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Carbohydrate metabolism
glucose- 6-phosphatase glucose-6- phosphate The document discusses glycogen metabolism and gluconeogenesis. It provides details on: Fructose -6- phosphate 1) Glycogen synthesis (glycogenesis) and breakdown (glycogenolysis) pathways in the liver and muscle. Key enzymes involved include glycogen synthase, glycogen phosphorylase and debranching enzyme. Fructose-1,6-bisphosphatase 2) Regulation of glycogen metabolism by hormones like insulin and glucagon via covalent modification of glycogen synthase and phosphorylase. Fructose-1,6-bisphosphate
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Carbohydrate metabolism
- 2. Glycogen metabolism & gluconeogenesis -Carbohydratemetabolic pathways for glucose homeostasis
- 3.
- 4. Liver glycogen Muscle glycogen maintainsblood glucose. supplies energy during muscle contraction.
- 5. Introduction Storage form ofcarbohydrates in animals Sites: Liver & muscle Glycogen: Functions Liver glycogen is used to maintain blood glucose. Muscle glycogen supplies energy during muscle contraction.
- 6. Glycogenesis It is thesynthesis 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.
- 7. 1. Synthesis ofUDP-Glucose. Glucose glucokinase (liver) ATP hexokinase (muscle) ADP Glucose-6- phosphate phosphoglucomutase Glucose-1- phosphate UDP-glucose pyrophosphorylase UTP PPi UDP -glucose ( UDP - )
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- 9. 2. Formation linearchain of glycogen by glycogen synthase Glycogen primer 13 UDP 13 UDP Glycogen synthase
- 10. 4.Formation of branchesin glycogen. Branching enzyme
- 11. 3. Elongation ofbranches to form glycogen. 1-6- bond Elongation by glycogen synthase Formation of branches by branching enzyme Glycogen
- 13. Glucose ADP 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 enzyme Glycogen
- 14. Glycogenolysis It is thedegradation 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.
- 15. Action of glycogenphosphorylase. Glycogen Pi Glycogen phosphorylase nGlucose-1 ph Limit dextrin
- 16. Action of debranchingenzyme. Limit dextrin Debranching enzyme (transferase activity) glucose Debranching enzyme ( 1,6 glucosidase)
- 17. Formation of glucose-6 - phosphate. Further action of glycogen phosphorylase Glucose-1- phosphate phosphoglucomutase glycolysis muscle Glucose-6- phosphate Glucose -6-phosphotase (liver ,kidney ) Glucose
- 18. Glycogen Glycogen phosphorylase Limit dextrin Debranchingenzyme (transferase activity) Debranching enzyme ( 1,6 glucosidase) Further action of glycogen phosphorylase Glucose-1- phosphate Glucose-6- phosphate Glucose
- 19. Regulation of glycogenmetabolism
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- 22. Regulation of glycogenmetabolism Glycogenesis and gluconeogenesis are controlled by the enzymes glycogen synthase and glycogen phosphorylase. Regulation of these enzymes is accomplished by 2 mechanisms 1.Covalent modification -brought about by Hormones 2. Allosteric regulation. -brought about by substrates
- 23. Regulation of glycogenmetabolism... 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.
