SYLLABUS 6: Glycogen Metabolism Flashcards
what is glycogen
storage form of glucose
made up of many glucose units linked together by C1 of 1 glucose - C4 of adjacent glucose
C1-C6 links btwn glucoses make branches
what does branching do for glycogen
increases soubility
allows several avialable sites to be degraded simultaneously
under what conditions is glycogen made / broken down?
made: high energy, carbs, glucose conditions
broken down: low-energy, carbs, glucose conditions; vigorous exercise/stress; diabetes
where is glycogen stored
the cytosol of cells
most in liver, muscle
function of glycogen in liver
produce glucose to release to other tissues that need energy
function of glycogen in muscles
provide mucle with glucose in times of need - eg exercise, fight, flight
what does glycogen breakdown
1) phosphorylase
2) debranching enzyme
what is the reaction of phosphorylase on glycogen
(glycogen)n + Pi-> (glycogen)n-1 + G1P
this is IRREVERSIBLE
describe how glycogen break down occurs
1) phosphorylates breaksdown glycogen to a smaller glycogen by 1 unit of glucose, + G1P
removal of glucose unit occurs repeatedly until 4 residues from a branch point
2) debranching enzyme moves 3 of the 4 residues to another chain
3) the 4th residue, in the 1-6 glycosidic bond w/ the other chain, is hydrolyzed by the glucosidase activity of the debranching enzyme
this produces glucose + a straight polymer
4) phosphorylase continues to degrade teh straight polymer to G1P til the next branch point
what happens to the G1P produced from glycogen breakdown?
1) G1P is muated to G6P by phophoglucomutase
2) G6P enters glycolysis in the muscle or liver
3) G6P is hydrolyzed to glucose
4) glucose exits into the blood to be transported to other tissues
when is glycogen phoshphorylase active vs inactive
active: phosphorylated state
inactive: dephosphorylated state
what is glucagon in the liver, epi in the liver in muscle’s, effect on glycogen breakdown
glucagon and epinephrine activate G proteins
G proteins activate adenylyl cyclase to make cAMP
cAMP activates PKA
activated cAMP-PKA promotes phosphorylation of phosphorylase kinase, makes it ACTIVE
so GLUCAGON AND EPI cause the ACTIVE, PHOSPHORYLATED state of PHOSPHORYLASE, which means GLYCOGEN BREAKDOWN occurs
what is insulin’s impact on phosphorylase/glycogen breakdown?
insulin stimulates protein phosphatases
this promotes the dephosphorylated state of phosphorylase
this makes phosphorylase INACTIVE
so NO GLYCOGEN BREAKDOWN occurs
what kind of action does phosphorylase do
phosphoralysis
what kind of action does the debranching enzyme do
hydrolysis
when is glycogen synthesized?
high energy conditions; when have lots of glucose
how does glycogen synthesis occur?
1) G6P -> G1P by phosphoglucomutase
2) G1P -> UDP-glucose + PPi, by UTP
this UDP-glucose adds glucose residues on to an already existing glycogen, extends it
the PPi is cleaved to 2Pi
UDP-glucose adds new glucose units to the core primer glucose in 1-4 glycosidic bonds
how many high energy bonds does glycogen synthesis require
requires 3 high energy bonds to add 1 glucose to a glycogen polymer:
1 from ATP to go from glucose to G6P,
2 from formation of UDP-glucose w/ release of PPi, which is hydrolyzed to Pi
what is glycogenin
small protein core of the glycogen polymer wehre a tyrosine-OH is linked to 1 or more glucose residues
it’s here that UDP-glucose adds new glucose units, in 1-4 glycosidic bonds
what catalyzes the addition of a glucose residue to a glycogen polymer? what kind of rxn is this?
glycogen synthase
IRREVERSIBLE
how is a branch of glucose links added to glycogen
once glycogen synthase irreversibly builds up a number of glucose links,
**branching enzyme **transfers 6-7 glucose residues from the end of its chain -> C6-OH group of a glucose residue in another chain
this forms the 1-6 branching points
what is high level of G6P effect on glycogen synthase?
activates it
when is glycogen synthase active?
