Glycogenolysis

Cheatsheet Content

### Overview of Glycogenolysis - **Definition:** The biochemical pathway by which glycogen, a stored form of glucose, is broken down into glucose-1-phosphate and glucose. - **Purpose:** To provide rapid glucose supply when energy is needed, primarily in muscle and liver. - **Location:** Occurs in the cytoplasm of cells, mainly liver and muscle cells. - **Key Regulators:** Hormones like glucagon (liver) and epinephrine (muscle and liver). ### Key Enzymes and Steps 1. **Glycogen Phosphorylase:** - **Function:** Catalyzes the sequential removal of glucose residues from the non-reducing ends of glycogen chains. - **Mechanism:** Uses inorganic phosphate ($P_i$) to cleave the $\alpha(1 \to 4)$ glycosidic bonds, producing glucose-1-phosphate. - **Regulation:** Activated by phosphorylation (phosphorylase kinase) and allosterically by AMP; inhibited by ATP and glucose-6-phosphate. - **Limitation:** Stops cleaving approximately four residues away from an $\alpha(1 \to 6)$ branch point. 2. **Debranching Enzyme (Glucan Transferase and Glucosidase):** - **Function:** Removes the $\alpha(1 \to 6)$ branch points in glycogen. - **Mechanism:** - **Transferase Activity:** Transfers a block of three glucose residues from a branch to a nearby non-reducing end of the main chain, forming a new $\alpha(1 \to 4)$ bond. - **Glucosidase Activity:** Hydrolyzes the remaining single glucose residue at the $\alpha(1 \to 6)$ branch point, releasing free glucose. This is the only step that produces free glucose directly. 3. **Phosphoglucomutase:** - **Function:** Isomerizes glucose-1-phosphate to glucose-6-phosphate. - **Mechanism:** Involves a glucose-1,6-bisphosphate intermediate. - **Significance:** Glucose-6-phosphate is a central metabolite that can enter glycolysis, the pentose phosphate pathway, or (in the liver) be dephosphorylated to free glucose. ### Fates of Glucose-6-Phosphate (G6P) 1. **In Muscle:** - G6P directly enters glycolysis to produce ATP for muscle contraction. - Muscle cells lack glucose-6-phosphatase, so G6P cannot be converted to free glucose and released into the bloodstream. 2. **In Liver:** - G6P can enter glycolysis for the liver's own energy needs. - G6P can be converted to free glucose by **Glucose-6-Phosphatase** (located in the ER lumen). - **Glucose-6-Phosphatase:** Dephosphorylates G6P to glucose, which is then transported out of the liver cells and into the bloodstream to maintain blood glucose levels. ### Regulation of Glycogenolysis - **Hormonal Control:** - **Glucagon (Liver):** Released by pancreatic $\alpha$-cells in response to low blood glucose. Activates glycogen phosphorylase via a cAMP-dependent protein kinase cascade, promoting glucose release from the liver. - **Epinephrine (Adrenaline) (Muscle & Liver):** Released from adrenal medulla during stress or exercise. Activates glycogen phosphorylase via a similar cAMP cascade ( $\beta$-adrenergic receptors) and also via calcium/calmodulin-dependent pathways ($\alpha$-adrenergic receptors), leading to glucose mobilization. - **Insulin:** Inhibits glycogenolysis by dephosphorylating glycogen phosphorylase. - **Allosteric Control:** - **AMP:** Allosterically activates muscle glycogen phosphorylase $b$ (the less active form) during exercise, indicating low energy status. - **ATP & Glucose-6-Phosphate:** Allosterically inhibit glycogen phosphorylase, signaling high energy levels and abundant glucose. - **Glucose (Liver):** Allosterically inhibits liver glycogen phosphorylase $a$ (the active form), promoting its dephosphorylation. - **Calcium Ions ($Ca^{2+}$):** In muscle, $Ca^{2+}$ released during contraction activates phosphorylase kinase, leading to rapid glycogen breakdown.