Unit 3: Glycogen

the protein core of a glycogen molecule is

a glycogenin protein

which cell types store glycogen

• muscles

• liver

only either ____ or ___ can occur at a time

glycolysis or gluconeogenesis

substrate for generating glycogen

glucose-1-phosphate

• this is what comes off as glucose are removed and simultaneously P’d as glycogen phosphorylase cleaves them during glycogenolysis

what makes glycogen such a good storage molecule

its highly branched structure allows for glucose molecules to be removed from it at many different ends at once

average length of a glycogen branch

13 glucose residues

the liver secretes

glucose from glycogen breakdown into the bloodstream

can our bodies convert fat to glucose or early glycolysis intermediates?

no

• thats why glycogen is helpful as a storage unit

glycogen structure

• alpha(1,6) links at branch points

• alpha(1,4) links within a single strand between glucose molecules

see how glycogen branches out from the center glycogenin

why are FAs more energy rich than glycogen?

since FAs have more reduced C-C bond

functions of glycogen

• maintains blood-glucose levels between meals

• keeps the brain supplied with glucose (except when starving)

• provides energy for sudden strenuous activity

• can provide energy in the absence of oxygen

many ____ surround glycogen molecules in cells

water

“well-fed hormone”

insulin

“hunger hormone”

glucagon

epinephrine

favors glycogenolysis

• fight or flight hormone

glucose molecules are removed from the glycogen’s ____ ends

nonreducing

initiation of gluconeogenesis when blood glu is high

• glucose enters a cell and gets P’d to glucose-6-phosphate by hexokinase so it can stay in the cell

• glucose-6-phosphate gets converted to glucose-1-phosphate by phosphoglucomutase

  • P’d Ser of phosphoglucomutase gives its P to the C6 of glucose-1-phosphate then the same Ser takes the P from the C1 of glucose, yielding glucose-6-phosphate

the formation of glycosidic linkages during glycogenesis is

endergonic

• so must be coupled with an exergonic rxn (UTP hydrolysis)

formation of glycosidic bonds during glycogenesis

• a sugar phosphate breaks the phsophoanhydride bond between the first and second P of UTP, yielding 2 Ps together and a sugar phosphate on the UMP

• now the sugar-phosphate-UMP has energy to attach to things

• the 2 P cleaves into 2 Pi

• so net rxn is

  • sugar-P + UTP —> UDP-sugar + 2Pi

• the rxn is driven by the removal of the 2 pi by other rxns

UDP-sugar

uridine diphosphate glucose

• has 2 phosphoryl bonds, so is highly energized

UDP-glucose can be

formed into glycogen by glycogenin, glycogen synthase, and branching enzyme

glycogenin is a

dimer

• nucleates into glycogen

initiation of glycogenesis (step 1)

• glycogenin has a Tyr side chains where growth nucleates from

• glucosyltrasnferase activity of glycogenin transfers the glucose from UDP-glucose onto the glycogenin

• the C1 of the glucose adds onto the OH of the Tyr of glycogenin

• now the glucose’s nonreducing end points out for other glucose to add onto it

• chain extending activity occurs (catalyzing alpha (1,4) linkages to add more glucose of oyther UDP-glucose on) until 6 more glucose have been added, since the glycogenin active site can only hold 6-7 sugars

how many sugars/glucose can the active site of glycogenin hold?

6-7

step 2 of glycogenesis

• glycogen synthase breaks the phosphodiester bond of UDP-glucose and forms a alpha(1,4) glycosidic bond between glucose and the growing chain at its nonreducing end

• so a UDP without a glucose is left as byproduct

• once the chain is about 13 sugars long, it will branch out via branching enzyme

step 3 of glycogenesis

• branching enzyme removes 6-7 terminal glucose molecules from the nonreducing end by breaking their glycosidic bonds (once there are at least 11 in the total chain) and moves them to a new section to form a new branch

• creates alpha (1,6) linkages at branch points at newly formed branches

• so now you have 2 chains instead of one, so even more glucoses and branches can be added by glycogen synthase and branching enzyme working together

how many glucose do you need in a chain before branching enzyme can form a new branch

11

the outermost tiers of glycogen are

not yet branched

the enzymes for glycogenesis and glycogenolysis are

very physically close to glycogen granules

• for easier regulation

3 enzymes that help form glycogen (glycogenesis)

• glycogenin

• glycogen synthase

• branching enzymes

3 enzymes that help convert glycogen to glucose-6-phosphate (which can be converted into glucose) (glycogenolysis)

• glycogen phosphorylase

• phosphoglucomutase

• debranching enzyme

step 1 glycogenolysis

• glycogen phosphorylase cleaves the alpha(1,4) linkages of glycogen from the nonreducing end to yield glucose-1-phosphate using a Pi to form a similar rxn to hydrolysis

• so Ps the sugar as it breaks it off

• stops removing glucoses once there are only 4 sugars left on the chain

glycogen phosphorylase is aka 

phosphorylase

step 2 glycogenolysis

• phosphoglucomutase isomerizes glucose-1-phosphate to glucose-6-phosphate

  • the P’d Ser of phosphoglucomutase Ps glucose-1-phosphate’s C6

  • then the Ser takes the P from the C1 of the glucose1,6-biphosphate, yielding glucose-6-phosphate

step 3 glycogenolysis

• debranching enzyme hydrolyzes the alpha(1,6) glycosidic bonds at branch points of glycogen

