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Transcript
Glycogen!Metabolism! ! Glycogen$→!Principal!storage!form!of!glucose!in!the!body$ - Structure:! o Glycogen!is!a!polymer!of!glucose!residues!linked!by!glycosidic!bond:!! ! Bet!alpha!1!carbon!and!alpha!4!carbon!with!an!oxygen!in!between! ! Alpha!means!glucose!units!are!in!trans!configuration! ! Alpha!(1!→!4)!glycosidic!bonds!mainly! ! Alpha!(1!→!6)!glycosidic!bonds!at!branch!points! ! ! - Glycogen!is!a!branched!homopolysaccharide!(polymer)!of!glucose!(only!glucose)! o Glucose!monomers!form!(a!1!→!4)!linked!chains!! o Branch=points!with!(a1!→!6)!links!every!8–12!residues!! o Molecular!weight!reaches!several!millions!bc!can!become!v!compact!with! residues!(more!compact!than!starch)! ! Glycogen$Storage$ - Glycogen!is!stored!in!hepatic!sites!of!liver!in!large!cytosolic!granules!! - Granules!contain!enzymes!that!synthesise!and!degrade!glycogen! - Glycogen!may!constitute!up!to!7%!of!the!liver’s!wet!weight! ! - In!the!body,!glycogen!is!stored!mainly!in!the! liver!and!skeletal!muscle!! - Muscle!glycogen!→!Provides!a!quick!source! of!energy!for!skeletal!muscle!contraction! - Liver!glycogen!→!Acts!as!a!reservoir!of! glucose!for!other!tissues!when!dietary! glucose!is!unavailable! o i.e.!to!buffer!blood!glucose!levels! ! ! ! ! Glycogen$Metabolism$$ - Synthesis!and!breakdown!of!glycogen!occur!by!different!pathways,!which!utilise! different!enzymes!! - Glycogenolysis!→!the!breakdown!of!glycogen!(and!its!subsequent!use!as!energy! source)! o GlycogeNOlysis!=!NO!more!glycogen! - Glycogenesis!→!the!synthesis!of!glycogen! ! Glycogenolysis$ - Enzymes!involved!in!glycogen!breakdown:!! o Glycogen!phosphorylase! o Glycogen!debranching!enzyme! o Phosphoglucomutase!! ! Enzyme$1:$Glycogen$Phosphorylase$$ - The!1st!step!in!glycogen!utilisation!is!the!phosphorolytic!cleavage!of!the!alpha!(1!→! 4)!glycosidic!linkages!of!glycogen,!releasing!glucose=1=phosphate!!! o This!is!catalysed!by!glycogen!phosphorylase! o Phosphorylated!at!alpha!1!position! ! ! Glucose!units!are!removed!from!glycogen!by!glycogen!phosphorylase!! - Catalyses!a!reaction!where!by!a!phosphate!group!causes!the!cleavage!at!the! glycosidic!bond!to!form!glucose=1=phosphate,!at!non=reducing!ends!of!glycogen!(free! alpha!4!carbons,!not!bonded)! ! - Glycogen!phosphorylase!acts!repetitively!on!non=reducing!ends!of!glycogen!branches!! o However,!it!cannot!remove!glucose!residues!from!the!branch!points! ! ∴!enzyme!ceases!to!work! o Its!action!stops!at!a!point!4!glucose!units!away!from!an!alpha!(1!→!6)!branch! point! o Further!degradation!by!glycogen!phosphorylase!can!only!occur!after!the! glycogen!debranching!enzyme!(i.e.!enzyme!2)!transfers!the!branches! ! Enzyme$2:$Glycogen$Debranching$Enzyme$$ - This!enzyme!has!2!independent!active!sites!on!a!single!polypeptide!chain!and! catalyses!2!successive!reactions:! o Transferase!activity! o Glucosidase!activity! ! - The!transferase!reaction!transfers!3!glucose!residues!from!a!4=residue!limit!branch! to!the!end!of!another!branch! o This!reduces!the!limit!branch!to!a!single!glucose!residue! - The!alpha!(1!→!6)!glucosidase!moiety!of!the!debranching!enzyme!then!catalyses!the! hydrolysis!of!the!alpha!(1!→!6)!linkage,!yielding!free!glucose! - This!is!a!minor!fraction!of!glucose!released!from!glycogen! ! Glycogen$Breakdown$ - Glycogen!phosphorylase!works!on! non=reducing!ends!until!it!reaches! four!residues!from!an!(alpha!1!→! 6)!branch!point!! - Debranching!enzyme!transfers!a! block!of!three!residues!to!the!non= reducing!end!of!the!chain! - Debranching!enzyme!cleaves!the! single!remaining!