Glycogenesis and Glycogenolysis Notes

Glycogen is a branched polymer of glucose and serves as a storage form of glucose.
Glycogen synthesis (glycogenesis) and degradation (glycogenolysis) mainly occur in the liver and skeletal muscle.
Glycogen is stored in the cytoplasm as granules, each with a central protein core.
The density of glucose is highest near the core in granules composed of linear chains, while it is highest at the periphery in branched chains, which allow for rapid glucose release on demand.
Liver glycogen is a source of glucose mobilized between meals to prevent low blood sugar.
Muscle glycogen is an energy reserve for muscle contraction.
Plants store excess glucose as starch, which consists of long alpha-linked chains of glucose.

Glycogenesis is the synthesis of glycogen granules, starting with a core protein called glycogenin.
The process begins with glucose-6-phosphate, which is converted to glucose-1-phosphate.
Glucose-1-phosphate is activated by coupling to UDP (uridine diphosphate), which allows its integration into the glycogen chain by glycogen synthase.
This activation occurs when glucose-1-phosphate interacts with UTP (uridine triphosphate), forming UDP-glucose and pyrophosphate ( $PP_i$ ).

Glycogen synthase is the rate-limiting enzyme of glycogen synthesis and forms the alpha-1,4-glycosidic bonds in the linear glucose chains of the granule.
Stimulated by glucose-6-phosphate and insulin.
Inhibited by epinephrine and glucagon through a protein kinase cascade that phosphorylates and inactivates the enzyme.

Branching enzyme (glycosyl alpha-1,4:alpha-1,6-transferase) introduces alpha-1,6-linked branches into the glycogen granule.
It hydrolyzes one of the alpha-1,4 bonds to release a block of oligoglucose.
The released oligoglucose is moved and added in a slightly different location, forming an alpha-1,6 bond to create a branch.

Glycogenolysis is the process of breaking down glycogen.
Glycogen phosphorylase is the rate-limiting enzyme of glycogenolysis.
Glycogen phosphorylase breaks bonds using inorganic phosphate instead of water.
The glucose-1-phosphate formed by glycogen phosphorylase is converted to glucose-6-phosphate by a mutase.

Glycogen phosphorylase breaks alpha-1,4-glycosidic bonds, releasing glucose-1-phosphate from the periphery of the granule.
It cannot break alpha-1,6 bonds and stops when it nears the outermost branch points.
Activated by glucagon in the liver.
Activated by AMP and epinephrine in skeletal muscle.
Inhibited by ATP.

Debranching enzyme is a two-enzyme complex that deconstructs the branches in glycogen.
Breaks an alpha-1,4 bond adjacent to the branch point and moves the small oligoglucose chain to the exposed end of the other chain, forming a new alpha-1,4 bond.
Hydrolyzes the alpha-1,6 bond, releasing the single residue at the branch point as free glucose.
This represents the only free glucose produced directly in glycogenolysis.
Glucose produced from glucose-1-phosphate must be converted by a mutase to glucose-6-phosphate before it can be converted to glucose via the enzyme glucose-6-phosphatase.

Glycogen storage diseases are genetic deficiencies that impact glycogen metabolism.
Clinical features depend on the affected enzyme, the degree to which the enzyme's activity is decreased, and which isoform of the enzyme is affected.
There are often different isoforms of the enzymes in the liver and muscle.
These diseases are characterized by accumulation or lack of glycogen in one or more tissues.