Glycogen synthesis.ppt

Glycogen synthesis is a basic process to store extra glucose and it is one of the most important process occuring in the body

1. Glycogen
Humans consume 160 g of glucoseper day
75%of that is in the brain
Body fluids contain only 20 gof glucose
Glycogen stores yield 180-200 gof glucose
So the body must be able to make its own
glucose

2. Inthewell-fedstatetheglucoseafterabsorptionis
takenbyliveranddepositedasaglycogen
Glycogenisaverylarge,branchedpolymerofglucose
residuesthatcanbebrokendowntoyieldsglucose
moleculeswhenenergyisneeded
GLYCOGEN SYNTHESIS

3. Liver(10%ofweight)and
skeletalmuscles(2%)
–twomajorsitesof
glycogenstorage
Glycogen isstoredin
cytosolicgranules in
muscleandlivercellsof
vertebrates
Glycogenservesasabuffertomaintainblood-glucose
level.
Stablebloodglucoselevelisespeciallyimportantfor
brainwhereitistheonlyfuel.
Theglucosefromglycogenisreadilymobilizedandis
thereforeagoodsourceofenergyforsudden,strenuous
activity.

5. Variation of liver glycogen levels
between meals and during the
nocturnal fast.

7. Mostglucoseresiduesinglycogenarelinkedbya-1,4-
glyco-sidicbonds,branchesarecreatedbya-1,6-
glycosidicbonds

8. Glycogen Synthesis
•Synthesisanddegradationof
glycogen require separate
enzymaticsteps
•Cellularglucoseconvertedto
G6Pbyhexokinase
•Threeseparateenzymaticsteps
arerequiredtoincorporateone
G6Pintoglycogen
•Glycogen synthase isthe
majorregulatorystep

9. •Phosphoglucomutase catalyzes the conversion of glucose 6-
phosphate (G6P) to glucose 1-phosphate (G1P).
Glucose 1-Phosphate formation

10. Synthesis of glycogen (glycogenesis)
-Glycogenissynthesizedfrommoleculesofα-D-glucose.
Theprocessoccursincytosol,andrequiresenergy
suppliedbyATP(forphosphorylationofglucose)&uridine
triphosphate(UTP).
A.SynthesisofUDP-glucose
B.Synthesisofaprimertoinitiateglycogensynthesis
C.Elongationofglycogenchain
D.Formationofbranchesinglycogen

11. Synthesis of glycogen (glycogenesis)
A.SynthesisofUDP-glucose
-α-D-glucoseattachedtoUDPisthesourceofallof
glucosylresiduesthatareaddedtothegrowingglycogen
molecule
-UDP-glucoseissynthesizedfromglucose-1-P&UTPby
UDP-glucosepyrophosphorylase
-Thehigh-energybondinpyrophosphate(PPi),the2
nd
productofthereaction,ishydrolyzedto2inorganic
phosphates(Pi)bypyrophosphatase,whichensuresthat
synthesisofUDP-glucproceedsindirectionofUDP-gluc
production
Note:G-6-PisconvertedtoG-1-Pbyphosphoglucomutase.
G-1,6-BPisanobligatoryintermediateinthisreaction

12. Figure 11.4. The structure of UDP-glucose.

13. UDP-glucoseisactivatedformof
glucose.
UDP-glucoseissynthesizedfrom
glucose-1-phosphate and
uridinetriphosphate(UTP)ina
reactioncatalizedbyUDP-
glucosepyrophosphorylase

14. Glycogensynthaseaddsglucose
tothenonreducing endof
glycogen

15. -Glycogensynthaseisresponsibleformakingα(1→4)
linkagesinglycogen.Thisenzymecan’tinitiatechain
synthesisusingfreeglucasanacceptorofamoleculeof
glucosefromUDP-glucose.Instead,itcanonlyelongate
alreadyexistingchainsofglucose.
-Therefore,afragmentofglycogencanserveasaprimerin
cellswhoseglycogenstoresarenottotallydepleted
-Intheabsenceofaglycogenfragment,aprotein,called
glycogenin,canserveasanacceptorofglucoseresidues
B. Synthesis of a primer to initiate glycogen
synthesis

16. -SidechainhydroxylgroupofaspecificTyrosineserves
asthesiteatwhichtheinitialglucoseunitisattached
-TransferoffirstfewmoleculesofglucosefromUDP-
glucosetoglycogeniniscatalyzedbyglycogeninitself,
whichcanthentransferadditionalglucosylunitstothe
growingα(1→4)-linkedglucosylchain
-Thisshortchainservesasanacceptoroffutureglucose
residues
Note:glycogeninstaysassociatedwith&isfoundin
centerofcompletedglycogenmolecule
B. Synthesis of a primer to initiate glycogen
synthesis

