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content/Biokemi/Metabolism/Glykogen/Slides.md

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+---
+föreläsare: Martin Lidell
+tags:
+  - biokemi
+  - glykogen
+  - slides
+date: 2025-12-03
+---
+[OCR — Slides.pdf]
+
+LPG001
+Martin Lidell
+Glykogenmetabolism
+
+Glykogenmetabolism – föreläsningsupplägg
+• Glykogen – en lagringsform av glukos
+• Glykogens funktioner
+• Hur sker nedbrytningen av glykogen?
+• Hur bildas glykogen?
+• Hur regleras glykogenmetabolismen?
+
+Gerty and Carl Cori
+The Nobel Prize in Physiology or Medicine 1947
+"for their discovery of the course of the catalytic conversion of glycogen"
+
+Triglycerider – en reducerad och vattenfri form av energiupplagring
+1 gram fett innehåller ca 6.75 ggr mer energi än hydrerad glykogen
+(1 g glykogen binder normalt 2 g vatten)
+Del av Tabell 9.1 i ”Om kroppens omsättning av kolhydrat, fett och alkohol”,
+Anders Eklund, Studentlitteratur, 2004
+
+Triglycerider en effektivare form av energilagring – varför har vi då glykogen?
+Varför behöver vi glykogen?
+Hjärnan behöver glukos även mellan måltider
+Muskel kan använda glukos som energikälla vid arbete; även anaerobt
+(fettsyror kan ej användas vid anaerobt arbete)
+Glukos kan ej bildas från fettsyror
+Kroppen behöver ett lager av glukos!
+
+Glukos – en essentiell energikälla
+Problem:
+Glukos kan inte lagras eftersom molekylen är osmotiskt aktiv.
+Höga koncentrationer av glukos skulle förstöra den osmotiska balansen i en cell och orsaka cellskador/celldöd.
+Table 27.1 in ”Biochemistry, 4th ed”, Garrett and Grisham, Brooks/Cole, 2010
+
+Hur kan en tillräcklig mängd glukos lagras utan att orsaka cellskador?
+Lösning:
+Glukos lagras som icke-osmotiskt aktiv polymer
+• Glykogen (djur)
+• Stärkelse; amylos och amylopektin (växter)
+Polymererna kan ses som lättmobiliserade lagringsformer av glukos, vilken kan frisättas när energi behövs
+
+Glykogen – en väldigt stor och grenad polymer av “glukosenheter”
+Strukturen är optimerad för att lagra/frigöra energi snabbt
+Glykogenet tillgodoser behovet av glukos på kort sikt
+Glykogenmetabolismen styrs av allostera effektorer och hormoner
+Vi kan lagra upp till ca 450 g glykogen; ungefär 1/3 i levern
+och resterande del främst i skelettmuskulaturen.
+
+Two types of glycosidic bonds in glycogen
+a-1,4-glycosidic linkages in linear parts
+a-1,6-glycosidic linkages at branching points
+
+b-particles / a-rosettes
+The elementary particle of glycogen is sometimes called the b-particle.
+The particle is about 21 nm in diameter, consists of up to 55000 glucose residues with about 2000 nonreducing ends.
+20–40 b-particles can cluster together to form a-rosettes.
+
+Different functions of glycogen in liver and muscle
+Liver glycogen serves in the maintenance of the blood glucose level between meals.
+Muscle glycogen serves as an energy reserve for the muscle itself. Muscles lack glucose-6-phosphatase and cannot release glucose to blood.