(alpha!1!→!6)– linked!glucose!! ! ! Enzyme$3:$Phosphoglucomutase$ - Responsible!for!shifting!the!phosphate!group!from!the!1!carbon!to!the!6!carbon! - Phosphoglucomutase!catalyses!the!reversible!reaction!(we!WANT!G6P):! o Glucose=1=phosphate!←→!glucose=6=phosphate! ! ! ! Fates$of$GlucoseI6IPhosphate$$ - In!skeletal!muscle!G6P!may!enter!glycolysis!and!serve!as!an!energy!source!! - In!liver!G6P!may!be!dephosphorylated!(to!glucose)!for!release!into!the!blood!to!be! transported! o Reaction!catalysed!by!Glucose=6=phosphatase! - Glucose=6=Phosphatase!catalyses!the!following!reaction:! o Glucose=6=phosphate!+!H2O!→!Glucose!+!Pi! - This!enzyme!is!not!present!in!skeletal!muscle,!only!present!in!the!liver!and!kidney! o Main!role!is!to!maintain!blood!glucose!levels!esp.!between!meals! ! Glycogenesis$ - Especially!prominent!in!liver!and!skeletal!muscle!! - The!starting!point!of!glycogen!synthesis!is!the!production!of!glucose=6=phosphate! (from!phosphorylation!of!glucose)! o Glucose!+!ATP!→!Glucose=6=phosphate!+!ADP!! ! Glycogen$Synthesis$$ - Step!1:!Production!of!Glucose=6=Phosphate!! o Glucose!+!ATP!→!Glucose=6=phosphate!+!ADP! o In!muscle!is!catalysed!by!the!enzymes!Hexokinase!I!and!Hexokinase!II!! o In!liver!is!catalysed!by!the!enzyme!Hexokinase!IV!(or!Glucokinase)!! - Step!2:!Glucose=6=phosphate!is!converted!to!Glucose=1=phosphate! o Using!enzyme!phosphoglucomutase!! - Step!3:!Synthesis!of!UDP=glucose!(an!activated!sugar!nucleotide)!from!Glucose=1= phosphate!and!UTP!(release!of!a!phosphate)! o Catalysed!by!UDP=glucose!phosphorylase! ! UDPIGlucose$and$Activated$Sugar$Nucleotides$$ - UDP=glucose!is!an!activated!sugar!nucleotide! - Sugar!nucleotides!are!substrates!for!polymerisation!of!monosaccharides!into! disaccharides!and!complex!polysaccharides! o E.g.!glucose!→!glycogen! - UDP=glucose!is!the!immediate!donor!of!glucose!residues!to!established! resides/branches! - A!glucose!residue!is!transferred!from!UDP=glucose!to!the!end!of!a!branched! glycogen!molecule!by!the!enzyme!glycogen!synthase!!! ! Enzyme$2:$Glycogen$Synthase$$ - Catalyses!the!transfer!of!the!glucose!moiety!of!UDP=glucose!to!the!hydroxyl!at!C4!of! the!terminal!residue!of!a!glycogen!chain!to!form!an!alpha!(1!→!4)!glycosidic!linkage:!! - ! The!alpha!1!carbon!of!the!glucose!group!is!then!attached!to!the!alpha!4!carbon!(non= reducing!end)!of!the!glycogen!chain!=!glycogen!with!extra!glucose!unit!and!UDP! ! Glycogen$Branching$$ - Only!existing!glycogen!chains!are!elongated!by!the!action!of!glycogen!synthase!!! - Elongated!glycogen!chains!can!have!branches! o Branching!increases!polymer!solubility! o Branching!creates!many!ends!for!enzyme!attack!when!rapid!release!of! glucose!is!necessary! ! ! Enzyme$3:$Glycogen$Branching$Enzyme$ - Transfers!a!segment!(approx.!7!glucose!residues)!from!the!end!of!a!glycogen!chain!to! the!C6!hydroxyl!of!a!glucose!residue!of!a!different!(adjacent)!chain!to!yield!a!branch! with!an!alpha!(1!→!6)!linkage! ! New$Glycogen$Chains$are$Initiated$by$Glycogenin$$ - Glycogen!synthase!can!add!glucose!units!to!an!existing!glycogen!chain!but!cannot! initiate!new!glycogen!chains! - Glycogenin!is!the!primer!on!which!new!chains!are!assembled!! o It!is!also!the!enzyme!that!catalyses!the!first!chain’s!assembly! ! - A!glycosidic!bond!is! formed!between!C1!of! the!glucose!moiety!from! UDP=!glucose!and!the! hydroxyl!oxygen!of! tyrosine194!(194! position)!of!Glycogenin! - This!yields!UDP!