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Glycogen Metabolism
Biochem and medical genetics
| Question | Answer |
|---|---|
| What is glycogen | Storage form of glucose Found in cytoplasm Present in granules ranging from 10-40nm |
| Structure of glycogen | Linear chain of glucose residues Protein backbone of glycogenin Primary glycosidic bond is an alpha 1-4 linkage Every 8-10 residues branch contains alpha 1-6 linkage One single reducing end Many non-reducing ends |
| Why do we need glycogen | Carbohydrate storage - limited efficiency so limited storage 200g stored in muscle and 70g in liver Fat has a higher energy yield but we still need glycogen to maintain blood glucose and produce ATP in absence of oxygen |
| Glycogen metabolism | In liver - glycogen broken down into glucose 6 phosphate then into free glucose to be released into the blood In muscle - glycogen broken down into glucose 6 phosphate which is used in metabolism to form ATP |
| Why does glycogen have a branched structure | Offers multiple end points for rapid degradation The branched structure increases the solubility so its easier to store at site of utilization Rapid use of energy |
| Glycogenolysis | Breakdown of glycogen Non-reducing ends are breakdown points Glycogen phosphorylase releases glucose 1 phosphate |
| Glycogen phosphorylase | Mediates a phosphorolysis reaction Producing glucose 1 phosphate not free glucose Means that glucose is already activated and is trapped in the cell Water needs to be excluded from active site - site is buried in narrow cleft |
| Phosphoglucomutase | Converts glucose 1 phosphate to glucose 6 phosphate This enters glycolytic pathway in muscles - 50% increase in ATP production In the liver this is converted to glucose in SER by glucose 6 phosphatase |
| Need for debranching enzyme | Phosphorylase is a progressive enzyme - binding and active site connected by 4/5 residues So cannot breakdown final few residues |
| Debranching enzyme | Transferase takes 4 residues and moves to the end point of another branch to create longer branches alpha 1-6 glycosidase breaks the final bond of the branch via hydrolysis Forms linear unbranched molecule |
| Regulation of glycolysis | Phosphorylase is the key site of regulation for glycogenolysis Regulation is different in the liver and in muscle due to their different roles The liver needs to respond to blood glucose level The muscle needs to respond to energy demand |
| Different forms of phosphorylase | 4 different states A phosphorylated active state - phosphorylase a A dephosphorylated inactive state - phosphorylase b Each can be in a tense or relaxed state Phosphorylase a prefers r Phosphorylase b prefers t |
| Allosteric regulation of phosphorylase in muscle | In resting muscle most phosphorylase is in the inactive b tense state Phosphorylase b can be transitioned to the r state by high conc of AMP This change is inhibited by ATP and glucose 6 phosphate |
| Why is AMP a good signal of energy | Only a small change in ATP conc is needed to cause a large change in AMP conc ATP converted to ADP ADP can be scavenged to form ATP |
| Allosteric regulation of phosphorylase in liver | Most phosphorylase is in active a relaxed state Can be transitioned to the T state by high concs of glucose Liver only takes up glucose when blood glucose is high Liver phosphorylase is insensitive to AMT/ATP |
| Covalent modification of phosphorylase | Phosphorylase b can be phosphorylated to phosphorylase a by phosphorylate kinase In muscle cells phosphorylate kinase is activated by adrenaline This is activated by glucagon in liver |
| Why use signalling cascades | Allows amplification of the signal Only need a small amount of hormone to activate a lot of phosphorylase |
| Allosteric regulation of phosphorylate kinase | As well as being phosphorylated by PKA, phosphorylate kinase can be activated allosterically by calcium In muscle calcium is released in response to muscular contraction In liver it is released in response to adrenaline |
| Glycogenesis | Starts with glucose 6 phosphate - powered by generation of UDP-glucose Glucose 6 phosphate is converted to glucose 1 phosphate by phosphoglucomutase This is converted to UDP glucose by UDP-glucose pyrophosphorylase Reaction driven by cleavage of PPi |
| What is glycogen | Storage form of glucose Found in cytoplasm Present in granules ranging from 10-40nm |
| Structure of glycogen | Linear chain of glucose residues Protein backbone of glycogenin Primary glycosidic bond is an alpha 1-4 linkage Every 8-10 residues branch contains alpha 1-6 linkage One single reducing end Many non-reducing ends |
| Why do we need glycogen | Carbohydrate storage - limited efficiency so limited storage 200g stored in muscle and 70g in liver Fat has a higher energy yield but we still need glycogen to maintain blood glucose and produce ATP in absence of oxygen |
| Glycogen metabolism | In liver - glycogen broken down into glucose 6 phosphate then into free glucose to be released into the blood In muscle - glycogen broken down into glucose 6 phosphate which is used in metabolism to form ATP |
| Why does glycogen have a branched structure | Offers multiple end points for rapid degradation The branched structure increases the solubility so its easier to store at site of utilization Rapid use of energy |