- 24. COVALENT MODIFICATION OF THE2 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)
- 25. Hormonal regulation -mainly by3 hormones; 1. epinephrine in fasting state 2.glucagon 3. insulin-In fed state
- 26. Regulation of glycogendegradation by c AMP During fasting condition and muscle contraction…… Glucagon,Epinehrine,Ca++ c AMP Via protein kinase and phosphorylase kinase Glycogen phosphorylase b (dephosphorylated Inactive) Glycogen phosphorylase a (phosphorylated active) Glycogenolysis
- 27. Regulation of glycogenformation by c AMP During fasting condition and muscle contraction…… Glucagon,Epinehrine,Ca++ c AMP Via protein kinase and phosphorylase kinase Glycogen synthase a (dephosphorylated active) Glycogen synthase b (phosphorylated inactive) Glycogenesis stopped
- 28. Regulation of glycogenformation by insulin During fed state and in resting muscle …… insulin phosphatase PO4 Glycogen synthase b (phosphorylated inactive) Glycogen synthase a (dephosphorylated active) Glycogenesis++
- 29. Regulation of glycogendegradation by insulin During fed state and in resting muscle …… insulin phosphatase PO4 Glycogen phosphorylase a (phosphorylated active) Glycogen phosphorylase b (dephosphorylated inactive) Glycogenolysis stopped
- 30. Allosteric regulation. • Glucose6-po4, and ATP are allostearic modulators. • They activate • Glycogen synthase • Inhibit glycogen phoshorylase
- 31. Allosteric regulation Glucose 6-po4,and ATP are allostearic modulators. activate Glycogen synthase glycogenesis Inhibit glycogen phoshorylase glycogenolysis This Occurs in fed state
- 32. Allosteric regulation. Fed state. liver Glycogen Glycogen phosphorylase Glycogen synthase Glucose-6glucoseGlucose-6ATPphosphate Glucose-1-phosphate phosphate Fasting state. liver Glycogen phosphorylase Glycogen Glucose-1-phosphate Glycogen synthase
- 33. Resting state. Glycogen muscle Glycogen phosphorylase Glycogen synthase Glucose-6ATP Glucose-6phosphateGlucose-1-phosphate phosphate Muscle contraction muscle Glycogen Glycogen phosphorylase calcium AMP Glucose-1-phosphate Glycogen synthase
- 34. Glycogen storage disorders Theseare 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.
- 35. Glycogen storage disorders TypeName Deficient enzyme Features I Von gierke’s disease Glucose- 6phosphatase Hepatomegaly, fasting hypoglycemia, lactic acidosis, hyperuricemia II Pompe’s disease Lysosomal maltase Accumulation of glycogen in lysosomes of liver, heart, muscle. Death before 2yrs
- 36. III Limit dextrinosis/ Cori’s disease Debranching enzyme IVAmylopectinosis/ Branching Anderson’s enzyme disease Accumulation of highly branched polysaccharide-limit dextrin. Fasting hypoglycemia ,hepatomegaly Accumulation of glycogen with few branches .mild hypoglycemia hepato splenomegaly
- 37. V McArdle’s Muscle disease phosphorylase II Accumulation of glycogenin muscles. Exercise intolerance
- 38.
- 39. Gluconeogenesis Definition The synthesis ofglucose from non – carbohydrate substrates. Substrates lactate Glycerol Glucogenic amino acids Propionate Sites: Liver (90%) kidney (10%) Sub cellular sites: Partly mitochondrial & partly cytosolic
- 40. Significance of gluconeogenesis 1.Maintenanceof 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.
- 41. Death from alcoholoverdose is due to hypoglycemia due to reduced gluconeogenesis!!!
- 42. Characteristics Glycolysis and gluconeogenesisshare the same pathway but in opposite direction. Gluconeogenesis utilizes all the seven enzymes of glycolysis catalyzing reversible reactions Gluconeogenesis also utilizes four special enzymes (the so called key enzymes of gluconeogenesis) for catalyzing the reversal of the three irreversible reactions of glycolysis
- 43. Glucose- 6- phosphataseis only present in liver and kidney but not in the muscle. Thus muscle cannot provide blood glucose by gluconeogenesis.
