Published on February 27, 2014
Glycogen metabolism & gluconeogenesis -Carbohydrate metabolic pathways for glucose homeostasis
Liver glycogen Muscle glycogen maintains blood glucose. supplies energy during muscle contraction.
Introduction Storage form of carbohydrates in animals Sites: Liver & muscle Glycogen: Functions Liver glycogen is used to maintain blood glucose. Muscle glycogen supplies energy during muscle contraction.
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.
1. Synthesis of UDP-Glucose. Glucose glucokinase (liver) ATP hexokinase (muscle) ADP Glucose-6- phosphate phosphoglucomutase Glucose-1- phosphate UDP-glucose pyrophosphorylase UTP PPi UDP -glucose ( UDP - )
Glycogen primer glycogenin Glycogen primer
2. Formation linear chain of glycogen by glycogen synthase Glycogen primer 13 UDP 13 UDP Glycogen synthase
4.Formation of branches in glycogen. Branching enzyme
3. Elongation of branches to form glycogen. 1-6- bond Elongation by glycogen synthase Formation of branches by branching enzyme Glycogen
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
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.
Action of glycogen phosphorylase. Glycogen Pi Glycogen phosphorylase nGlucose-1 ph Limit dextrin
Action of debranching enzyme. Limit dextrin Debranching enzyme (transferase activity) glucose Debranching enzyme ( 1,6 glucosidase)
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
Glycogen Glycogen phosphorylase Limit dextrin Debranching enzyme (transferase activity) Debranching enzyme ( 1,6 glucosidase) Further action of glycogen phosphorylase Glucose-1- phosphate Glucose-6- phosphate Glucose
Regulation of glycogen metabolism
Regulation of glycogen metabolism 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
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.
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)
Hormonal regulation -mainly by 3 hormones; 1. epinephrine in fasting state 2.glucagon 3. insulin-In fed state
Regulation of glycogen degradation 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
Regulation of glycogen formation 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
Regulation of glycogen formation by insulin During fed state and in resting muscle …… insulin phosphatase PO4 Glycogen synthase b (phosphorylated inactive) Glycogen synthase a (dephosphorylated active) Glycogenesis++
Regulation of glycogen degradation by insulin During fed state and in resting muscle …… insulin phosphatase PO4 Glycogen phosphorylase a (phosphorylated active) Glycogen phosphorylase b (dephosphorylated inactive) Glycogenolysis stopped
Allosteric regulation. • Glucose 6-po4, and ATP are allostearic modulators. • They activate • Glycogen synthase • Inhibit glycogen phoshorylase
Allosteric regulation Glucose 6-po4, and ATP are allostearic modulators. activate Glycogen synthase glycogenesis Inhibit glycogen phoshorylase glycogenolysis This Occurs in fed state
Allosteric regulation. Fed state. liver Glycogen Glycogen phosphorylase Glycogen synthase Glucose-6glucose Glucose-6ATPphosphate Glucose-1-phosphate phosphate Fasting state. liver Glycogen phosphorylase Glycogen Glucose-1-phosphate Glycogen synthase
Resting state. Glycogen muscle Glycogen phosphorylase Glycogen synthase Glucose-6ATP Glucose-6phosphate Glucose-1-phosphate phosphate Muscle contraction muscle Glycogen Glycogen phosphorylase calcium AMP Glucose-1-phosphate Glycogen synthase
Glycogen storage disorders These 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.
Glycogen storage disorders Type Name 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
III Limit dextrinosis/ Cori’s disease Debranching enzyme IV Amylopectinosis/ 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
V McArdle’s Muscle disease phosphorylase II Accumulation of glycogen in muscles. Exercise intolerance
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
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.
Death from alcohol overdose is due to hypoglycemia due to reduced gluconeogenesis!!!
Characteristics Glycolysis and gluconeogenesis share 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
Glucose- 6- phosphatase is only present in liver and kidney but not in the muscle. Thus muscle cannot provide blood glucose by gluconeogenesis.
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
1. Carboxylation of pyruvate to oxaloacetate mitochondria Pyruvate ATP+CO2 biotin, Pyruvate carboxylase ADP+Pi mg2+ oxaloacetate Cytoplasm
2. Transport of oxaloacetate to cytosol Oxaloacetate Pyruvate Malate dehydrogenase oxaloacetate NADH Malate dehydrogenase malate malate NAD+ Cytoplasm Malate shuttle
3. Decarboxylation of cytosolic oxaloacetate to phospho enol pyruvate (PEP). Phospho enol pyruvate GDP+CO2 Phospho enol pyruvate carboxy kinase GTP Pyruvate Oxaloacetate oxaloacetate malate malate Cytoplasm
4. formation of fructose -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
4. Dephosphorylation of fructose -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
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- 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
Key enzymes of gluconeogenesis 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
Substrates lactate Glycerol Glucogenic amino acids glycine Phenyl alanine alanine Tyrosine serine isoleucine Threonine cysteine valine methionine Arginine Glutamic acid Histidine Aspartic acid Propionate
Lactate glucose glucose- 6-phosphatase glucose-6- phosphate Fructose -6- phosphate Lactate NADH Lactate dehydrogenase Cytoplasm oxaloacetate malate Pyruvate oxaloacetate malate NAD+
Cori’s cycle Cycle that 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+
Significance Of Coris Cycle 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.
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
Glucogenic amino acids glucose glucose- 6-phosphatase glucose-6- phosphate Cytoplasm phosphoenolpyruvate oxaloacetate malate aminoacids Pyruvate oxaloacetate malate citrate fumarate -ketoglutarate Succinyl coA
Glucose alanine cycle liver blood glucose gluconeogenesis pyruvate transamination alanine muscle glucose glycolysis pyruvate transamination alanine Significance 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
propionate glucose glucose- 6-phosphatase glucose-6- phosphate Cytoplasm phosphoenolpyruvate oxaloacetate malate Pyruvate oxaloacetate malate citrate fumarate -ketoglutarate Succinyl coA propionate
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)
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
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