Glycogen Metabolism Flashcards
Insulin causes glycogen ___
Glucagon causes glycogen __
During prolonged fasting/starvation, the brain can also use __ as a fuel source
Insulin = glycogen synthesis
Glucagon = glycogen breakdown
Prolonged fasting/starvation -> brain can use ketone bodies
Glycogen is synthesized and stored in what two types of tissue? How do they differ in what they do w/ the glycogen?
Both breakdown the glycogen into glucose 1-phosphate then glucose 6-phosphate
THE MUSCLE locks glucose 6-phosphate into the cell to use for glycolysis –> energy
THE LIVER breaks down glucose 6-phosphate with glucose 6-phosphatase in gluconeogenesis –> glucose to release to blood for other cells during fasting
Structure of glycogen
Linear polymer of glucose residues aligned in repeating a-1,4 glycosidic linkages, with periodic branches formed by a-1,6 glycosidic linkages
Steps of glycogen synthesis
- Glucose-6-phosphate –phosphoglucomutase–> Glucose-1-phosphate
- Glucose-1-phosphate + UTP –UDP-glucose pyrophosphorylase -> PPi + UDP-Glucose
- PPi is broken down into two Pi, whcih drives the rxn
-
Glycogen synthase transfers UDP-glucose to glycogen to form a-1,4 linkages
- Glycogen synthase deficiency -> type O glycogen storage disease in hepatocytes -> low BG, high ketone
-
Glycosyl 4,6 transferase creates branches via a-1,6 glycosidic linkages
- Deficiency -> Type IV/Anderson’s glycogen storage disease in skeletl muscle and hepatocytes -> hepatomegaly, splenomegaly, muscle damage, myoglobin in urine
3 benefits of branching
- Increases the # of ends on the molecule for more rapid storage or removal of glucose when needed
- Better for energy storage
- Increases glycogen solubility
Two main enzymes of glycogenolysis
Glycogen phosphorylase: removes single glucose residues by hydrolyzing a-1,4 glycosidic linkages from the ends of linear chains and phosphorylates them –> glucose-1-phosphates
Debranching enzyme has 2 enzymatic activities
- Glucosyl 4,4 transglycosidase transfers residues between branches in a-1,4 glycosidic linkages
- a-1,6 glucosidase hydrolyzes a-1,6-glycosidic linkages, producing glucose
De novo glycogen synthesis
Glycogenin is a “primer” with intrinsic enzymatic activity;
It transfers glucose from UDP-glucose to glycogenin to make short chain of a-1,4-linked residues then glycogen synthase and Branching enzyme picks up where it left off
Process of glycogenolysis
- Glycogen phosphorylase shortens linear chains to 4-residue branches
- Glucosyl 4,4 transglycosidase transfers 3 glucose residues from shroter chains to longer chains (which glycogen phosphorylase will further hydrolyze)
- a-1,6 glucosidase hydrolyzes that single glucose residue’s a-1,6 linkage on that short branch
Deficiency of glycogen phosphorylase causes
Type V/McArdle glycogen storage disease in muscle
Type VI (Hers) glycogen storage disease in liver
Exercise induced muscle cramps and pain, myoglobin in blood, hepatomegaly
Glycogen phosphorylase requries what cofactor?
pyridoxal phosphate (PLP) - the active form of vitamin B6
The major product of glycogen breakdown is Glu
Glucose-1-phosphate (the glucose from debranching is less)
What happens to the glucose-1-phosphates generated from glycogenolysis?
