Lecture 4: Glycogen Metabolism Flashcards
What is the major storage form of glucose?
Glycogen is the major storage form of glucose in animals.
- Polymer that is is long and has many branches and tends to coil so can have lots of glucose compacted and stored in a tight place
- hydrophilic
Liver vs. muscle glycogen
- It makes up to 10% of the wet weight of liver (~100 g) in humans.
- Liver glycogen is used to regulate blood glucose levels; a 24-hour fast will deplete glycogen levels in the liver.
- Glycogen accounts for 1-2% of muscle weight (~450 g). Small amounts are found in the brain. The total body glycogen content has an energy content of ~600 kcal.
- Muscle glycogen serves as a rapid source of energy but will suffice for only ~20 sec.
Glycogen structure linkages
Glucose residues are joined with 𝛼-1,4 glycosidic bonds and branched with 𝛼-1,6 glycosidic bonds every 4-5 residues.
- Before joining, C1 was a carbonyl carbon (- C=O) (anomeric), C4 and C6 had an alcohol (-C–OH) group attached.
What is the directionality of glycogen?
Reducing and non-reducing ends
- Reducing end (glycogenin): The glucose unit at the end of each glycogen chain with anomeric carbon which can open up the ring to form a linear structure in which its aldehyde moiety is available for reaction with alcohols (form hemiacetals) or metal ions
- Nonreducing end: cannot change into linear form because the anomeric carbon cannot open to react.
Where is glycogen synthesis particularly important?
Glycogen synthesis from glucose takes place in many tissues, but it is particularly important in liver and muscle where its magnitude and functional relevance is more significant.
Where does glucose for glycogen synthesis come from?
Glucose from the bloodstream enters cells via a glucose transporter.
- In the liver → GLUT2 is the main transporter; its high Kt = 66 mM entails that glucose enters the liver only when the blood concentration is that high.
- In the muscle → GLUT4 is the main transporter; its low Kt = 5 mM means that, the skeletal muscle has first ‘dibs’ on blood glucose, compared to the liver.
Enzymes of glycogenesis
Its synthesis requires three enzymes:
- autocatalytic glucosylation of glycogenin → which provides a priming oligosaccharide chain
- glycogen synthase → which extends the oligosaccharide chain
- branching enzyme → which is responsible for the synthesis of highly branched polymers
What do the glycogen branching enzymes do?
Creates 𝜶-1,6 glycosidic branches
- transfers a block of glucose units in 𝛼-1,6 linkage from one chain to form a branch in an 𝛼-1,6 linkage in another chain.
More branches = ??
- More glycogen solubility
- More ends accessible for synthesis and degradation
What does glycogen synthase do?
Glycogen synthase adds glucose to non-reducing ends.
Steps of glycogen synthesis
- glucose → glucose-6-phosphate via hexokinase (reaction 1 of glycolysis)
- glucose-6-phosphate → glucose-1-phosphate via phosphoglucomutase
- glucose-1-phosphate + UTP → UDP-glucose + PPi (PPi → 2Pi + lots of energy released) via glucose-1-phosphate uridylyltransferase
- UDP-glucose donates the glucosyl group to a tyrosine of the enzyme glycogenin. Glycogenin (37 kDa) extends the glucan chain, by autocatalysis, by six to seven glucosyl units in α (1 → 4) glycosidic linkages using UDP-glucose.
- Glycogenin and glycogen synthase are firmly bound in a 1:1 complex. As the glucan chain grows, glycogen synthase dissociates from glycogenin and continues the synthesis of glycogen by adding new glucose residues from UDP-glucose.
- The branching enzyme creates branches by transferring a few α (1 → 4) glucan units from a linear chain into the same or a neighbouring chain via α (1 → 6) linkage.
How is G6P redirected to glycogenesis instead of glycolysis?
Once G6P accumulates it will directly inhibit HK and is then redirected to glycogen storage
Outcome of glycogen synthesis
Ultimately thousands to millions of glucose residues are added to glycogenin to form a large and highly branched molecule of GLYCOGEN with many non-reducing ends and a few reducing ends.
Storage form of glucose in plants
primarily utilize starch as glucose storage which is similar to glycogen but less branching
Where in the cell is glycogen synthesized?
Glycogen is synthesized in the cytoplasm of living organisms of the three domains: archaea, bacteria, and eukarya.
Thousands to millions of glucose residues are added to glycogenin.
What is an anomeric carbon?
An anomeric carbon in a carbohydrate molecule is a carbon atom derived from the carbonyl carbon compound (the ketone or aldehyde functional group) of the open-chain form of the carbohydrate molecule.
- Can react with alcohol to form hemiacetal (or hemiketal)
Anomeric carbons of the reducing and non-reducing ends of glycogen
- Reducing end: There is only one anomeric carbon in glycosidic bond
- Non-reducing end: There are two anomeric carbons in glycosidic bond
Mechanism of glycogen phosphorylase
Glycogen phosphorylase catalyzes a phosphorolysis reaction. Instead of water, an inorganic phosphate attacks C1, liberating glucose 1-phosphate.
Major glycogen breakdown and glucose export in the liver
Glycogen breaks down via glycogen debranching transferase and glycogen phosphorylase
- Glycogen debranching transferase takes off 3 glucose at a time from branches and adds to the main polymer making them available for action of phosphorylase
- Glycogen phosphorylase creates G6P which can enter last reaction gluconeogenesis pathway via enzyme G6Pase to create glucose
- Export of glucose → GLUT2 (liver) opens only when glucose concentration is very high (Kt = 66 mM).
Thermodynamics of glycogen synthesis and breakdown
Glycogen synthesis and breakdown are not simply the reverse of one another; Glycogen synthesis is thermodynamically favorable because it is coupled to UTP hydrolysis
- Synthesis: driven by PPi hydrolysis
- Breakdown: driven by phosphorolysis