| Glycogenolysis | Breakdown of glycogen Non-reducing ends are breakdown points Glycogen phosphorylase releases glucose 1 phosphate |
| Glycogen phosphorylase | Mediates a phosphorolysis reaction Producing glucose 1 phosphate not free glucose Means that glucose is already activated and is trapped in the cell Water needs to be excluded from active site - site is buried in narrow cleft |
| Phosphoglucomutase | Converts glucose 1 phosphate to glucose 6 phosphate This enters glycolytic pathway in muscles - 50% increase in ATP production In the liver this is converted to glucose in SER by glucose 6 phosphatase |
| Need for debranching enzyme | Phosphorylase is a progressive enzyme - binding and active site connected by 4/5 residues So cannot breakdown final few residues |
| Debranching enzyme | Transferase takes 4 residues and moves to the end point of another branch to create longer branches alpha 1-6 glycosidase breaks the final bond of the branch via hydrolysis Forms linear unbranched molecule |
| Regulation of glycolysis | Phosphorylase is the key site of regulation for glycogenolysis Regulation is different in the liver and in muscle due to their different roles The liver needs to respond to blood glucose level The muscle needs to respond to energy demand |
| Different forms of phosphorylase | 4 different states A phosphorylated active state - phosphorylase a A dephosphorylated inactive state - phosphorylase b Each can be in a tense or relaxed state Phosphorylase a prefers r Phosphorylase b prefers t |
| Allosteric regulation of phosphorylase in muscle | In resting muscle most phosphorylase is in the inactive b tense state Phosphorylase b can be transitioned to the r state by high conc of AMP This change is inhibited by ATP and glucose 6 phosphate |
| Why is AMP a good signal of energy | Only a small change in ATP conc is needed to cause a large change in AMP conc ATP converted to ADP ADP can be scavenged to form ATP |
| Allosteric regulation of phosphorylase in liver | Most phosphorylase is in active a relaxed state Can be transitioned to the T state by high concs of glucose Liver only takes up glucose when blood glucose is high Liver phosphorylase is insensitive to AMT/ATP |
| Covalent modification of phosphorylase | Phosphorylase b can be phosphorylated to phosphorylase a by phosphorylate kinase In muscle cells phosphorylate kinase is activated by adrenaline This is activated by glucagon in liver |
| Why use signalling cascades | Allows amplification of the signal Only need a small amount of hormone to activate a lot of phosphorylase |
| Allosteric regulation of phosphorylate kinase | As well as being phosphorylated by PKA, phosphorylate kinase can be activated allosterically by calcium In muscle calcium is released in response to muscular contraction In liver it is released in response to adrenaline |
| Glycogenesis | Starts with glucose 6 phosphate - powered by generation of UDP-glucose Glucose 6 phosphate is converted to glucose 1 phosphate by phosphoglucomutase This is converted to UDP glucose by UDP-glucose pyrophosphorylase Reaction driven by cleavage of PPi |
| Glycogen synthase | Forms the alpha 1-4 linkages to grow the glycogen molecule The cost of this is 1 molecule of ATP used as UTP Glycogen + UDP glucose = glycogen (n+1) |
| Use of branching enzyme | When the chain is 11 residues ling the branching enzyme takes 7 residues and joins them to an internal site via an alpha 1-6 glycosidic bond This must be 4 residues from another branch point |
| Primer of synthesis | Glycogenin, a glucosyltransferase, acts as the primer and catalyst for the addition of the first few glucose residues 2 identical subunits that add glucose units to one another Once the chain in 8 residues long, glycogen synthase takes over |
| Regulation of glycogen synthase | Key site of regulation for glycogen synthesis Exists in an active a state and an inactive b state Inhibited when phosphorylated and activated when dephosphorylated |
| Regulation of glycogenesis | Glycogen synthase can be phosphorylated by PKA Provides reciprocal regulation with glycogenolysis PKA will phosphorylate phosphorylate kinase which phosphorylates glycogen phosphorylase and activate it whilst inhibiting glycogen synthase |
| Role of insulin | Activates protein phosphatase 1 - dephosphorylates glycogen phosphorylase and glycogen synthase Inhibits glycogen synthase kinase which reduces phosphorylation of glycogen synthase |
| Glycogen storage disease - Type 1 | Enlarged liver and kidneys Massive glycogen accumulation Blood glucose low High blood lactate Lactic acidaemia - hypoglycaemic coma Caused by mutation in glucose 6 phosphatase |
| Glycogen storage disease - Type 3 | Structure of both liver and muscle glycogen is abnormal Caused by a mutation in debranching enzyme Results in increased amount of glycogen with short outer branches |
| Glycogen storage disease - Type 5 | Results from a deficiency in muscle phosphorylase Results in painful cramps when performing strenuous activity pH increases due to breakdown of phosphorylate kinase and increase in ADP |
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