10. Glycogen Synthesis and Utilisation Flashcards
What are the 2 roles of glycogen?
Why is glycogen a good (medium-term) energy store?
How is glycogen mobilised?
1. Liver (100g): glucose absorbed from gut 1-3hrs after meal. Beyond this, liver glycogen is used to maintain BG levels. Broken down to glucose-6-P to glucose -> to blood transporter.
2. Muscle (400g): glycogen used to maintain muscle during bursts of activity (=instant e.g. sprinting). NB the enzyme converting glucose-6-P to glucose isn’t in muscle tissue so it’s broken down and used in the same cell for glycolysis.
Readily mobilisable - acts as a glucose buffer and less osmotically active than glucose.
By the liver (to maintain BG), or ATP via anaerobic glycolysis/aerobic metabolism (in muscle)
Describe the structure of glycogen.
How and why is glycogen branched?
Gycogenin primer (protein). Long chains of glucose molecules join to it between C1 and C4, adding at end to form chains.
Glycogen branching enzyme adds branches linked to C6. Branches every 12-14 residues. Also a debranching enzyme that breaks glycogen. Branched because it aids solubility - more places where you can make/break down glycogen = rapid mobilisation.
Describe how glycogen is made.
Describe how glycogen is broken down to glucose.
Convert glucose-6-phosphate -> glucose-1-phosphate. React with UTP to produce UDP-glucose and pyrophosphate (PPi). Glycogen synthase takes UDP-glucose and adds 1 glucose onto the glycogen chain to make glycogen+1. PPi is broken down into 2 Pi (provides energy for the reaction).
Glycogen phosphorylase produces glucose-1-phosphate from glycogen+1, which can then be converted back to glucose-6-phosphate
Describe how glycogen metabolism is controlled in the liver and muscles.
What controls glycogen synthase?
Liver: aim to maintain BG levels, insulin increases glucose storage (liver and muscles) -> glycogen. Glucagon released into blood -> glycogen breakdown (liver only, not muscle)
Muscles: aim to provide energy in muscle, links release to muscle contraction - released on adrenalin or nerve impulse (Ca2+)
Phosphorylation: glycogen synthase is inactive when phosphorylated. Hormones affect the phosphorylation state of enzyme and thus its activity
Glycogen synthase activity is controlled by multiple phosphorylation sites. What promotes dephosphorylation and phosphorylation?
What has an allosteric effect on the process?
.
Glycogen synthase dephosphorylation (i.e. activation) is promoted by insulin via activation of protein phosphate-1. This produces glycogen+1.
Glycogen synthase phosphorylation via (protein kinase A) PKA and phosphorylase kinase, which are both controlled by cAMP, and in turn glucagon (liver) and adrenaline (muscle)
Glucagon = inactivates protein phosphate and promotes kinases.
Glucose-6-phosphate - high levels activate glycogen storage
All of this activates glycogen synthase and elongates glycogen chain.
How does the liver break down glycogen? (Glycogenolysis)
Catalysed by glycogen phosphorlyase (GP) = breaks 1-4 links adding in a phosphoryl group.
In liver glucose-6-phosphate can be dephosphorylated and exported as glucose via glucose-6-phosphatase. Thus maintaining BG during short-term fast. Stimulated by glucagon via phosphorylation. NB: when glycogen phosphorylase is phosphorylated its ACTIVE (other way around with glycogen synthase)
P CAN ONLY BE TAKEN OFF G-6-P IN LIVER
How does the muscle break down glycogen (glycogenolysis)?
Is it linked to low blood glucose?
All glycogen in muscle feeds into glycolysis and energy production in that cell only. If anaerobic = produces lactate which can be recyled via cori cycle. Glycogen breakdown is stimulated by contraction and adrenalin.
Glycogenolysis is due to phosphorylation (activation) of glycogen phosphorylase.
No because the muscle lacks the enzyme that removes P so the glucose remains phosphorylated and in the muscle cell.
What is the main difference in control of glycogen breakdown between the muscle and liver paths?
What happens in the path?
How does insulin affect the path?
Muscle = responds to adrenaline. Liver = responds to glucagon.
Adrenaline/glucagon bind to GPCR -> activate GP -> activate adenyl cyclase -> produces cAMP. cAMP levels increase -> activates PKA -> phosphorylates (activates) glycogen phosphorylase kinase -> phosphorylates glycogen phosphorylase -> activates breakdown of glycogen to shorter chain of glycogen and glucose-1-phosphate.
Binds to insulin receptor and activates phosphodiesterase breaks down cAMP = turns off all the enzymes that were turned on by glucagon = Reciprocal control!
How does muscle contraction link to breakdown of glycogen?
What else can cause breakdown?
Directly: Ca2+ released as muscle contracts, so Ca levels high in muscle when contracting. Ca2+ activates phosphorylase kinase directly and allows it to phosphorylate glycogen phosphorylase and break down glycogen.
ATP levels drop because lots of energy used. AMP activates phosphorylase kinase, leading to glycogen breakdown
Explain reciprocal control in terms of inslin and glucagons’s effects.
Insulin: dephosphorylates -> promotes glycogen synthesis -> breaks down cAMP via phosphodiesterases = can turn kinases off
Glucagon/adrenaline: phosphorylates by kinases, increases glycogen breakdown (phosphorylase), done partly by increasing cAMP in cells
What are disorders of glycogen metabolism?
Describe Type I (von Gierke’s)
Describe Type 3 (Cori’s)
Autosomal recessive diseases. Enzymes are expressed as different isoforms so get tissue specific effects (liver/muscle)
Deficient in glucose-6-phosphatase which is usually found in liver and without it glucose can’t be phosphorylated and remains trapped in liver cell. See hypoglycaemia and lacticacidemina
Deficiency in debranching enzyme -> hypoglycaemia
Describe glycogen metabolism disorder Type V (McArdle’s)
How would you diagnose it?
Autosomal recessive deficiency in muscle tissue phosphorylase so can’t break down glycogen in muscle. Hard to start exercising - need to take it slow (avoid fast burst, no more than 6s) and easy gently into 2nd wind: metabolic effect, normally use muscle glycogen as first burst of energy but over a period of time start using other fuels transported in blood e.g. BG or fats, and burn those in muscle instead. Rapid exercise would cause muscle damage, cramping and locking - low ATP. Range of phenotypes: some can do more activity than others.
Markers of muscle damage in blood/urine post intense exercise: CK/myoglobin. Would see large glycogen molecules in biopsy (pic). Presense/absence of phospharylase via staining. Sequencing (genetic markers). Forearm test.
Describe glycogen metabolism disorder Type VI (Her’s)
How is it treated?
Why should glucagon (a common treatment for hypoglycaemia) not be used?
Deficiency in liver phosphorylase. So able to run etc. but can’t maintain BG between meals. Hypoglycemia.
Slow release sugars and glucose
No point because no glycogen phosphorylase in liver so no effect. Need to use glucose instead
