Glycogen Synthesis and Mobilisation Flashcards
1
Q
Why store glycogen instead of glucose?
A
o Much less osmotically active.
o Much easier to mobilize quickly
to/from liver to maintain blood glucose
within muscle to generate ATP via glycolysis and aerobic metabolism
2
Q
What is the structure of glycogen?
A
- Branched polymer of 10,000 to 40,000 glucose residues
- Glycogen is a chain of glucose molecules attached to each other by alpha (α) 1,4 – glycosidic bonds between carbon atoms on adjacent glucose molecules.
- The chain of glucose molecules can also branch off using 1,6 carbon links to form branches. (has many branches – around every 10 carbons)
3
Q
What is required for glycogen synthesis to begin?
A
For glycogen synthesis to begin it needs a primer (a starting protein to which the first glucose can bind to begin the chain)
- The primer is a dimer (2 molecules of the same protein attached to each other), called glycogenin.
- Once the first few glycose residues are bound to glycogenin, glycogen synthase takes over and starts adding more glucose
4
Q
What is the glycogen synthesis pathway and what steps are involved?
A
- So to make Glycogen you need 2 starting materials:
1. Glucose-6-phosphate (G6P)
2. Glycogenin primer
3. Step 1: G6P – G1P (mutase) - Step 2: G1P – UDP-glucose through hydrolysis with uridine triphosphate (UTP)
- Step 3: UDP-glucose added to growing glycogen chain attached to the glycogenin primer.
o (enzyme – Glycogen synthase adds the UDP-glucose to growing chain by catalysing the 1,4-glycosidic bond) - Step 4: Branches added to growing glucose chains using the branching enzyme (a transferase) to create alpha 1,6 bonds
5
Q
How is glycogen stored and what is the advantage of doing so?
A
- Glycogen is stored as a large macromolecule, called macroglycogen.
- Stored as granules in the cytoplasm
- What is the advantage of storing glycogen as a large branched macromolecule, rather than a straight chain of glucose?
o Lots of free enzymes so can be broken down or built up very easily to adjust blood glucose concentrations
6
Q
How is glycogen broken down? What is this called? What steps and enzymes are involved?
A
- Depends on 3 enzymes which control 3 important steps in glycogen degradation:
o Step 1: breakdown of glycogen branches – debranching enzyme, α-1,6-glucosidase
o Step 2: removal of terminal glucose molecules by breaking 1,4 links – enzyme glycogen phosphorylase.
o Step 3: conversion of G1P to G6P – enzyme phosphoglucomutase.
o Lastly, in liver, glucose 6-phosphatase removes the phosphate group and free glucose can be released into blood - Whole process controlled by glucagon, which phosphorylates the enzyme glycogen phosphorylase to its active form
- Glucose-6-phosphate can also be used to produce ATP
7
Q
How does glycogenolysis occur differently in the liver to the muscle?
A
- In liver:
o G6P can be de-phosphorylated (removal of phosphate group) to glucose to go directly in the blood stream to maintain glucose homeostasis.
o Occurs during periods of fasting to maintain constant glucose levels. - In muscle:
o All G6P from glycogen goes directly into glycolysis to produce energy so it never undergoes conversion to glucose.
o Used as a medium –term course of energy
o During anaerobic respiration, lactate produced by glycolysis can be recycled via the Cori cycle (travels to liver where it is converted to glucose).
8
Q
How is glycogen metabolism controlled?
A
- Delicate balance between glycogen synthesis and break down
o Why is it important to regulate these two processes very well? - In general, the control of Glycogen production and breakdown is carried out by the following hormone/signalling molecules:
- Insulin
- Glucagon
(these are both antagonistic hormones that control glucose homeostasis - produced by pancreas) - Adrenaline
- Calcium
(these both act on muscles during activity via alpha and beta adrenergic receptors)
There are variations in their effects between liver and muscle.
9
Q
How is the amount of glycogen stored controlled?
A
- Insulin released after a meal will stimulate glycogen production by:
o Activating glycogen synthase
o Inhibiting glycogen phosphorylase - Glucagon released between meals stimulates glycogen breakdown by:
o Inhibiting glycogen synthase
o Activating glycogen phosphorylase - Antagonistic mechanisms
10
Q
What are the differences between glycogen synthase and glycogen phosphorylase?
A
- In their inactive (dormant) phase, glycogen synthase is phosphorylated while glycogen phosphorylase is de-phosphorylated.
- Therefore, the addition or removal of phosphate groups will activate/inhibit both enzymes antagonistically.
- Phosphate groups can be added by a number of kinases:
o Protein kinase A (PKA) – activated by cAMP, and glycogen synthase kinase (GSK) - Phosphate groups are removed by phosphatase enzymes.
- Insulin also carries out reciprocal control by completely switching off any activity of enzymes controlled by by glucagon/adrenaline/calcium by activating phosphodiesterase (PDE) enzymes that break down cAMP in the cytosol
11
Q
What are the 2 ways in which insulin works to cause glycogen synthesis?
A
- Insulin is shown to work in 2 ways to cause glycogen synthesis – via phosphodiesterase and via protein phosphotase
12
Q
What are the differences in the ways that insulin and glucagon work?
A
- Glucagon leads to phosphorylation of glycogen synthase (inactivation) and glycogen phosphorylase (activation; shown on the diagram as phosphorylase a) via cAMP, protein kinase A and phosphorylase kinase
- Insulin reverses cAMP-induced phosphorylation
o I.e. insulin leads to dephosphorylation of glycogen synthase (activating it) and dephosphorylation of glycogen phosphorylase (making it inactive) via protein phosphatase
13
Q
What are the key points about glycogen synthesis and breakdown, and its regulation?
A
- In general:
o Insulin removes phosphate groups (activating GS and inactivating GP). Insulin works in the liver and muscles to increase glucose uptake and storage
o Glucagon, adrenaline and calcium add phosphate groups, activating GP and inhibiting GS. Glucagon acts only on liver to break down glycogen, not on muscle (no receptors). Adrenaline and calcium work only in muscle.
o Glycogen breakdown occurs mostly during exercise since adrenaline in the system and calcium in the muscle act together to ensure glycogen breakdown to release glucose 6 phosphate for energy in a short period of time.
o Hormones act through their receptors to bring about effects: Insulin receptor, Glucagon receptor and B-adrenergic receptors.
o Glucose-6-phosphate can also act as an allosteric activator of glycogen synthase.
14
Q
What are glycogen storage diseases and how often do they occur?
A
- A number of autosomal recessive diseases related to defects in Glycogen storage affecting different enzymes of the glycogen metabolic pathway.
- Different isoforms of the enzymes means that disease can affect different parts of the system.
- Rare (around 1 in 40,000)
15
Q
What is McArdle’s disease?
A
- Caused by genetic defect in the muscular glycogen phosphorylase enzyme (myophosphorylase) gene – PYGM – over 95 different mutations have been identified in patients.
- Cannot breakdown glycogen in the muscle so experience muscle weakness.
- Experience a “second wind” during exercise caused by re-uptake of glucose in the muscle.
- Rapid exercise will cause muscle damage, cramping and locking due to depletion of ATP.
- 1:100,000 – 167,000 people affected
- Range of phenotypes depending on mutation