17. Glycogenininitiatesglycogensynthesis.
Glycogeninisanenzymethatcatalyzesattachmentofa
glucosemoleculetooneofitsowntyrosineresidues.
Glycogeninisadimer,andevidenceindicatesthatthe2
copiesoftheenzymeglucosylateoneanother.
Tyr active site

active site Tyr
Glycogenin dimer

18. AglycosidicbondisformedbetweentheanomericC1ofthe
glucosemoietyderivedfromUDP-glucoseandthehydroxyl
oxygenofatyrosineside-chainofGlycogenin.
UDPisreleasedasaproduct.H
O
OH
H
OHH
OH
CH
2OH
H
O H
H
OHH
OH
CH
2OH
H
O
HH
C
CH
NH
C
H
2
O
O
H
O
OH
H
OHH
OH
CH
2OH
H
H
C
CH
NH
C
H
2
O
O
1
5
4
3
2
6
H
O
OH
H
OHH
OH
CH
2OH
H
H
O
1
5
4
3
2
6
POPOUridine
O
O

O
O

C
CH
NH
C
H
2
HO
O
tyrosine residue
of Glycogenin

O-linked
glucose
residue
+ UDP
UDP-glucose

19. GlycogeninthencatalyzesglucosylationatC4oftheattached
glucose(UDP-glucoseagainthedonor),toyieldanO-linked
disaccharidewithα(1-4)glycosidiclinkage.
Thisisrepeateduntilashortlinearglucosepolymerwith
α(1-4)glycosidiclinkagesisbuiltuponGlycogenin.H
O
OH
H
OHH
OH
CH
2OH
H
O H
H
OHH
OH
CH
2OH
H
O
HH
C
CH
NH
C
H
2
O
O
H
O
OH
H
OHH
OH
CH
2OH
H
H
C
CH
NH
C
H
2
O
O
1
5
4
3
2
6
H
O
OH
H
OHH
OH
CH
2OH
H
H
O
1
5
4
3
2
6
POPOUridine
O
O

O
O

C
CH
NH
C
H
2
HO
O

UDP-glucose
O-linked
glucose
residue
(14)
linkage
+ UDP
+ UDP

20. C.Elongationofglycogenchainbyglycogen
synthase
-
Elongationofglycogenchaininvolvestransferofglucose
fromUDP-glucosetothenon-reducingendofgrowing
chain,forminganewglycosidicbondb/wtheanomeric
hydroxylofC-1ofactivatedglucose&C-4ofaccepting
glucosylresidue
Note:“non-reducingend”ofaCHOchainisoneinwhich
anomericCofterminalsugarislinkedbyaglycosidic
bond,makingterminalsugar“non-reducing”.
-Theenzymeresponsibleformakingα(1→4)linkagesin
glycogenisglycogensynthase
Note:UDPreleasedwhenthenewα(1→4)glycosidicbond
ismadecanbeconvertedbacktoUTPbynucleoside
diphosphatekinase(UDP+ATP↔UTP+ADP)

21. D. Formation of branches in glycogen
-Ifnoothersyntheticenz’sactedonthechain,resulting
structurewouldbealinearmoleculeofglucosylresidues
attachedbyα(1→4)linkages.
-Oneoftheenyzmeisfoundinplanttissuescalled
amylose.Incontrast,glycogenhasbrancheslocated,on
av.,8glucosylresiduesapart,resultinginahighly
branched,tree-likestructurethatisfarmoresolublethan
unbranchedamylose
-BranchingalsoincreasestheNo.ofnon-reducingendsto
whichnewglucosylresiduescanbeadded(andalso,from
whichtheseresiduescanberemoved),therebygreatly
acceleratingtherateatwhichglycogensynthesis&
degradationcanoccur,&dramaticallyincreasingthesize
ofthemolecule

22. 1. Synthesis of branches:
-Branchesaremadebyactionof“branchingenzyme”,
amylose-α(1→4)→α(1→6)-transglucosidase.Thisenz
transfersachainof5to8glucosylresiduesfromnon-
reducingendofglycogenchain[breakingα(1→4)bond]
toanotherresidueonthechainandattachesitbyanα
(1→6)linkage
-Resultingnew,non-reducingend,aswellastheoldnon-
reducingendfromwhichthe5to8residueswere
removed,cannowbeelongatedbyglycogensynthase
2. Synthesis of additional branches :
-Afterelongationofthesetwoendshasbeenaccomplished
byglycogensynthase,theirterminal5to8glucosyl
residuescanberemoved&usedtomakefurther
branches

23. A branching enzyme forms -1,6-linkages
Glycogen synthase
catalyzesonly-1,4-linkages.
Thebranchingenzyme is
requiredtoform -1,6-
linkages.
Branching is important
becauseitincreasesthe
solubilityofglycogen.
Branchingcreatesalarge
numberofterminalresidues,
thesitesofactionofglycogen
phosphorylaseandsynthase.

24. Figure 11.5. Glycogen synthesis.