glycogen metabolism Flashcards
What happens to excess glucose?
Is stored in the liver and muscles as glycogen
glycogen definition
a highly branched polymer of alpha glucose that is soluble and can be broken down rapidly when required, acting as a readily accessible storage form for glucose
what is the process of breaking down glycogen called?
glycogenolysis
what mediates glycogenolysis?
glycogen phosphorylase
what is the mediation in response to?
low energy signals, low blood glucose and during the fight of flight response
what is the opposite process of glycogenolysis and what mediates it?
glycogenesis, mediated by glycogen synthase and in response to high blood glucose
where is glycogen found?
found in the cytoplasm as granules ranging from 10-40nm
brief structure of glycogen
primary glycosidic bond is an alpha 1-4 linkage, and then the branches are alpha 1-6 linkage
every 8-10 residues contain a branch with a 1-6 linkage
where is glycogen stored and relative percentages?
liver -10% of liver mass is glycogen
muscle- 2% of muscle mass is glycogen
200g in muscle, 70g in liver
what are the different functions of glycogen in each storage location? + how are they regulated
in liver, used to increase blood glucose= liver needs to respond to the blood glucose level
in muscle, used directly to form ATP for muscle contractions- muscle needs to respond to energy demand
why is glycogen not used as the sole storage, instead of using fat too?
fat has a higher energy yield than glucose produced from glycogen- 38kj/g compared to 17kj/g
fat is insoluble so doesn’t bind to water, whereas glycogen binds to water, so the resulting body weight would be significantly higher as for every g of glycogen 2g of water is stored
why is glycogen present?
maintain a constant blood glucose concentration for red blood cells, the brain and renal medukka
need to be able to produce ATP rapidly in the absence of oxygen
benefits of a branched structure
offers multiple end points for rapid degradation
branched structures increase the solubility meaning that it is easier to store close to the site of utilisation, whereas lipids need to be transported by albumins
mechanistic definition of glycogenolysis
the catabolism of a polymer of glycogen during sequential removals of glucose monomers via phosphorolysis, catalysed by glycogen phosphorylase
glycogen phosphorylase function
glycogen phosphorylase phosphorylates a glucose subunit in the alpha 1-4 linear chain, which results in the production of glucose-1-phosphate, not free glucose
what does the formation of G-1-P result in?
glucose is already activated and its trapped in the cell, as the phosphate means that the glucose cannot diffuse out or move through specific GLUT transporters
what occurs in the phosphorolysis reaction and how does the structure of the enzyme accommodate for this?
the reaction requires water to be excluded from the active site, which is achieved by having the active site buried in a narrow cleft of the enzyme
what happens afterwards to the glucose-1-phosphate molecule?
glucose-1-phosphate is converted to glucose-6-phosphate
catalysed by the enzyme phosphoglucomutase
differences in the liver and muscles
the glucose-6-phosphate produced by phosphoglucomutase can be used directly in muscles
in the liver, the glucose 6-phosphate is converted to glucose inside the smooth endoplasmic reticulum, mediated by glucose 6-phosphatase
structure of glycogen phosphorylase
a homodimer, where each subunit has a binding site and an active site
binding site connected to the active site by a narrow crevice about 30 amino acids long
what is a difficulty for glycogen phosphorylase and how is it overcome?
it can only act on linear 1-4 alpha chains and will immediately come to a halt four residues from a 1-6 chain
a debranching enzyme is used to straighten out the chain
what is the debranching enzyme in eukaryotes? + functions
a transferase- transfers three glucose residues from the four residue glycogen branch to a nearby chain
and an alpha 1-6 glucosidase- cleaves the remaining alpha 1-6 bond to release a molecule of glucose and glycogen
regulation in the liver explained
most phosphorylase is in the a-relaxed state
phosphorylase A can be transitioned to the T state when there are high concentrations of glucose, thus preventing glycogenolysis
liver only takes up glucose when blood glucose is high, due to GLUT 2
liver phosphorylase is insensitive to AMP/ATP
regulation in the muscles explained
in resting skeletal muscle, the majority of phosphorylase is in the inactive b-tense state
it becomes active-R when high concentrations of AMP are detected, encouraging glycogenolysis
high concentrations of ATP and glucose-6-phosphate prevent the change, preventing glycogenolysis
Why is AMP a good signalling molecule?
