Chapter 13 The Glycogen Metabolism Flashcards
What is glycogen?
a storage carbohydrate of glucose.
What are our major sources of glucose for metabolism?
ingested glucose, gluconeogenesis, and glycogen
Why is glucose stored in the form of glycogen as opposed to free glucose?
to avoid osmotic shock
Why do we need glycogen?
storing glucose allows for a quick release of energy rich molecules for those organs that absolutely depend upon it.
Glucose can be metabolized in the absence of oxygen, so our muscles can use it when we are oxygen deficit.
Where can we find glycogen?
mostly skeletal muscle and liver.
How is glycogen classified?
glycogen is a branched homopolysaccharide.
contains alpha (1–>4) linked glucose subunits
contains alpha (1—>6) branches
Is glycogenin an enzyme?
pseudo enzyme
What is the limitation of glycogenin?
glycogenin is used to start the process but once the glycogen chain is longer it does not fit in the active site.
What is function of phosphoglucomutase?
interconversion of glucose-6-phosphate and glucose-1-phosphate
glucose-1-phosphate to glucose-6-phosphate
Glucose entry reactions
- glucose to glucose-6-phosphate catalyzed by hexokinase
- glucose-6-phosphate to glucose-1-phosphate by phosphoglucomutase.
- glucose-1-phosphate to UDP glucose, PPi leaving group
What does the priming step of glycogen synthesis involve?
The OH of a tyrosine residue connected to glycogenin carries out a nucleophilic attack on the oxygen of UDP-glucose. PPi is leaving group.
In the subsequent steps the 4’-OH carries out the nucleophilic attack on another UDP glucose continuing the process.
What happens to glycogenin after 6-8 UDP-glucoses have been added?
The chain is too large, glycogenin does not fit, glycogen synthase comes in and does the same job that glycogenin was doing.
What is the job of the glycogen branching enzyme?
It will cut an alpha 1-4 bond typically 4 glucose units and then form an alpha 1-6 connection. Glycogen synthase will start to extend the branches as well.
Are branching enzymes regulated?
Branching enzyme is unregulated, branches are added as needed
Glycogen phosphorylase
a phosphoric acid does nucleophilic attack on carbon 1, this gives us glucose-1-phosphate and glycogen shortened by one reside.
How many times does glycogen phosphorylase phosphorylate the glycogen?
glycogen phosphorylase removes successive glucose molecules until it reaches the fourth glucose unit from a branch.
Why can glycogen phosphorylase not act within 4 residues of a branch point?
due to the physical size of the enzyme not being able to reach a branch due to crowding
Which cofactor does glycogen phosphorylase use?
The pyridoxal phosphate (PLP cofactor).
What specifically does the glycogen phosphorylase use from the cofactor?
the phosphoric acid group
What is the debranching enzyme used for?
they are used to remove glucose residues 4 units within the branch.
three glucose residues are shifted to a nearby non-reducing end and they are reattached via alpha-1-4 linkage.
the single glucose residue remaining at the branch is released as free glucose by the debranching enzyme’s alpha-1-6 glucosidase activity.
Is glycogen phosphorylase processive or distributive?
Processive because it continues to act on the substrate without dissociating.
What happens to glucose-1-phosphate in the muscle?
Glucose-1-phosphate is converted to glucose-6-phosphate and then directly enters glycolysis.
What happens to glucose-1-phosphate in the liver?
Liver wants to send glucose from glycogen to rest of the body. Glucose-6-phosphate in liver goes to the ER lumen where the phosphate group is stripped off.
The free glucose then leaves the ER and enters the blood through the GLUT2 transporter.
Why is glucose-6-phosphatase located in the ER?
if this enzyme were cytoplasmic it would remove phosphate groups off of glucose that were planning to go through glycolysis.
How does insulin regulate glycogen synthesis?
insulin released when glucose is high, inhibits glycogen breakdown, and stimulates glycogen synthesis.
How does glucagon regulate glycogen synthesis?
glucagon released when glucose is low. Glucagon binds to GPCR, stimulates synthesis of cAMP, activation of protein kinase A results in phosphorylation of glycogen phosphorylase stimulating glycogen breakdown.
When is glycogen synthase active?
when it is not phosphorylated
When is glycogen phosphorylase active?
when it is phosphorylated
What is the glycogen code?
phosphorylated results in glycogen breakdown
unphosphorylated results in glycogen synthesis
What is the regulation of glycogen metabolism by glucagon and epinephrine?
glucagon and epinephrine bind to a GPCR.
The GPCR undergoes a conformational change and activates G alpha s.
G alpha s activates adenylate cyclase which stimulates the synthesis of cAMP.
cAMP activates protein kinase A
Protein kinase A phosphorylates phosphorylase kinase activating it.
Phosphorylase kinase phosphorylates glycogen phosphorylase activating it.
Glycogen phosphorylase breaks down glycogen.
Regulation of glycogen metabolism by insulin
insulin activates protein phosphatase-1.
Protein phosphatase-1 dephosphorylates glycogen synthase making it active.
Protein phosphatase dephosphorylates glycogen phosphorylase inactivating it and also dephosphorylates phosphorylase kinase so it cannot phosphorylate the glycogen phosphorylase.
What is the major kinase that regulates glycogen synthase?
Glycogen synthase kinase
What is the effect of GSK on glycogen metabolism?
GSK inhibits glycogen synthesis by phosphorylating and inhibiting glycogen synthase.
How is the activity of GSK regulated?
Insulin phosphorylates IRS
Deactivation of PI3 kinase.
Generates PIP2 ligand PDK-1 and Akt to the membrane.
PDK and Akt is a kinase
Turns GSK kinas off
Glycogen synthase becomes active.
How does insulin regulate GSK through both GSK and PP1?
insulin inhibits GSK and activates PP1 which activates glycogen synthase
What is allosteric regulator of muscle glycogen phosphorylase?
ATP, AMP, and glucose-6-phosphate.
AMP high, favors the shift to relaxed state frees more glucose residues.
What is allosteric regulator of liver glycogen phosphorylase?
glucose, glucose inhibits phosphorylase
What are glycogen targeting proteins?
responsible for bringing together glycogen synthase, glycogen phosphorylase, and protein phosphatase on the glycogen particle.
Insulin results in the phosphorylation of GM, PPI is activated. Activation of PP1 results in dephosphorylation of PK, GP, and GS.
glucagon or epinehprine bind to second site and cause PP1 to dissociate from glycogen particle. PKA phosphorylates Inhibitor 1 protein which binds to and inhibits any activity of PP1.
