Glycogen/GSD - Abali 3/8/16 Flashcards
glycogen basics
storage form of glucose
glucose molecules attached in numerous chains to a core protein, glycogenin - base for elongating/degrading chains
glycogenolysis: first means of maintaining blood sugar
next step: gluconeogenesis (*remember: always running in the background to clear lactate from RBCs)
fuel sources within the body
- where do you find glycogen?
RBCs (exclusive) and brain (gl + ketones in starvation) NEED GLUCOSE as fuel at all times
1. proteins : breakdown of sk muscle → fuel gluconeogenesis
2. fats : useful for ATP production, not for gluconeogenesis
3. glycogen (small store)
- liver - used to regulate blood glucose levels
- skeletal muscle - used as fuel for muscles only (no G6Pase = can’t form, secrete glucose for use by other tissues)
maintenance of blood glucose
carried out by hepatic glycogen
- as post-prandial glucose levels drop, glycogenolysis and background gluconeogenesis pick up to compensate and maintain blood glucose
cardiac muscle and glycogen
cardiac muscle has v little glycogen
- uses primarily FA beta ox for energy
- doesn’t get much benefit from glycolysis
consequence: anything that interrupts flow of oxygenated blood to heart leads to serious damage/death
lactic acidosis and uric acid
in lactic acidosis, body will try to get rid of buildup via URAT1 transporter (organic anions - lactate - out, urate in) in kidneys
consequence: buildup of uric acid
*can also happen in ketoacidosis!
glucose polymers
starch: least branched, alpha 1:4 glycosidic bonds
cellulose: beta 1:4 glycosidic bonds
glycogen: most branched, alpha 1:4 glycosidic bonds
*glycogen and amylopectin (form of starch) also contain occasional alpha 1:6 bonds at branch points holding two chains together
why is glycogen a good source of energy?
why is it a better fuel reserve than fats?
- can be rapidly broken down into glucose
- enzymes of glycogen metab are bound to the surface
- many terminal glucoses particles = lots of potential to release glucose
- don’t need oxygen to generate energy (can take glucose through anaerobic resp)
why glycogen > fats for rapid energy?
- fats need oxygen for beta ox
- fats have to be mobilized from adipose tissue to wherever you need energy
- brain needs glucose → animals can’t turn fats into glucose
steps of glycogenesis
-
trap glucose: glucose → glucose-6-P
* glucokinase [liver], hexokinase [everywhere else] -
transitions: G6P → G1P → UDP-glucose
* phosphoglucomutase; G1P uridyl transferase -
glycogen synthase goes to work: strips glucose from UDP-glucose, adds it to an alpha 1:4 chain on glycogen (seeded on glycogenin core)
* glycogen synthase -
branching: if alpha1:4 chain is at least 11 residues long, at least 6 of those residues can be shifted and made into a new branch
* branching enzyme
steps of glycogenolysis
-
4trimming: glycogen branches stripped down to branches of 4 units each. released as G1P → isomerized into G6P → glucose [via G6Pase]
* glycogen phosphorylase -
debranching-step1: blocks of 3 residues are shifted from one terminal branch to another
* debranching enzyme -
debranching-step2: the single remaining residue on the cut branch (the alpha 1:6 moiety) is removed → linear chain of alpha 1:4 linkages. released as glucose
* debranching enzyme
implication: wayyyy more alpha 1:4 linkages than alpha 1:6s → much more glucose will be released through glycogen phosphorylase activity (90%) than debranching enzyme activity (10%)
glycogenolysis: fate of glycogen in the liver
the liver expresses G6Pase
- can modify G6P → glucose for release into bloodstream for brain/RBCs
- allows liver to regulate blood sugar levels
glycogenolysis: fate of glycogen in the skeletal muscle
skeletal muscle DOES NOT EXPRESS G6Pase
- G6P is stuck in cells and sent into glycolysis → pyruvate
- if anaerobic: pyruvate → lactate [lactate DH]
- if aerobic: pyruvate → acetyl CoA [PDH] → TCA cycle
glycogen metabolism regulation: basics
1. allosteric regulation
2. hormonal regulation
- glucagon, epinephrine : activate glycogenolysis
-
insulin
- shuts down glycogenolysis (dephosphorylates/deactivates glycogen phosphorylase)
- triggers glycogenesis (dephosphorylates/activates glycogen synthase)
3. neuronal regulation
allosteric regulation of glycogen metabolism
+ = glycogenesis: G1P → glycogen
[via glycogen synthase]
- = glycogenolysis: glycogen → G1P
[via glycogen phosphorylase]
LIVER
+ : G6P [buildup from import, leftover from glycolysis]
- : glucose, ATP, G6P [“endpdts” of glycogen phosphorylase]
*general rule: high energy inhibits buildup
MUSCLE
+ : G6P [buildup from import, leftover from glycolysis]
- : ATP, G6P; Ca, AMP
*general rule: high energy inhibits buildup
covalent regulation of glycogen metabolism: epinephrine
receptors in liver and muscle
activates cAMP → PKA pathway → phosphorylates target
- P’s glycogen synthase: deactivates it
- P’s glycogen phosphorylase: activates it
covalent regulation of glycogen metabolism: glucagon
receptors in liver ONLY
activates cAMP → PKA pathway → phosphorylates target
- P’s glycogen synthase: deactivates it
- P’s glycogen phosphorylase: activates it
regulation of glycogen metabolism: Ca
Ca is elevated in active muscle
activates phosphorylase kinase
- P’s glycogen phosphorylase: activates it
takeaway: high Ca leads to glycogenolysis
what causes upregulation of glycogenolysis?
