Glycogen structure, synthesis and breakdown Flashcards
Describe the basic structure of glycogen
- α(1–>4) linked glucose
- α(1–>6) linked branch points
- Polydisperse
What does polydisperse mean
- No specific structure in every molecule, so where the branches are is different and length vary differently- and precise structures vary from molecule to molecule
What is the starting point of a glycogen molecule
- Glycogenin-Present as homodimer so there are two starting points where all glucose attaches
Describe the structure of glycogen
- Glycogenin homodimer
- Inner region – B-chains, two branch points
- Outer region – A-chains, not branched
How many glucose residues does a typical glycogen molecule contain and what is the theoretical maximum
- Typical glycogen molecules found in vivo contain around 1500 glucose residues
- (Theoretical maximum of ~55000)
Describe how branching occurs
- As glycogen grows
- when 13 residues have been added the branching enzyme recognises the target and makes a branch
- the new chain is then grown
Why are the outermost chains unbranched
- Makes the glucose easily accessible
2. Easier to get glucose off unbranched chain
What percentage of glucose does the outermost tier contain
- Outermost tier always contains 34.6% of the glucose of the glycogen molecule
What is glycogenin
- It is an enzyme
- Primer for formation is glycogenin
- Protein homodimer found at the core of a glycogen molecule
- Not necessarily in the centre
How are other proteins involved
- Other proteins are associated with each glycogen molecule
- These are proteins involved in synthesis and breakdown, including control
- No rigid stoichiometry (amounts)
How is glycogen synthesised at first
- Glycogenin is able to catalyse the addition of glucose to itself
- First glucose added to Tyr195 (amino acid can vary) but always to hydroxyl group of tyrosine side chain
- Subsequent glucose added to growing chain
When does the enzyme involved in the synthesis of glycogen change
- Once about 10-20 residues added the main synthetic enzyme takes over
- Glycogen synthase takes over
What are the activated precursors used in glycogen synthesis
- UDP-glucose – in eukaryotes (uracil diphosphate)
2. (ADP-glucose used in bacteria and plants [starch])
How is UDP-glucose formed
- UTP + glucose-1-phosphate –>UDP-glucose
- Formation of UDP-glucose releases a 2-phosphate group from UTP (Pyrophosphate)
- UDP is attached at carbon 1- alpha carbon
What drives the UDP-glucose formation
- Pyrophosphate is hydrolysed to form 2 inorganic phosphates catalysed by pyrophosphorylase
- Removal of product drives the reaction
How is glucose attached to the growing chain
- addition is a glycosyl transfer with release of UDP- only glycosyl part is attached
- Mechanism -double SN2? or SNi? – latest evidence is for SNi
- Whichever mechanism, the α conformation is retained
What is the branching enzyme
- amylo-(1,4 –> 1,6)transglycosylase
How does branching occur
- A terminal chain section of ~7 residues is transferred to the C6-OH of another glycogen chain
- Chain which has already been grown is taken from the end of one chain and put on to be a branch
- Enzyme cleaves alpha-1,4 linkage on growing chain to form 1,6 linkage on another chain- forms branch
- This new chain can be extended using glycogen synthase
- May not grow If glycogen synthase activity is blocked by number of other chains
What are the 3 enzymes responsible for degradation
- Glycogen phosphorylase
- Glycogen debranching enzyme
- Phosphoglucomutase
Describe the main function of glycogen phoshporylase
- Primary enzyme in degradation
Describe the main function of glycogen debranching enzyme
- Removes branches
Describe the main function of phosphoglucomutase
- Also has role in synthesis
2. Conversion of released units into glucose
Describe the relationship between degradation and synthesis
- Occurs by a different pathway to synthesis
- Ensures that energetically this is possible
- Both can be controlled to allow very fine regulation
- Not at equilibrium- wouldn’t be effective
What does glycogen phosphorylase do
- Takes inorganic phosphate present in cytosol and solution in cells
- Use addition of inorganic phosphate to position 1 to produce glucose-1-phosphate
What does the structure of glycogen phosphorylase mean
- Because of structure can only get itself within 5 residues of a branch
- Can’t get active site to position 1
What is the mechanism that glycogen phosphorylase uses
- Via a carbocation (SN1)
- Carbocation is stabilised by pyridoxal phosphate which is covalently linked to the enzyme
(PLP is active form of Vit B6)
What are the two roles of debranching enzyme
- Eukaryotic enzyme is bi-functional
2. Acts as a transferase and α-1,6 glucosidase
What does debranching enzyme do
- The Phosphorylase gets to within 5 residues
- Debranching enzyme cleaves an alpha 1,4 linkage and moves chunk of chain onto adjacent branch
- Then hydrolyses 1,6 linkage to remove a single unit
- Forms longer chain which can be broken down by phosphorylase because there is no branch point
What does phosphoglucomutase do
- converts G-1-P into G-6-P
- Phosphate attached to serine on enzyme
- Attaches to glucose to form bisphosphate intermediate
- Phosphate on 1 carbon goes onto the enzyme
- Equilibria, by changing concentration of 1-P or 6-P can change direction
What happens to the G-6-P formed
- G-6-P enters glycolysis
2. OR in liver it can be dephosphorylated to form glucose for the blood
What happens when glucose levels are plentiful
- G-6-P is formed by hexokinase
- Changes equilibrium position
- Phosphoglucomutase converts G-6-P in to G-1-P
- G-1-P is substrate to form UDP-glucose for glycogen synthesis
- Phosphoglucomutase is acting to help synthesis
Describe Liver/muscle capacity for synthesis and degradation
- In liver – synthetic capacity and degradative capacity are about equal
- In muscle – degradation can happen about 300 times faster than synthesis
- Synthetic capacity of the muscle can increase with training