+
+The three steps in glycogen degradation (glycogenolysis)
+1. release of glucose 1-phosphate from glycogen
+2. remodeling of the glycogen substrate to permit further degradation
+3. conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism
+
+Polysaccharides can be degraded by hydrolysis or phosphorolysis
+
+Glycogen phosphorylase – key enzyme in glycogen degradation
+Cleaves substrate by addition of orthophosphate (Pi) to yield glucose 1-phosphate
+Phosphorolysis
+Allosteric enzyme regulated by reversible covalent modification
+
+Glycogen phosphorylase cannot cleave α-1,6 bonds, stops 4 residues from branch → limited degradation
+
+Debranching enzyme needed — dual activity: transferase + α-1,6-glucosidase
+
+α-1,6 linkage hydrolyzed → glucose + shortened glycogen
+
+Phosphoglucomutase converts G1P → G6P (reversible)
+
+Glucose-6-phosphatase in liver/kidney allows release of glucose to blood
+
+Metabolism of G6P:
+1. fuel (muscle)
+2. glucose release (liver)
+3. NADPH/ribose-5-P (many tissues)
+
+Four steps in glycogen synthesis:
+1. UDP-glucose activation
+2. primer
+3. elongation
+4. branching
+(occurs in cytosol)
+
+UDP-glucose: activated glucose donor
+Synthesized from G1P + UTP, catalyzed by UDP-glucose pyrophosphorylase
+Driven by pyrophosphate hydrolysis
+
+Glycogen synthase: key enzyme in glycogenesis
+Adds glucosyl units to non-reducing end via α-1,4 bonds
+Needs existing chain ≥4 residues
+
+Glycogen synthesis requires primer:
+Glycogenin (two subunits)
+Autocatalytic polymerization on tyrosine
+UDP-glucose donor
+Synthase later extends chain
+
+Branching enzyme:
+Break α-1,4, form α-1,6
+Transfers block of ~7 residues
+Rules:
+• chain ≥11 long
+• block includes non-reducing end
+• new branch ≥4 residues away from existing
+
+Summary of glycogen synthesis
+
+Glycogen metabolism control:
+Key enzymes: glycogen phosphorylase & glycogen synthase
+Mechanisms:
+• Allosteric regulation (glucose, G6P, AMP, ATP)
+• Reversible phosphorylation (glucagon, epinephrine, insulin)
+
+Regulation of glycogen degradation:
+Phosphorylase b ↔ phosphorylase a
+R ↔ T states
+Allosterics + phosphorylation
+
+Different isozymes:
+Liver vs muscle glycogen phosphorylase → different responses
+
+Liver phosphorylase:
+Purpose: export glucose
+Acts as glucose sensor:
+• senses glucose → inactive
+• no glucose → active
+
+Muscle phosphorylase:
+Purpose: energy for contraction
+Sensors:
+• AMP → activate
+• ATP/G6P → inhibit
+
+Regulation of glycogen synthase:
+G6P sensor:
+• senses G6P → activate
+• no G6P → inactive
+Phosphorylated form = inactive (b)
+Dephosphorylated = active (a)
+
+Allosteric summary:
+Glc-6-P stimulates synthesis
+AMP stimulates degradation (muscle)
+ATP & G6P inhibit degradation (muscle)
+Glucose inhibits degradation (liver)
+
+Hormones:
+INSULIN
+• released when blood glucose high
+• stimulates glucose uptake and storage as glycogen/fat
+
+GLUCAGON
+• low blood glucose
+• targets liver to raise blood glucose via glycogenolysis & gluconeogenesis
+
+ADRENALINE
+• stress
+• activates glycogenolysis & lipolysis
+
+Hormonal overview:
+• Insulin → favors synthesis
+• Glucagon/Epinephrine → favor degradation
+Mechanism: phosphorylation states of phosphorylase and synthase
+
+Hormonal stimulation of phosphorylase:
+Glucagon/epinephrine → kinase cascades → active phosphorylase
+
+Phosphorylase kinase activated by Ca2+ + phosphorylation
+
+Protein phosphatase 1 (PP1):
+Dephosphorylates phosphorylase & kinase → inhibits degradation
+
+Hormonal regulation of PP1:
+• Glucagon/Epi inhibit PP1
+• Insulin activates PP1
+
+Hormonal inhibition of glycogen synthase:
+Glucagon/Epi → phosphorylation → inactive synthase
+
+Insulin stimulation of glycogen synthase:
+Insulin inactivates GSK3, activates PP1 → activates synthase (dephosphorylation)
+
+Insulin favors synthesis:
+PP1 activates synthase + inactivates phosphorylase
+
+Glucagon/Epi favor degradation:
+PKA activation → phosphorylase activation + synthase inhibition
+
+Summary table:
+Glucagon (liver): synthesis ↓, degradation ↑
+Epinephrine (muscle/liver): synthesis ↓, degradation ↑
+Insulin: synthesis ↑, degradation ↓
+
+Enzymes involved:
+Degradation:
+• Glycogen phosphorylase
+• Debranching enzyme
+• Phosphoglucomutase
+• Glucose-6-phosphatase
+• Protein kinase A
+• Phosphorylase kinase
+• PP1
+
+Synthesis:
+• Hexokinase/glucokinase
+• Phosphoglucomutase
+• UDP-glucose pyrophosphorylase
+• Inorganic pyrophosphatase
+• Glycogenin
+• Glycogen synthase
+• Branching enzyme
+• Protein kinase A
+• GSK3
+• PP1
+
+Summary:
+• Liver glycogen maintains blood glucose
+• Muscle glycogen fuels muscle
+• Glycogen phosphorylase → breakdown
+• Glycogen synthase → synthesis
+• Regulated by allosterics + hormones
+• Glucagon/Epi → degradation
+• Insulin → synthesis
+
+Läsanvisningar:
+Kapitel 21 i Biochemistry, 10th ed, Berg et al. 2023
+Instuderingsfrågor på Canvas