Chapter 21 Glycogen Metabolism

Front 1

glycogen

Back 1

-large polymer of glucose (up to 106 gluc/molecule)
-granules of 10-40nm in cytosol of most cells
-most residues in alpha-1,4-glycosidic bonds; branches made with alpha 1,6 linkages

Front 2

major glycogen storage sites

Back 2

liver--community oriented; 10% of weight
muscle--selfish; 2% of weight

Front 3

glycogen phosphorylase

Back 3

-key enzyme in glycogenolysis
-catalyzes sequential removal of glucose residues from non-reducing end of glycogen molecule by phosphorolysis

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advantages of phosphorolysis over hydrolysis

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energetically: released sugar already phosphorylated
advantage for muscle: can retain charged glucose phosphate since it lacks glucose 6-phosphatase

Front 5

structure of glycogen phosphorylase

Back 5

coenzyme=pyridoxal phosphate
binding sites can accommodate 4-5 glucose units which can be phosphorylated without dissociation at each step (processive reaction)

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pyridoxal phosphate

Back 6

-derivative of vitamin B6
-covalently linked to a lysine residue at active site of glycogen phosphorylase by a schiff-base
-serves as an acid-base catalyst--doesn't donate its phosphate

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glycogen phosphorylase reaction

Back 7

1) PLP donates proton to "free" phosphate (in solution)
2) phosphate donates proton to glycogen
3) bond is broken to a glucose carbocation and glycogen(n-1)
4) carbocation=unstable so attacked by phosphate yielding PLP + glucose 1-P

Front 8

phosphoglucomutase

Back 8

-converts glucose 1-P to glucose 6-P
-adds its phosphoryl group to make gluc 1,6 bp then it takes phosphoryl group on 1

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transferase (glycogen metabolism)

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moves 3 glucose residues from branched glycogen chain to main chain--it leaves 1 1,6-linked glucose

Front 10

debranching enzyme

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alpha 1,6 glucosidase--hydrolyzes remaining 1,6 linked residue to glucose after transferase has moved 3 to main chain

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why is branching important?

Back 11

-enhances solubility of molecule
-increases sites for degradation and synthesis

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3 fates of glucose 6-P

Back 12

glycolysis, PPP, blood for use by other tissues

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regulation of glycogen phosphorylase

Back 13

-allosteric effectors that signal energy charge of cell
-hormones (insulin, epinephrine, glucagon) via phosphorylation

Front 14

forms of glycogen phosphorylase

Back 14

-R (active) and T (inactive): interconverted by allosteric effectors
-a (usually active) and b (usually inactive): interconverted by phosphorylation/dephosphorylation

Front 15

R and T state interconversion of glycogen phosphorylase

Back 15

high [AMP]-->stabilizes R state
high [ATP]--> negative allosteric effector--competes with AMP
glucose 6-P also favors T state (feedback inhibition)

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a and b interconversion of glycogen phosphorylase

Back 16

phosphorylase b--usually inactive unless high [AMP]
phosphorylase a--always active
in resting muscle, almost all is in form b
when exercise starts, high [AMP] activates b form and hormones will lead to phosphorylation (and thus form a)

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a and b interconversion of glycogen phosphorylase in liver

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a is most responsive T-to-R transition
-glucose acts as negative regulator--liver exports gluc to other parts of body so fi there is gluc present from diet, no need to mobilize more
-insensitive to regulation by AMP--liver doesn't undergo dramatic changes in energy charge

Front 18

phosphorylase kinase

Back 18

-phosphorylates phosphorylase a
-requires Ca++ and phosphorylation
-PKA catalyzes phosphorylation and cAMP activates PKA
-can be partly activated by Ca++ (has calmodulin as subunit) which is important because muscle contraction is triggered by release of Ca++

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epinephrine/glucagon and glycogen synthesis

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-hormones elevate cAMP and cAMP allosterically activates PKA which phosphorylates phosphorylase kinase which phosphorylates phosphorylase a

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how does cAMP activate PKA?

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by freeing up catalytic site
regulatory subunit occupies kinase catalytic site with pseudosubstrate--released when cAMP binds

Front 21

glucose transport into cells

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GLUT: family of glucose transporters
GLUT 1,3,4,5--> at normal glucose levels, can easily take up glucose from bloodstream
GLUT 2--> in pancreas and liver--only under high glucose concentrations will it take up glucose

Front 22

activated glucose (glucose donor)

Back 22

uridine diphosphate glucose

Front 23

reaction involving UDP

Back 23

gluc 1-P + UTP<----->UDP-gluc + PPi----> 2Pi
catalyzed by UDP-glucose pyrphosphorylase (first part, readily reversible, but hydrolysis of pyrophosphate drives rxn)

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glycogen synthase

Back 24

-adds glycosyl units to non-reducing terminal residues of glycogen in an alpha 1,4 linkage
-can only add units to a chain > 4 residues long so needs primer (glycogenin)

Front 25

glycogenin

Back 25

-"primer" for glycogen synthesis
-has 2 identical units--each has oligosaccharide of alpha-1,4 glucose units
-is a glycosyltransferase
-each subunit catalyzes addition of glucosyl to the other--initially at Tyr-OH
-remains in glycogen molecule

Front 26

branching in glycogen synthase

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involves transfer of ~7-C segment from an alpha-1,4 linkage to an alpha 1,6 linkage

Front 27

storage of glucose in glycogen requires how much energy?

Back 27

2 ATP/glucose

Front 28

how is glycogen synthase regulated?

Back 28

key regulatory enzyme
-can be regulated by phosphorylation
-hormonally controlled by cAMP like glycogen phosphorylase but phosphorylation has opposite effect--decreases enzyme activity

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protein phosphatase 1

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-inactivates phosphorylase kinase and phosphorylase a by dephosphorylating them
-decreases rate of glycogen breakdown
-removes phosphoryl group from glycogen synthase b to convert it to active a form

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reguation of protein phosphatase 1 by glucose

Back 30

-gluc activates PP1
-liver sense change in [gluc]--phosphorylase a is sensor
-PP1 binds tight to phos a when in R state but is inactive when bound
1) glucose binds to and inhibits glycogen phos a in liver--forms T state
2) T state of phos a doesn't bind PP1 so dissociates and activates
3) free PP1 dephosphorylates glyc phos a and glyc. synth b--activates synthesis

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insulin regulation of glycogen synthesis

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1) insulin stimulates protein kinases
2) protein kinases phosphorylate and inactivate glycogen synthase kinase
3) prevents continued phosphorylation of glycogen synthase so PP1 can dephosphorylate and activate it

Front 32

epinephrine and glucagon regulation of glycogen synthesis

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inhibit PP1
-PKA phosphorylates regulatory subunit Gm releasing catalytic subunit (reduces activity)
-PKA phosphorylates an inhibitor that inactivates PP1

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glycogenolysis

Back 33

breakdown of glycogen

Front 34

we can digest which linkages binding glucose moleculres

Back 34

alpha 1,4--not beta 1,4

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sites of glycogen storage

Back 35

liver and muscle