medical-notes/content/Biokemi/Metabolism/🧂 Glykogen/Slides.md

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föreläsare: Martin Lidell
tags:
  - biokemi
  - glykogen
  - slides
date: 2025-12-03
---

# 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
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