Chapter 25: Glycogen Synthesis

Glycogen synthesis and degradation

Occur by different pathways; synthesis uses UDP-glucose, while degradation uses glycogen phosphorylase.

UDP-glucose

Activated form of glucose used as the substrate for glycogen synthase.

Phosphoglucomutase

Enzyme common to both glycogen synthesis and degradation; interconverts glucose 1-phosphate and glucose 6-phosphate.

UDP-glucose pyrophosphorylase

Catalyzes formation of UDP-glucose from glucose 1-phosphate and UTP.

UDP-glucose pyrophosphorylase reaction

Glucose 1-phosphate + UTP → UDP-glucose + pyrophosphate (PPi).

Pyrophosphate hydrolysis

Makes the UDP-glucose formation reaction irreversible.

Glycogen synthase

Key regulatory enzyme that transfers glucose from UDP-glucose to the C-4 hydroxyl of a glycogen chain, forming α-1,4-glycosidic bonds.

Glycogen synthase substrate requirement

Can only add glucose to an existing chain of at least 4 residues.

Glycogenin

Priming enzyme and protein core that initiates glycogen synthesis by forming a short α-1,4-glucose chain (10–20 residues).

Glycogenin attachment

Remains covalently bound to glycogen through a tyrosine residue.

Branching enzyme

Creates α-1,6 linkages in glycogen by transferring a 7-residue segment from a chain to a nearby branch point.

Branching enzyme requirements

The donor chain must have at least 11 residues, and the new branch forms about 4 residues inward.

Regulatory enzyme of glycogen synthesis

Glycogen synthase (active when dephosphorylated, inactive when phosphorylated).

Glycogen synthase a form

Active, unphosphorylated enzyme form.

Glycogen synthase b form

Inactive, phosphorylated enzyme form.

Phosphorylation effect comparison

Opposite for glycogen synthase and glycogen phosphorylase (phosphorylation activates phosphorylase but inactivates synthase).

Allosteric activator of glycogen synthase b form

Glucose 6-phosphate; shifts the enzyme from T (inactive) to R (active) state.

Epinephrine or glucagon effect on glycogen synthase

Inhibit glycogen synthesis by activating protein kinase A (PKA) and glycogen synthase kinase, which phosphorylate glycogen synthase.

Reciprocal regulation

When glycogen breakdown is stimulated, glycogen synthesis is inhibited (and vice versa).

Turning on glycogen synthesis

Occurs when epinephrine/glucagon signals stop, PKA becomes inactive, and PP1 (protein phosphatase 1) becomes active.

Protein phosphatase 1 (PP1)

Dephosphorylates glycogen synthase b (activating it) and dephosphorylates phosphorylase kinase and glycogen phosphorylase (inactivating them).

PP1 effect

Shifts metabolism from glycogen breakdown to glycogen synthesis.

PP1 structure

Has a catalytic subunit and regulatory subunits that target it to glycogen.

Regulatory subunit in muscle

GM subunit (glycogen-targeting subunit for muscle).

Regulatory subunit in liver

GL subunit (glycogen-targeting subunit for liver).

PKA effect on PP1

Phosphorylates GM, causing it to dissociate from PP1 catalytic subunit, reducing PP1 activity.

PP1 inhibitors

Become active when phosphorylated by PKA; inhibit PP1 during glycogen breakdown signaling.

Insulin signaling and glycogen synthesis

Insulin activates glycogen synthesis by inactivating glycogen synthase kinase, allowing PP1 to activate glycogen synthase.

Insulin and glucose uptake

Stimulates translocation of GLUT4 transporters to the plasma membrane, increasing glucose entry into cells.

Glucose 6-phosphate effect

Activates glycogen synthase (even in b form), promoting glycogen synthesis.

High blood-glucose levels

Inhibit glycogen degradation and stimulate glycogen synthesis in liver.

Liver phosphorylase sensitivity

Directly inhibited by glucose binding.

Glucose effect on liver phosphorylase

Binds to phosphorylase a, converting it from R to T state and exposing its phosphorylated serine for removal by PP1.

PP1 action after glucose binding

Dephosphorylates phosphorylase (inactivating it) and activates glycogen synthase (activating it).

Type 1 diabetes

Autoimmune destruction of pancreatic β-cells leading to no insulin production, high glucagon, high blood glucose, and ketoacidosis.

Type 1 diabetes metabolic effects

Poor glucose uptake, increased lipolysis, increased fatty acids and ketone body production (fruity breath).

Type 2 diabetes

Insulin resistance; insulin present but cells fail to respond properly, resulting in high blood glucose.

Type 2 diabetes characteristics

Impaired glucose uptake, continued inhibition of hormone-sensitive lipase, less fatty acid release than type 1.

Insulin resistance cause

Overwhelmed signaling pathway leading to reduced cellular response to insulin.