Glycogen and Pentose Phosphate Pathway Flashcards
Describe the structure of glycogen and why it is important
Glycogen is a highly branched polymer of glucose molecules. Its presence greatly increases the amount of glucose available between meals. Its highly branched form is better than a linear form for rapidly mobilizing large amounts of glucose. This rapid mobilization is critical to reverse rapidly falling blood-glucose levels because gluconeogenesis is too slow of a process.
Linear glucose chains are formed by a-1,4 glycosidic linkages, branch points are formed by a-1,6 glycosidic linkages.
What are the four steps of glycogen synthesis?
1 - Glucose-6-P -> Glucose-1-P
2 - Glucose-1-P + UTP -> UDP-glucose
3 - Activated UDP-glucose transferred to hydroxyl group at a C-4 terminus of glycogen
4 - Branching is achieved via “branching enzyme”
What enzyme is involved in the first step of glycogen synthesis?
Step 1 = Glucose6P -> Glucose1P
Enzyme: Phosphoglucomutase
“Mutates glucose’s phosphate groups from 6 to 1”
What occurs in the second step of glycogen synthesis?
Glucose-1P is bound to UTP to produce UDP-glucose and one pyrophosphate group (the outer 2 PO4 of UTP). Don’t need to know the enzyme that catalyses this step. UDP-glucose is the activated form of glucose that can be polymerized onto glycogen.
What enzyme is involved in the third step of glycogen synthesis and what happens?
UDP-glucose is added to the hydroxyl group at the C-4 terminus of a glycogen chain. This is catalyzed by GLYCOGEN SYNTHASE, which can only add glucose to a chain that is 4 residues long or longer. The chain must be initiated by the protein GLYCOGENIN. GLYCOGEN SYNTHASE creates an a-1,4-glycosidic linkage.
What enzyme is involved in the fourth step of glycogen synthesis and what happens?
The BRANCHING ENZYME transfers a polysaccharide chain of 6-7 residues to an internal site on the original chain, forming an a-1,6 glycosidic linkage. This branch point must be at least 4 residues away from any other branch points. These branches increase the number of terminal glucose molecules available for increased synthesis or breakdown of the glycogen molecule, thus branching increases the rate of both synthesis and degradation. Branching also increases the solubility of glycogen. If branching does not occur, then the glycogen structure is abnormal and breakdown is slower, resulting in greater hypoglycemia and exercise intolerance. This is an inborn error of metabolism.
What are the three primary steps and enzymes of glycogen breakdown?
1 - Release of glucose-1P from glycogen: GLYCOGEN PHOSPHORYLASE
2 - Remodeling of the remaining glycogen to permit further degradation: DEBRANCHING ENZYME
3 - Conversion of Glucose-1P to G6P for metabolism or export from cell: PHOSPHOGLUCOMUTASE
What enzymes are involved in the first step of glycogen breakdown and what happens?
Glycogen (n residues) + Pi -> G1P + Glycogen (n-1 residues)
Catalysed by GLYCOGEN PHOSPHORYLASE, which stops when there are four residues between it and a branch point. The debranching enzyme then remodels the glycogen polymer.
What enzymes are involved in the second step of glycogen breakdown and what happens?
The DEBRANCHING ENZYME acts when there are four residues remaining on a chain before the branch point. The enzyme moves the outer three residues to the end of the adjacent branch. This leave one residue with an a-1,6 glycosidic bond attached. A GLYCOSIDASE enzyme clips this bond, releasing a free glucose molecule that is then converted to G6P by HEXOKINASE.
What enzymes are involved in the third step of glycogen breakdown and what happens?
Glucose-1-phosphate is converted into G6P by PHOSPHOGLUCOMUTASE. G6P can then enter glycolysis in muscle cells (or other cells where it is found). In liver cells, G6P may enter glycolysis or move to the ER and be dephosphorylated by glucose-6-phosphatase to form free glucose which may be exported into the blood stream for use by other tissues.
How are glycogen synthesis and breakdown regulated?
Both processes are reciprocally regulated by allosteric interactions and by hormone driven phosphorylation/dephosphorylation. The hormones involved are INSULIN and GLUCAGON. Glycogen synthase and Glycogen Phosphatase both exist in phosphorylated and dephosphorylated forms, and phosphorylation activates or inactivates them in inverse fashion.
Dephosphorylated forms: Glycogen Synthase is active, Glycogen Phosphorylase is inactive (Glycogen Synthesis)
Phosphorylated form: Glycogen Synthase is inactive, Glycogen Phosphorylase is active (Glycogen Breakdown)
What is the general hormone milieu for the fed state vs the fasted state, and what major intracellular effect does this have?
In the fed state, insulin is high and glucagon is low. This results in a relative decrease of phosphorylation inside cells.
In the fasted state, insulin is low and glucagon is high. This results in a relative increase of phosphorylation inside cells.
How are glycogen synthase and glycogen phosphatase allosterically regulated in the fed state?
Glycogen synthase is allosterically activated by G6P, thus synthase will be more active after meals when G6P concentrations are high, leading to increased glycogen synthesis.
Glycogen phosphatase, by comparison, is allosterically inhibited by both G6P and ATP. This leads to a decrease in glycogen breakdown during the fed state.
How is glycogen degradation allosterically regulated in muscle cells?
Glycogen degradation is stimulated by both calcium and AMP in muscle cells.
Calcium: Muscle contraction stimulates calcium release. Calcium binds to calmodulin and the complex activates a phosphorylase which phosphorylates glycogen phosphorylase, activating it.
AMP: AMP allosterically actives glycogen phosphorylase, activating it without the need for phosphorylation. This leads to greater glucose release in exercising muscles where AMP is higher.
What is the order of enzymes and phosphorylations by which cAMP stimulates glycogen degradation, and what effect does insulin have on this system?
Enzymes involved:
PKA - Protein Kinase A
Phosphorylase kinase (A and B, A is active)
PP1 - Phosphoprotein phosphatase 1
Glycogen phosphorylase (A and B, A is active)
Glucagon and Epinephrine both increase cAMP levels:
cAMP -> PKA -> Phosphorylase kinase B to A -> Glycogen phosphorylase B to A -> glycogen breakdown
Insulin can directly inhibit this pathway:
Insulin -> PP1 (dephosphorylator) -> Phosphorylase kinase A to B -> decreased phosphorylation of Glycogen phosphatase -> decreased glycogen breakdown
