Glycogen Metabolism Flashcards
In muscle glycogen is broken down to…
Glucose-6-phosphate
Which enters glycolysis to generate energy during muscle contraction
In liver…glycogen is boken down to …
Glucose and released into the bloodstream to maintain blood
Liver glycogen —> G6P —> glucose +Pi
Glycogen structure
Glucose added lineraly in repeating
Alpha-1,4 linkages
Branches with alpha-1,6 links
Glycogen synthesis-phosphoglucomutase
Step1: G6P —> G1P
(Phosphoglucomutase)
Reversible (glycogen breakdown pathway)
Glycogen syn.
UDP-glucose pyrophosphorylase
Step2:
G1P + UTP —> UDP-glucose +2Pi
Glucose is activated with a UDP carrier molecule
Pyrophosphate is hydrolyzed to drive activation
Glycogen syn.
Glycogen synthase
Step 3: addition fo glucose to glycogen
Generates the alpha-1,4 linkage and extends linear polymer N+1
Glycogen synthase deficiency
Causes Type O glycogen storage disease
Affects liver cells mostly
Less glycogen —> less blood glucose —> more ketone bodies —> death
Glycogen syn.
Glycogen branching enzyme (glycosyl 4,6 transferase)
Generates brach points containing a-1,6 linkages
Transferes flucose to C-6 hydroxyl of more interior positioned glucose
Increase…
- # of ends for rapid addition and removal
- Amount glucose stored
- Solubility
Branching enzyme deficiency —>
Type IV (or Andersens) glycogen storage disease
Liver and muscle cells
Causes hepatomegaly, splenomegaly, and damage to muscle can results in myoglobin detected in the urine
De novo glycogen synthesis
Initiation of glycogen beings with protein Glycogenin, a glycogen ‘primer’
Glycogenin catalyzes the transfer of glucose from UDP-glucose to glycogenin to make a short cahin of alpha1,4-linked residues
Glycogen breakdown
Glycogen phosphorylase
- Removes a1,4 linkages off linear nonreducing ends —> G1P
2. Pyridoxal phosphate (PLP, active Vitamin B6) is an essential cofactor of glycogen phosphorylase
Glycogen phosphorylase deficiency
Type V (or McArdle) glycogen storage disease in muscle (excercise induced muscle crampls and pain, myoglobin in blood)
OR
Type VI (or Hers) glycogen storage disease in liver (hepatomegaly)
Breakdown - debranching enzyme
Glucosyl 4,4-transglycosidase:
Transfers 3 glucose residues (yellow) to another linear chain
A-1,6-glucosidase:
Removes single a-1,6 linked residues to produce glucose
Major product of breakdown
G1P
Converted to G6P by phosphoglucomutase —> glycoysis or gluconeogensis depending on tissue
Debranching enzyme deficiency
Type IIIa (Cori or Forbes) diseae
Affects liver, skeletal muscle, cardiac muscle,
Hepatomegaly in infants and generalized myopathy
Liver-specific deficiency = Type IIIb…hepatomegaly in infants
Type VII disease
Muscle PFK-1 is fucked
Exercised induced cramps and pain
Hemolytic anemia
Type XI disease (Fanconi-Bickel)
GLUT2 fucked
Liver
Failure to thrive, enlarge liver, rickets, kidney dysfunction
Clinical case:
Cyanotic, limp at birth due to bradycardia during contractions
Mother had numerous UTIs, sever loss of appetite and recurrent vomiting
Therefore newborn is malnourished, low weight…heart and resp. Rates are rapid
Low serum glucose
WHAT IS GOING ON????
- Fetal glycogen is major fuel in early hours of life
- Healthy full term babies are born with adequate glycogen stores to survive short term (12 hours) postnatal caloric deprivation
- B/c mother was markedly anorexic during last trimester…when fetal liver normally stores glycogen,,,fetal liver glycogen stores were below normal
- Patient became profoundly hypoglycemic within 5 hours of birth because of low to depleted glycogen stores
NOTE: during labor, neonates produce Epinephrine…
Regulation of glycogen metabolism
- Phosphorylation
=glycogen synthase
=glycogen phosphorylase
=phosphorlase kinase - High blood glucose —> glycogen synthesis
- Low blood glucose —> breakdown
Regulation of epinephrine/glucagon cascade
- Binding of Epi (muscle) or glucagon (liver cells, epi) activates GPCR Gsalpha
- Rise [cAMP] —> activates PKA phosphorylation cascade begins
- PKA phosphorylates/activates
- phosphorylase kinase —> phosphorylates/activates glycogen phosphorylase - Cascade and allosteric regulators amplify signal
- Glycogen breakdown provides glucose
Muscle: glucose for glycolysis muscle contraction
Liver - glucocse to elevate blood glucose level
Regulation of glycogen phosphorylase
Dephosphorylated GS = active
Phosphorylated = inactive
Phosphorylation status mediated by opposing activites of GSK3 and PP1
Glucagon (from alpha cells) = fast activation
Epi (from adrenal medulla) = fast activation
Cortisol (adrenal cortex) = chronic activation
Insulin (betal cells) = inactivation
