What is the key enzyme in glycogen synthesis?
Glycogen synthase
How does glycogen synthase work?
It transfers a glucose moiety from UDP-glucose to the C-4 terminal residue of a glycogen chain to form an alpha 1-4 glycosidic bond. Breaking the phosphate bond b/w glucose and UDP provides the energy for this synthesis.
How do we make UDP-glucose?
UDP-glucose phorphosrylase is the enzyme that performs the following reaction:
Glucose 1-phosphate + UTP + H20 –> UDP-glucose + 2 Pi
UTP first transfers a single phosphate onto glucose 1-Pi to form UDP-glucose. The pyrophosphate is then immediately cleaved to yield two free phosphates.
What does glycogen synthase need in order to synthesize glycogen?
- UDP-glucose
- A primer - an oligosaccharide of glucose residues. Glycogen synthase needs about 10 glucose units for it to start working.
Glycogenin
The enzyme that makes the primer for glycogen synthase to then add glucose units to.
Glycogenin is a dimer - one subunit transfers glucose onto its other subunit. Each subunit of glycogenic catalyzes the addition of eight glucose units to the other subunit. Glycogenin stays on the end once it has synthesized a primer.
What is responsible for the branching in glycogen?
A branching enzyme cleaves alpha 1-4 linkages and takes a block of about 7 glucoses and synthesizes an alpha 1-6 linkage. Then glycogen synthase can extend the branched polymer.
What is the key regulatory enzyme in glycogen synthesis?
Glycogen synthase
How is glycogen synthase regulated?
- Allosterically - High glucose 6-Pi is an allosteric effector (b/c when we have high glucose, we want to turn on glycogen synthase to store the glucose). Insulin also facilitates glycogen synthesis by increasing the number of glucose transporters (GLUT4) in the plasma membrane.
- Covalent Modification - Glycogen Synthase B is phosphorylated and inactive. Glycogen Synthase A is active and not phosphorylated. PKA activates glycogen phosphorylase and at the same time inhibits glycogen synthase. PP1 inactivates glycogen phosphorylase but activates glycogen synthase.
PKA and PP1 ensure that both pathways - glycogen breakdown and synthesis - don’t run simultaneously.
Regulation of glycogen synthesis
Glucagon and Epinephrine stimulate glycogen breakdown by turning on PKA. PKA turns on Phosphorylase used in glycogen breakdown and simultaneously turns off glycogen synthase.
PP1
removes the phosphate from glycogen synthase b to activate it (stimulating glycogen synthesis). It also removes phosphate from the enzymes that degrade glycogen to turn them into the inactive b form (inhibits glycogen breakdown).
