- 6-phosphatase glucose-6- phosphateCytoplasmphosphoenolpyruvate oxaloacetate malateaminoacids Pyruvateoxaloacetate malatecitratefumarate -ketoglutarate Succinyl coA 56. Glucose alanine cycle liverbloodglucose gluconeogenesis pyruvate transaminationalaninemuscle glucoseglycolysis pyruvate transaminationalanineSignificance This glucose-alanine cycle is of primary importance in conditions of starvation Alanine also serves to transport ammonia for disposal in the non-toxic form 57. propionate glucose glucose- 6-phosphatase glucose-6- phosphateCytoplasmphosphoenolpyruvate oxaloacetate malatePyruvateoxaloacetate malatecitratefumarate -ketoglutarate Succinyl coApropionate 58. Regulation of gluconeogenesis GLYCOLYSIS AND GLUCONEOGENESIS ARE RECIPROCRALLY REGULATED.Gluconeogenesis is regulated by the following mehanisms:1.Hormonal regulation (long term regulation) 2.Allosteric regulation (long term regulation) 59. Regulation of gluconeogenesis 1.Hormonal regulation (long term regulation) Induction by -Glucagon,epinephrine,glucocorticoids Repression by -insulin 2.Allosteric regulation (long term regulation) -Allosteric inhibition by AMP -Allosteric activation by acetyl CoA 60. Thank you 61. Thank u!!Mail me@ ganeshprasadbond@gmail.comganesh.bond1@facebook.com