• transfers the last 3 glucose residues of 4 total attached to a branch point to a nearby nonreducing end, forming 1 longer chain

• then debranching enzyme removes the single glucose at the branch point off, yielding 1 glucose molecule

• the unbranched polysaccharide can easily be acted on now to remove glucoses

• so debranching enzyme acts as both a transferase and a hydrolase

debranching enzyme acts as

both a transferase and a hydrolase

____ in muscle and most tissues feeds directly into glycolysis

glucose-6-phosphate

the liver excretes

glucose-6-phosphate to the blood (but most convert the glucose-6-phosphate to glucose first)

conversion of glucose-6-phosphate to glucose

• so the liver can transport glucose-6-phsophate from glycogenolysis out to the blood to be used as glucose

• a G6P transporter lets G6P into the ER lumen, then glucose-6-phosphatase removes the P from glucose-6-phoaphate to yield glucose and a Pi

• both the glucose and Pi moves out of the ER (glucose via GLUT2) and Pi via a Pi transporter) and into the bloodstream to be used

is glucose-6-phosphate used as energy for the liver?

no its gets converted into glucose to be transported into the bloodstream

glycogen storage diseases

• when people have inherited defected enzymes for glycogenolysis or glyconeogenesis

• so affects liver and muscle cells the most since that’s where glycogen gets broken down the most

• can cause slow developmental growth, enlarged liver since you have an excess of glycogen, weak muscles, muscle pain/cramping

• can use enzyme replacement therapy, but doesn’t always help

hormonal regulation of glycogen phosphorylase

• phosphorylase can be in a or b form (a is active)

• phosphorylase b kinase phosphorylates phosphorylase b to make it into a form, which is active (triggering glycogenolysis)

• PP1 (phosphorylase phosphatase-1) converts phosphorylase a to b form by removing the Ps from a form

• glucagon from the liver, epinephrine, Ca2+, AMP, PKA all incr the /activate phosphorylase b kinase to incr the conversion of b to a form, making it active

• the Ser’s of phosphorylase get P’d and unP’d

PP1 (phosphorylase phosphatase-1) ___ phosphorylase

inactivates

• by removing its P and turning it into b form (triggering glycogenesis)

phosphorylase b kinase ____ phosphorylase

activates and Ps

• makes it into a (active) form, triggering glycogenolysis

steps of how PKA activates phosphorylase b kinase

• muscle and liver cells GPCRs receive epinephrine or glucagon (respectively) and their galpha protein gets activated, activates adenylyl cyclase to make cAMP, which activates PKA, which activates phopshorylase b kinase to form phosphorylase a (active form)

• phosphorylase in a form cleaves sugars from glycogen

• so glycogenolysis is encouraged

things that activate phosphorylase b kinase

• Ca2+

• AMP

• epinephrine

• glucagon

• P’d Ser of the enzyme (this is what activates it)

phosphorylase in the liver

• is a glucose sensor

• once glucose levels get high, glucose binds to the allosteric sites of phosphorylase a, causing the Ser’s face out of the phosphorylase when it is P’d so that they can be removed easier (allows for regulation) to convert it to phosphorylase b form

• when insulin comes in (bc glucose levels high), it also helps convert phosphorylase a to phosphorylase b to inhibit glycogenolysis since glucose levels are high again

glycogen synthase in inactive when

P’d

glycogen synthase is ___ regulated

hormonally

regulation of glycogen synthase

• when blood glu is high, insulin inhibits GSK3 (glycogen synthase kinase-3), which phosphorylates glycogen synthase at its 3 Ser’s a to b form (inactive)

• high blood glu causes insulin to activate PP1, which removes the P from glycogen synthase b to form glycogen synthase a (active)

• glucose-6-phosphate can also activate PP1

• glucagon and E inhibit PP1

• before GSK3 can turn a into b, casein kinase 2 (CKII) must prime the glycogen synthase

where is glycogen synthase P’d

at its 3 Ser residues

• all 3 must be P’d to make it into the inactive glycogen synthase b form

which form of glycogen synthase is the activated form?

a form

• in which its 3 Ser residues all lack P’s

how does glucose-6-phosphate allosterically effect PP1

since G6P being high means there is enough glucose in the body, so it activates PP1 to dephosphorylate glycogen synthase b to a form, to encourage glyconeogenesis when glucose levels are high

regulation of glycogen synthase and glycogen phosphorylase

glucagon and E stimulate ____ and inhibit ____

stimulate phosphorylase and inhibit synthase

• since blood glu is low, so need to make glucose/lyse glycogen to do glycogenolysis

insulin inhibits ___ and stimulates ___

inhibits phosphorylase and stimulates synthase

• since blood glu is high so can synthesize glycogen

image

muscle cells store glycogen for

its own needs

• since muscles need a lot of energy during exercise, so do glycolysis to get ATP

  • Glucagon's primary target is the liver, where it signals the release of stored glucose into the bloodstream to raise blood sugar levels

• can NOT do gluconeogenesis (occurs in liver)

• lacks a glucagon receptor since it doesn’t respond to glucagon