ACTIVE in the DEPHOSPHORYLATED state
INACTIVE in the PHOSPHORYLATED state
insulin’s effect on the glycogen synthesis enzymes?
HIGH levels of insulin stimulates PROTEIN PHOSPHATASE 1
this DEPHOSPHORYLATES phosphorylase and glycogen synthase
ACTIVATES glycogen synthase -> INCREASES glucose utilization
INACTIVATES phosphorylase -> DECREASES glycogen breakdown
what are the effects of glucagon/epi on glycogen synthesis?
INCREASE in EPI in MUSCLE or EPI/GLUCAGON in LIVER:
promotes PHOSPHORYLATED state
this STIMULATES GLYCOGEN BREAKDOWN by phoshporylating phosphorylase
this iNHIBITS GLYCOGEN SYNTHESIS by promoting phosphorylation of glycogen synthase
what phosphorylates glycogen synthase?
cAMP-PKA
this inactivates it
what occurs to phosphorylate and activate phosphorylase?
1) cAMP-PKA phosphorylates **phosphorylase kinase **
this activates phosphorylase kinase
2) activated phosphorylase kinase **phosphorylates phosphrylase **
this activates phosphorylase
what is the impact of an INCREASE IN EPI in Muscle
INCREASES glycogen breakdown
this PRODUCES G6P
G6P enters GLYCOLYSIS and ATP production for exercise, fight, flight, or stress
what is impact of INCREASED EPI/GLUCAGON on LIVER
Epi and Glucagon transcriptionally activate 6-phosphatase, an enzyme present in liver and not in muscle
6-phosphatase hydrolyzes G6P to glucose + Pi
this glucose then leaves the liver -> other tissue
why doesn’t increased epi/glucagon in liver cause -> glycolysis?
INCREASED epi/glucagon = DECREASED F2,6bisP
DECREASED F2,6 bis P = INCREASED the G6Pase
this blocks glycolysis and keeps G6P from hydrolyzing to glucose
why can G6P in the muscle enter glycolysis in the presence of increased epi? why doesn’t it get broken down to glucose, like in the liver?
the isoforms of F2,6 bis P kinase and phosphatase in muscle are different from those in the liver; they show opposite properties:
phosphorylation INCREASES the kinase activity, and DECREASES the phosphatase activity, in muscle, thus INCREASING F2,6 bis P levels and stimulating PFK activity and glycolysis in muscle
what’s the difference btwn the F2,6 bis P in liver vs muscle
MUSCLE F2,6 bis P is a POSITIVE effector, stimulator, of PFK; so high EPI levels -> glycolysis
LIVER F2,6 bis P is an INHIBITOR of PFK; so high EPI levels -> glucose -> other tissues
what causes neuronal signal for glycogen breakdown in muscle?
INCREASE in EPI -> INCREASE in Calcium
Calcium binds Calmodulin, a subunit of Phosphorylase kinase, and activates it - even when it’s in its low-active dephosphorylated state
this PROMOTES GLYCOGEN breakdown
this provides neuronal signal for regulation of glycogen breakdown
how does phosphorylase act as a “glucose sensor” in the liver?
in absence of glucose, phosphorylase binds protein phosphatase-1
this prevents phosphatase from dephosphorylating phosphorylase (= ACTIVE) and glycogen synthase (= INACTIVE)
so no glycogen synthesis occurs in the absence of glucose
in the presence of glucose,
glucose binds phosphorylase
this causes a conformational change, releases phosphatase-1 from phosphorylase
now phosphatase-1 is free; dephosphorylates phosphorylase (= INACTIVE) and glycogen synthase (= ACTIVE)
this allows glycogen to be synthesized in high glucose conditions
what causes glycogen storage diseases
glycogen breakdown is blocked
this interferes w/ liver’s ability to provide glucose & muscle’s ability to carry out muscular function under stress conditions
what organs can glycogen storage diseases impact
liver primarily
also organs with lysosomes
skeletal muscle
heart
RBC
