Glycogen Metabolism (Exam II) Flashcards
What is the structure of glycogen and where is it stored?
Glycogen is a branched chain homopolysaccharide made from α-D-glucose. The primary bond is an α-1,4 glycosidic linkage. After every eight to ten glucose units, there is a branch attached by an α-1,6 linkage.
Glycogen is stored in the cytoplasm as large hydrated granules. Each granule can contain as many as 55,000 glucose units. Glycogen is found in the cytoplasm of liver and skeletal muscle cells primarily
How does the function of glycogen differ in liver and muscle? What is the biochemical basis for the difference, i.e. what pertinent enzyme is present in liver but not in muscle?
The function of liver glycogen is to maintain the blood glucose concentration, particularly during the early stage of a fast.
The function of muscle glycogen is to serve as a fuel reserve for synthesis of ATP that will power muscle contraction. Muscle glycogen is not available to other tissues because muscle lacks the enzyme glucose-6-phosphatase, a protein of the ER membrane.
Where and how is glycogen synthesized?
Glycogenesis occurs in the cytoplasm and can be divided into several stages.
- Synthesis of UDP-glucose
- glucose + ATP + kinase → glucose-6-phosphate + ADP
- glucose-6-phosphate + mutase → glucose-1-phosphate
- glucose-1-phosphate + UTP + glucose-1-P transuridylase → UDP-glucose + PPi
- Requirement of Primer to Initiate Glycogen Synthesis
- Glycogen synthase cannot initiate glycogen synthesis and can only add glucose to an existing chain. Consequently, glycogenesis requires a primer.
- The protein glycogenin (a homodimer) can prime glycogen synthesis and attach glucose residues through auto-glucosylation. The hydroxyl group of a specific tyrosine side-chain (tyr-194) serves as the site at which the initial glucosyl unit can be attached to the glycogenin.
- Elongation of Glycogen Chains
- A new glycosidic bond is formed between the -OH group on C-1 of the activated sugar and C-4 of the accepting sugar (the α-1,4 linkages in glycogen).
- Enzyme: glycogen synthase
- Branching in Glycogen
* Branching is catalyzed by “branching enzyme” also called glucosyl 4:6 transferase. This enzyme cleaves an α-1, 4 bond and transfers a chain (6 to 8 glucosyl residues) from the nonreducing end of the glycogen chain to another residue on the chain. The two chains are linked by an α-1,6 bond.
Where and how is glycogen degraded?
Glycogenolysis occurs primarily in the cytoplasm and involves 2 stages.
A. Shortening of chains
- The first step is catalyzed by the enzyme glycogen phosphorylase. This enzyme uses Pi to cleave the α-1,4 glycosidic bonds between the glucose residues at the nonreducing ends of the glycogen chain, releasing glucose 1-P; α-1,4 exoglucosidase; phosphorolysis; rate-limiting.
- This enzyme stops attacking α-1,4 glucosidic bonds four glucosyl residues from an α-1,6 branch point. The resulting structure is called a “limit dextrin.”
- Glucose-1-phosphate + mutase → glucose-6-phosphate
- The next step in glycogenolysis depends on the tissue under consideration. In liver the glucose 6-phosphate is hydrolyzed to free glucose by glucose 6-phosphatase. In peripheral tissues the glucose 6-phosphate produced will be oxidized in the glycolytic pathway.
B. Removal of branches
- The second stage is catalyzed by debranching enzyme. The debranching enzyme is a bifunctional protein that has two catalytic activities. The first is a 4-α-D-glucantransferase activity in which the outer three glucosyl residues of the limit dextrin are transferred to a nonreducing end by the breaking and formation of α-1,4 bonds (4,4 transferase activity), leaving only one glucosyl residue in α-1,6 linkage.
- This bond then is cleaved hydrolytically by the second activity of the debranching enzyme, which is its amylo-α-1,6 glucosidase activity. Free (non-phosphorylated) glucose is the product.
Which form, a or b, is the phosphorylated form for synthase, for phosphorylase, for phosphorylase kinase? For which of these enzymes is the phosphorylated form the active form?
Glycogen phosphorylase exists in two forms: 1) a or active form: phosphorylated 2) b or inactive form: dephosphorylated.
The a and b forms are interconverted by the action of phosphorylase kinase and phosphoprotein phosphatase.
Phosphorylase kinase, responsible for the phosphorylation and activation of glycogen phosphorylase, is itself regulated by phosphorylation dephosphorylation..
How does cAMP coordinate the regulation of glycogen metabolism?
cAMP regulates glycogen metabolism through the simultaneous activation of glycogenolysis and inhibition of glycogenesis through protein phosphorylation by cAMPdependent PKA.
What effect does phosphoprotein phosphatase have on synthase b, phosphorylase a, and phosphorylase kinase a? How is the activity of this phosphatase affected by glucagon? by insulin?
Phosphoprotein phosphatase converts:
- synthase b to synthase a (inactive)
- phosphorylase a to phosphorylase b (inactive), and
- phosphorylase kinase a to phosphorylase kinase b (inactive)
Phosphatase is promoted by insulin and inhibited by glucagon.
What is the consequence of epinephrine binding to β-adrenergic receptors? to α-adrenergic
Epinephrine binds to β-adrenergic receptors on the plasma membrane of both liver and muscle cells, and stimulates glycogen degradation via cAMP and PKA.
Intracellular Ca+2 is increased in liver cells in response to epinephrine binding to α-adrenergic receptors, activating phospholipase C, and generating IP3 (plus DAG) from PIP2.
The IP3 causes release of Ca+2 from the endoplasmic reticulum into the cytosol.
Ca+2 activates cytoplasmic glycogenolysis by activating phosphorylase kinase, and the free glucose produced in liver enters the blood.
DAG activates PKC that phosphorylates (inactivates) glycogen synthase.
How does Ca+2 affect glycogen metabolism? What are the causes of an intracellular rise in Ca+2 in muscle? Liver?
Ca+2 activates sarcoplasmic glycogenolysis by activating phosphorylase kinase, and the glucose 6-P produced enters glycolysis to power contraction Ca+2 activates cytoplasmic glycogenolysis by activating phosphorylase kinase, and the free glucose produced in liver enters the blood.
Ca+2 also is required for maximal activation of phosphorylase kinase a.
In what tissue does AMP have an effect on glycogen metabolism? What effect does it have?
AMP is a positive allosteric effector on phosphorylase b in the muscle. The AMP to ATP ratio reflects the energy state in muscle cells.
An increase in the ratio signals low energy and the need for glycogen degradation. AMP functions as an allosteric activator of muscle phosphorylase (myophosphorylase) b, directly activating this dephosphorylated form (b form) of the enzyme.
How do glucose and glucose 6-P affect glycogen metabolism?
When glucose is plentiful, hepatic glycogenolysis is decreased by glucose itself acting as an allosteric inhibitor of hepatic phosphorylase a.
The glucose 6-P formed from glucose is an allosteric activator of glycogen synthase b in both liver and muscle, thus increasing glycogenesis in these key sites of glycogen storage.
Summarize glycogen metabolism and all of its regulation
