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)
- release of glucose 1-phosphate from glycogen
- remodeling of the glycogen substrate to permit further degradation
- 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:
- fuel (muscle)
- glucose release (liver)
- NADPH/ribose-5-P (many tissues)
Four steps in glycogen synthesis:
- UDP-glucose activation
- primer
- elongation
- 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