Converted to glucose-6-phosphate by phosphoglucomutase, and enters the glycolytic or gluconeogenic pathways, dpending on whether the tissue is in muscle or liver
Deficiency in the debranching enzyme
type IIIa (Cori of Forbes) glycogen storage disease
Affects liver, skeletal, and cardiac muscle -> infants’ hepatomegaly & generalized myopathy
Liver specific version -> type IIIb glycogen storage disease: infants’ hepatomegaly
Pompe’s disease - enzyme affected, where, and symptoms
Lysosomal acidic a-glucosidase (basically lysosome form of glycogenphosphorylase)
Muscle (skeletal & cardiac)
Lethal within 2 yrs in kids; myopathies in adults
Von Glerke’s disease
Glucose 6-phosphatase
Hepatocytes
Hepatomegaly or Splenomegaly
Type 0 glycogen storage disease
Glycogen synthase
Liver
Low blood glucose, high ketone bodies, early death
Andersen’s disease
Branching enzyme
Liver, skeletal muscle
Hepatomegaly, Splenomegaly, Myoglobin in urine
McArdle’s
Muscle phosphorylase
Skeletal muscle
Exercise-induced cramps and pain; myoglobin in urine
Hers’s glycogen storage disease
Liver phosphorylase
Liver
Hepatomegaly
Tarui’s
Muscle PFK-1
Muscle, erythrocytes
Exercise induced ramps and pain; myoglobin in urine; hemolytic anemia
Fanconi-Bickel
GLUT2
Liver
Failure ot thrive, enlarged liver, rickets, kidney dysfunction
During the last trimester, babies’ livers…
Start storing glycogen so they can survive the postnatal caloric deprivation (12 hrs until nursing)
So if the mom was anorexic, then the baby would have failure to thrive because no glycogen storage
During labor and birth, neonates produce the hormone ___
epinephrine to promote glycogenolysis
In the fasting state, glucagon promotes glycogenolysis in the ___. Epinephrine promotes it in the ___
Glucagon in liver
Epinephrine in muscles
How does phosphorylation impact glycogen synthase and glycogen phosphorylase? When would phosphorylation occur?
Phosphorylation - occurs in the fasting state via glucagon
INHIBITS glycogen synthase
ACTIVATES glycogen phosphorylase
Insulin signaling does what to glycogen synthase and glycogenphosphorylase?
It dephosphorylates them, which activates glycogen synthase and inhibits glycogen phosphorylase.
Phosphorylase kinase
Phosphorylates and activates glycogen phosphorylase
Remember glucagon phosphorylates -> wanna break down glucose
High BG -> insulin –> dephosphorylates all 3 enzymes (glycogen synthase, glycogen phosphorylase, phosphorylase kinase)
Activates glycogne synthase
Inactivates glycogen phosphorylase & phosphorylase kinase
–> glycogen is synthesized
Epinephrine/Glucagon Cascade (low BG)
- Epinephrine & glucagon bind to GPCR
- Adenylyl cyclase > cAMP > PKA
- PKA phosphorylates phosphorylase kinase
- Phosphorylase kinase phosphoryaltes glycogen phosphorylase
- Breaks down glycogen to glucose-1-phosphate
-
Phosphoglucomutase converts it to glucose 6-phosphate
- Powers glycolysis in muscles to power contraction
- Powers gluconeogenesis in the liver to increase BG
Ca++ and AMP can amplify the glucagon/epinephrine cascade by enhancing
PKA and glycogen phosphorylase
Insulin signaling stimulates ____ , which hydrolyzes phosphate groups to inactivate glycogen phosphorylase.
Phosphorylase phosphatase (PPI) inactivates glycogen phosphorylase
Glucose as an allosteric inhibitor
In the liver, glucose can bind allosteric sites on glycogen phosphorylase to make its phosphorylate serine residues more accessible to PP1 –> PP1 dephosphorylates and inactivates glycogen phosphorylase
Glucagon and epinephrine __ PP1
inhibit
Glucose and glucose 6-phosphate can allosterically ___ glycogen synthase
activate
When BG is low, glycogen synthase is ____ by ___.
phosphorylated by glycogen synthase kinase 3 (GSK3)
Insulin signals __ GSK3 activity, maintaining glycogen synthase in its unphosphorylated, active state
inhibit GSK3
What enzyme do muscle cells lack that liver cells have?
Glucose-6-phosphatase.
Thus, any glucose-6-phosphate generated from glycogenolysis in teh muscle is used within the muscle cell in the glycolytic pathway
Why does glucose 6-phosphatase deficiency cause the symptoms of GSD?
This enzyme is crucial in glycogenolysis & gluconeogenesis–> hypoglycemia between meals
Other mechanisms get deployed instead: Alanine from muscle protein breakdown becomes lactate and it outcompetes uric acid in kidney cells -> uric acid lvls also increase -> gout