very small concentration, around 10 mM, compared to a very large ATP, thus only a small change in ATP causes a large change in AMP
covalent modification of phosphorylase + regulation
phosphorylase B in the muscles can be phosphorylated to phosphorylase a by phosphorylase kinase
in muscle cells, phosphorylase kinase is activated by adrenaline
in liver cells, phosphorylase kinase is activated by glucagon,
what is the benefit of converting more phosphorylase B into phosphorylase A?
greater concentrated of phosphorylase enzymes will be in the R state, so more will be converting the glycogen into glucose
will all be sensitive to glucose now
how is phosphorylase kinase activated ?
- adrenaline/glucagon bind to the Gs beta adrenergic receptor/glucagon receptor, activationg adenyl cyclase
- adenyl cyclase then converts ATP to cAMP
- cAMP activates PKA
- PKA converts phosphorylase kinase b to phosphorylase kinase a
- phosphorylase kinase a converts glycogen phosphorylase b to glycogen phosphorylase a which then catalyses glycogenolysis
allosteric regulation of phosphorylase kinase explained
phosphorylase kinase can be activated allosterically by calcium
calcium binds to the sigma subunit, calmodulin
glycogenesis definition
the process of glycogen synthesis, where glucose monomers are added to existing chains of glycogen for storage
stages of glycogenesis
- glucose- 6-phosphate is converted to glucose 1-phosphate, catalysed by phosphoglucomutase
- glucose 1-phosphate then converted to UDP-glucose and a PPi using a UTP molecule, catalysed by UDP-glucose pyrphosphorylase
- UDP-glucose plus an existing glycogen molecule adds an extra glucose molecule to the glycogen, catalysed by glycogen synthase, releasing UDP
what drives the forward reaction?
glucose 6 phosphate to 1-phosphate is reversible
driven forward by the cleavage of pPi by pyrophosphatase
glycogen synthase energy cost + function
forms 1 1-4 linkages to grow glycogen molecules
cost is 1 molecule of ATP in the form of UTP to UDP
What does continued synthesis require + at which point?
when the chain is more than 11 residues long, the branching enzyme takes 7 residues and joins them to an internal site via an alpha 1-6 glycosidic bond
the new bond must be at least 4 residues away from another branching point
what happens before glycogen synthase takes over + when?
initially, when there is no starting glycogen molecule glycogenic, a glycosyltransferase, acts as the primer and catalyst for the addition of the first few glucose residues
it is formed of two identical subunits that add glucose units from UDP-glucose to one another
once the chain is 8 residues long, the glycogen synthase takes over
what two forms does glycogen phosphorylase exist in?
an active a state
inactive b state
regulation of glycogen phosphorylase
becomes inhibited when phosphorylated, activated when dephosphorylated
PKA, signalled by glucagon and adrenaline, phosphorylates phosphorylase kinase which will phosphorylate glycogen phosphorylase activating it increasing glucose production
the PKA will phosphorylate glycogen synthase, so inhibiting it, so less glycogen is unnecessarily synthesised, reducing glucose storage
what is this type of regulation called?
reciprocal regulation
insulin’s role in reciprocal regulation
activates protein phosphatase 1 which:
- dephosphorylates glycogen synthase, thus activating it- more glycogen formed
- dephosphorylates glycogen phosphorylase, deactivating it
inbits glycogen synthase kinase, which reduces the phosphorylation of glycogen synthase
different types of glycogen storage disease explained
type 1- Von Gierke’s Disease-glucose 6-phosphatase deficiency - no glucose 6-phosphatase, so the G6P formed in glycogenolysis cannot be converted to glucose, massive glycogen accumulation , low blood glucose, enlarged liver and kidneys
type III- both liver and muscle glycogen is abnormal, mutation in the debranching enzyme, results in an increased amount of glycogen with short outer branches
type V- deficiency in muscle phosphorylase- painful cramps, increase in pH due to breakdown of phosphocreatine and increase in ADP
