Glycogen Breakdown and Debranching Enzyme

Glycogen Breakdown

• Glycogen breakdown requires four enzymes: one for glycogen degradation, two for remodeling, and one for product conversion.
• Glycogen phosphorylase is the key regulatory enzyme. It cleaves glycogen by adding orthophosphate, a process called phosphorolysis, to produce glucose 1-phosphate.
• Phosphorolysis is energetically favorable because the glucose is already phosphorylated.
• Phosphorylase sequentially removes glucosyl residues from the non-reducing ends of glycogen.
• Glucose 1-phosphate is readily converted to glucose 6-phosphate by phosphoglucomutase.
• Phosphorylase stops breaking down glycogen when it encounters branch points. Alpha-1,6 bonds are not cleaved.

Debranching Enzyme

• Alpha-1,6 bonds at branch points require further action.
• A transferase shifts three glucosyl units to another branch.
• A debranching enzyme (alpha-1,6 glucosidase) hydrolyzes the remaining alpha-1,6 bond, releasing a free glucose molecule.
• The free glucose is phosphorylated to glucose 6-phosphate by hexokinase.
• This whole process transforms the branched structure into a linear one, allowing phosphorylase to continue.
• In eukaryotes, these transferase and debranching enzyme activity occur in a single polypeptide.

Glucose-6-Phosphate

• Glucose 1-phosphate, produced by glycogen breakdown, must be converted to glucose 6-phosphate.
• Phosphoglucomutase facilitates this conversion by shifting a phosphoryl group.
• The enzyme uses a phosphorylated serine residue in its active site to transfer the phosphoryl group from C-1 to C-6, then back to the serine, yielding the product glucose 6-phosphate.

Liver Function

• The liver maintains blood glucose levels.
• During activity or between meals, the liver releases glucose into the blood.
• The liver contains glucose 6-phosphatase that cleaves glucose 6-phosphate, releasing free glucose that can be transported out of the liver into the blood.
• This phosphatase is also involved in gluconeogenesis.
• Glucose 6-phosphatase is on the smooth endoplasmic reticulum.

Glycogen Phosphorylase Regulation

• Glycogen phosphorylase is regulated by energy state signals and hormones.
• Phosphorylase exists in two forms: phosphorylase a (active) and phosphorylase b (inactive).
• Phosphorylase a is generally more active. This form is in equilibrium between an active relaxed (R) state and a less active tense (T) state.
• Muscle phosphorylase is primarily in the b form unless stimulated during muscle contraction.
• Liver phosphorylase is usually primed for activity as the liver is responsible for maintaining glucose levels.
• Muscle phosphorylase b is activated by AMP, which stabilizes the R state.
• ATP and glucose 6-phosphate inhibit the b form through feedback inhibition.
• The liver version shows a prominent response triggered by the binding of glucose to the active site, shifting from the active R to the inactive T state. This allows for modulation depending on blood glucose levels.
• Phosphorylase b converts to phosphorylase a by phosphorylation of a serine residue.

Phosphorylase Kinase Regulation

• Phosphorylase kinase is a large enzyme crucial for activating phosphorylase b.
• Phosphorylase kinase activation directly depends on the binding of calcium ions to calmodulin, a calcium sensor.
• This activation is paramount in the muscle, as calcium release triggers contraction. Epinephrine triggers this activation.
• Additional activation requires the phosphorylation of the protein kinase A targets of the kinase.

Muscle Fiber Types and Glycogen Metabolism

• Skeletal muscle has three fiber types: type I (slow-twitch), type IIb (fast-twitch), and type IIa (intermediate).
• Type I fibers use cellular respiration, rely less on glycogen and glycogen phosphorylase.
• Type IIb fibers rely on glycogen for energy; glycogen and phosphorylase are abundant. Contain high amounts of glycolytic enzymes.
• Type IIa are trainable, and can interconvert their glycogen metabolism capacity.