+! glycogenin!with!a! glucose!unit!attached!! - This!is!repeated!until!a! short!linear!glucose! polymer!with!alpha!(1! →!4)!glycosidic!linkages! is!built!on!Glycogenin! - Typically!end!up!with!a! polymer!with!8!glucose! units!attached,!and!a! glycogenin!molecule!at! the!end! - This!is!catalysed!by! glycogenin! - When!reach!8,!glycogen! synthase!takes!over,! further!extending!the! glycogen!chain! ! ! ! ! ! - - Initial!primer,!then!branches!and! chains!=!different!tiers!of! glycogen! Outer!tier!remains!unbranched! Can!end!up!with!large!molecule! ~55,000!glucose!monomers! which!gives!a!diameter!of!~21! nanometers! ! ! Regulation$Of$Glycogen$Metabolism$ Coordinated!Regulation!Of!Glycogen!Synthesis!And!Breakdown! ! - Glycogen!Phosphorylase!and!Glycogen!Synthase!are!reciprocally!regulated! (something!that!inhibits!one!will!activate!the!other)!by:!! o Allosteric!effectors!! o Reversible!phosphorylation!! o Hormones!! ! ! - Allosteric$Regulation$of$Glycogen$Phosphorylase$$ o Glycogen!phosphorylase!is!subject!to!allosteric!control! ! Transitions!between!“relaxed”!(R)!(active)!&!“tense”!(T)!(inhibited)! conformations! o Allosteric!regulation!by!AMP,!ATP,!and!glucose=6=phosphate! o AMP!(present!significantly!when!ATP!is!depleted)!activates!glycogen! phosphorylase!(R!conformation!enhanced)!and!glycogen!breakdown!is! activated!bc!more!energy!is!needed! o ATP!and!G6P!inhibit!glycogen!phosphorylase!(enhance!the!T!conformation)! ! ∴!glycogen!breakdown!is!inhibited!when!ATP!and!glucose=6= phosphate!are!plentiful!! o Glycogen!synthase!is!activated!by!G6P!(opposite!to!its!effect!on!glycogen! Phosphorylase)!! ! i.e.!glycogen!synthesis!is!activated!! ! ∴!active!when!intracellular!glucose=6=phosphate!levels!are!high!! - Regulation$by$Reversible$Phosphorylation$$ o Covalent!attachment!of!a!phosphoryl!group!alters!the!catalytic!properties!of! many!enzymes! o Phosphoryl!groups!are!usually!attached!at!specific!Serine,!Threonine!or! Tyrosine!amino!acid!residues!in!a!protein!chain! ! Bc!these!have!an!OH!group! ! ! o o ATP!serves!as!the!phosphoryl!donor! Protein!Phosphorylation!and!Dephosphorylation!! ! Phosphoryl!Groups!Are!Attached!and!Removed!by!Diff!Enzymes!! ! Some!enzymes!are!activated!by!phosphorylation! ! Other!enzymes!are!inactivated!by!phosphorylation! ! ! - Glycogen!Phosphorylase!Can!Be!Interconverted!Between!Active!and!Inactive!Forms! by!Reversible!Phosphorylation! o Becomes!more!active!when!there!are!phosphoryl!groups!attached! ! ! ! - Hormonal$Control$of$Glycogen$Metabolism$$ Control!of!glycogen!synthesis!and!breakdown!is!also!under!hormonal! control:!! ! The!main!hormones!regulating!glycogen!metabolism!are!insulin,! glucagon!and!epinephrine!(adrenaline)!! ! Insulin!induces!the!synthesis!of!glycogen!! ! Glucagon!and!epinephrine!promote!glycogen!breakdown!and! release!of!glucose!! Cell!Signalling!Cascades!and!Hormonal!Regulation!! o Signal!molecule!(e.g.!hormone)!binds!to!its!receptor!on!the!membrane!of!a! target!cell!! o This!triggers!formation!of!2nd!messengers!(e.g.!cAMP)!responsible!for! translating!receptor!occupation!into!cellular!responses!(chemical!cascade)! o The!binding!of!glucagon!to!its!receptor!stimulates!adenylate!cyclase,!which! catalyses!conversion!of!ATP!into!cyclic!AMP!(cAMP)!! o - ! ! ! ! 3.$Effect$of$Insulin$on$Glycogen$Metabolism$$ - Insulin!triggers!a!separate!signal!cascade!that!leads!to!activation!of!Phosphoprotein! Phosphatase!!! o This!phosphatase!catalyses!removal!of!phosphate!residues!from!Glycogen! Phosphorylase!and!Glycogen!Synthase!!! ! ! ! ! ! !