- 44. 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
- 45. 1. Carboxylation ofpyruvate to oxaloacetate mitochondria Pyruvate ATP+CO2 biotin, Pyruvate carboxylase ADP+Pi mg2+ oxaloacetate Cytoplasm
- 46. 2. Transport ofoxaloacetate to cytosol Oxaloacetate Pyruvate Malate dehydrogenase oxaloacetate NADH Malate dehydrogenase malate malate NAD+ Cytoplasm Malate shuttle
- 47. 3. Decarboxylation ofcytosolic oxaloacetate to phospho enol pyruvate (PEP). Phospho enol pyruvate GDP+CO2 Phospho enol pyruvate carboxy kinase GTP Pyruvate Oxaloacetate oxaloacetate malate malate Cytoplasm
- 48. 4. formation offructose -1,6-bisphosphate by reversal of glycolysis Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Dihydroxy acetone phosphate 1,3-bisphosphoglycerate Cytoplasm 3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate oxaloacetate malate Pyruvate oxaloacetate malate
- 49. 4. Dephosphorylation offructose -1,6-bisphosphate to fructose-6- phosphate Fructose -6- phosphate H2 O Fructose- 1,6-bisphosphatase Pi Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Dihydroxy acetone phosphate 1,3-bisphosphoglycerate Cytoplasm 3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate oxaloacetate malate Pyruvate oxaloacetate malate
- 50. 5. Dephosphorylation ofglucose -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- phosphate glucose Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Cytoplasm Dihydroxy acetone phosphate 1,3-bisphosphoglycerate 3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate oxaloacetate malate Pyruvate oxaloacetate malate
- 51. Key enzymes ofgluconeogenesis 4 glucose glucose- 6-phosphatase glucose-6- phosphate 3 Fructose -6- phosphate Fructose-1,6-bisphosphatase Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Cytoplasm Dihydroxy acetone phosphate 1,3-bisphosphoglycerate 3-phosphoglycerate 2-phosphoglycerate Pyruvate phosphoenolpyruvate Phosphoenolpyruvatecarboxy kinase 2 Pyruvate carboxylase 1 oxaloacetate oxaloacetate malate malate 1
- 52. Substrates lactate Glycerol Glucogenic amino acids glycine Phenylalanine alanine Tyrosine serine isoleucine Threonine cysteine valine methionine Arginine Glutamic acid Histidine Aspartic acid Propionate
- 53. Lactate glucose glucose- 6-phosphatase glucose-6- phosphate Fructose-6- phosphate Lactate NADH Lactate dehydrogenase Cytoplasm oxaloacetate malate Pyruvate oxaloacetate malate NAD+
- 54. Cori’s cycle Cyclethat operates between liver and muscle, for efficient utilization of lactate muscle liver glucose glucose gluconeogenesis pyruvate NADH LDH glycolysis blood pyruvate + NAD Lactate dehydrogenase NADH+H+ lactate lactate NADH+H+
- 55. Significance Of CorisCycle Lactate accumulation causes muscle cramps during strenuous muscular exercise Cori’s cycle prevents such excessive accumulation of lactate and ensures efficient reutilization of lactate by the body.
- 56. Glucose Glycerol Glucose-6 phosphatase Glucose -6-phosphate Fructose -6- phosphate Fructose- 1,6-bisphosphatase Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Dihydroxy acetone phosphate Glycerol
- 57. Glucogenic amino acids glucose glucose-6-phosphatase glucose-6- phosphate Cytoplasm phosphoenolpyruvate oxaloacetate malate aminoacids Pyruvate oxaloacetate malate citrate fumarate -ketoglutarate Succinyl coA
- 58. Glucose alanine cycle liver blood glucose gluconeogenesis pyruvate transamination alanine muscle glucose glycolysis pyruvate transamination alanine Significance Thisglucose-alanine cycle is of primary importance in conditions of starvation Alanine also serves to transport ammonia for disposal in the non-toxic form
- 59.
- 60. Regulation of gluconeogenesis GLYCOLYSISAND GLUCONEOGENESIS ARE RECIPROCRALLY REGULATED. Gluconeogenesis is regulated by the following mehanisms: 1.Hormonal regulation (long term regulation) 2.Allosteric regulation (long term regulation)
- 61. Regulation of gluconeogenesis… 1.Hormonalregulation (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
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- 63. Thank u………!! Mail me@ganeshprasadbond@gmail.com ganesh.bond1@facebook.com