acute and chronic stress trigger glycogenolysis
- physiologic (increased use of blood glucose during exercise)
- pathologic (blood loss/shock)
- psychological (acute/chronic threats)
4 hormones [sources] : triggers → effect on glycogenolysis
acute and chronic stress trigger glycogenolysis
- glucagon [pancreatic alpha cells] : hypoglycemia → rapid activation
- epinephrine [adrenal medulla] : acute stress, hypoglycemia → rapid activation
- cortisol [adrenal cortex] : chronic stress → chronic activation
- insulin [pancreatic beta cells] : hyperglycemia → inhibition
LIVER
fasting state
[blood] → tissue response
[glucagon high, insulin low]
→
glycogenolysis high,
glycogenesis low
LIVER
carb meal
[blood] → tissue response
[glucose high: insulin high, glucagon low]
→
glycogenolysis low,
glycogenesis high
LIVER
exercise/stress
[blood] → tissue response
[glucose high, epi high]
→
glycogenolysis high
MUSCLE
fasting
[blood] → tissue response
[insulin low]
→
glucose transport low
glycogenesis low
MUSCLE
carb meal
[blood] → tissue response
[insulin high]
→
glucose transport high
glycogenesis high
MUSCLE
exercise/stress
[blood] → tissue response
[epi high; tissue levels of AMP high]
→
glycogenesis low
glycogenolysis high
glycolysis high
key enzymes in glycogen metabolism
- glucose 6 phosphatase : converts G6P → glucose for export
- alpha 1,6 glucosidase (aka debranching enzyme)
- glycogen phosphorylase : breaking down alpha 1:4 glycosidic linkages
- branching enzyme
PAS-D staining
periodic acid-Schiff-diastase
PAS stains glycogen
diastase = alpha amylase, which breaks glycogen down
PAS-diastase staining allows you to see glycogen stores by showing you a before/after of degradation
von Gierke disease
type I
glucose 6 phosphatase deficiency
enzyme affected : G6Pase
glycogen : normal
tissues affected : liver, kidney
- inability to export glucose from gluconeogenesis or glycogenolysis → severe hypoglycemia
tx : frequent feeding with carbs (uncooked starch), possibly nasogastric tube to feed while sleeping
Pompes disease
type II
alpha 1,4 glucosidase deficiency
enzyme affected : alpha 1,4 glucosidase (aka acid maltase)
glycogen : accumulates in lysosome due to inability to degrade
tissues affected : heart
- accumulation of glycogen in cardiac tissue leads to LVH, cardiomegaly
- typically, death before 2
- might also see accumulation/weakness in muscle
tx : recombo alpha 1,4 glucosidase given to pt might help some symptoms
Coris disease
type III
alpha 1,6 glucosidase deficiency
[debranching enzyme]
enzyme affected : alpha 1,6 glucosidase (aka debranching enzyme)
glycogen : shorter branches, impeded glycogenolysis
tissues affected : liver
- hepatomegaly
- hypoglycemia
Andersens disease
type IV
alpha 4,6 glucosidase deficiency
[branching enzyme]
enzyme affected : alpha 4, 6 glucosidase (aka branching enzyme)
glycogen : no branches : long, insoluble chains
tissues affected : liver
- hepatomegaly
- cirrhosis (presents as infantile cirrhosis → failure to thrive, death)
McArdles disease
type V
glycogen phosphorylase (muscle isozyme) deficiency
enzyme affected : glycogen phosphorylase (muscle)
glycogen : normal, but accumulates
- can’t be broken down for use in anaerobic glycolysis; dependent on circulating glucose or eventual FA beta ox
tissues affected : muscle
- decreased exercise tolerance w/ muscle cramps
- myoglobinuria
Hers’ disease
type VI
glycogen phosphorylase (liver isozyme) deficiency
enzyme affected : glycogen phosphorylase (liver)
glycogen : normal, but accumulates
- can’t be broken down for blood glucose regulation
tissues affected : liver
- hepatomegaly
- fasting hypoglycemia
- why only fasting? you still have gluconeogenesis runnning in background!
Taruis disease
type VII
muscle PFK1 deficiency
enzyme affected : phosphofructokinase (muscle)
glycogen : normal
tissues affected : muscle
- decreased exercise tolerance
- myoglobinuria
- hemolytic anemia
causes of hyperuricemia
- increased lactate/other anion being secreted → antiport-ing of urate through URAT-1
- increased G6P can lead to increase in purine synth through HMP pathway → uric acid
- decreased hepatic concentration of P (inhibitor of AMP deaminase) → increased purine catabolism, producing uric acid
- P would typically be released by G6Pase, of which there is none in von Gierkes disease
- no G6Pase → no P → no inhibition of AMP deaminase (rate limiting enzyme for A nt → uric acid) → more uric acid
von Gierke’s disease : buildup of TAGs and cholesterol
lack of G6Pase forces the G6P released through glycogenolysis to go through glycolysis
→ buildup of acetyl CoA
→ increase TAG synth
→ increase synth/secretion of VLDL
