BioChem Glycogen (20)
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What is the structure of glycogen?
glycogen is composed of glucose molecules linked linearly by alpha(1-->4) bonds with branched chains linked via alpha(1-->6) bonds to the main glucose chain every eight residues or so
In which tissues is glycogen primarily synthesized and stored?
liver and muscle
Why is the total amount of glycogen stored in muscle about 4 time higher than in the liver?
because there's more muscle than there is liver
After how many hours of fasting are most liver glycogen stores are depleted?
Why does the liver break down glycogen? Why does the muscle break down glycogen?
- Liver: to maintain blood glucose levels (especially during fasting)
- Muscle: to make ATP for muscle contractions
What are two ways the liver can produce glucose?
- 1. glycogen (starch-like polymer) - a short term fix for a few hours
- 2. gluconeogenesis (new synthesis from small molecule precursors) - lasts many days
Why bother to make glycogen, why not just have free glucose available and floating around (3 reasons this is bad?
- 1. glucose would leak out of wherever it's stored because it can be moved by facilitated transport
- 2. high glucose in a cell would cause water to rush in attempting to even out the solute concentration, but would just result in high osmotic pressure that'd burst the cell
- 3. glucose would glycate (glucose damage) proteins
As in other biosynthetic processes involving polymerization of monosaccharides, glucose is activated by formation of:
UDP-glucose, the sugar nucleotide immediate precursor for glycogen synthesis
- catalyzes the addition of several glucose residues to itself, specifically on the -OH group of its tyrosine
- specific primer-forming protein for glycogen synthesis
- exactly what it sounds like: catalyzes glucose chain elongation, aka the synthesis of glycogen
- attaches the C1 of an activated UDP-glucose to the -OH group on C4 of a terminal glucose on a glycogen chain (chain is a pre-formed primer)
- leads to the formation of a linear polymer of glucose residues
What is the limiting step of glycogen synthesis?
glycogen synthase chain elongation
What does the presence of a glycogen chain primer suggest?
either that glycogen is never totally degraded OR that the primer (polymer of glucose residues) can be formed de novo
transglycosidase (branching enzyme)
- when a linear glycogen chain reaches about 12-16 units long, branching enzyme splits off a terminal fragment 7 glucose units & re-attaches it through a (1-->6) linkage to a glucose at least 4 (usually 8-10)residues away from any previously existing branch
- this transfer results in TWO chains with free C4-OH termini that can now each be elongated by glycogen synthase
What is the benefit of glycogen existing in a branched structure?
- because it is branched, there are numerous ends at which glycogen breakdown can occur
- a single linear molecule could only be broken down slowly
- branching means glycogen activation can occur in a matter of seconds (it's a fast process)
What's the final glycogen molecule like?
- it's of very high molecular weight (>1,000,000)
- is spherical
- has no free anomeric (C1) carbons in
Under what physiologic condition does the liver synthesize glycogen?
glycogenesis occurs in the liver when blood sugar levels rise above resting levels (when there's an excess of fuel)
What are the enzymes that carry out glycogen synthesis?
- Glycogen synthase
- Branching enzyme
What are the enzymes that carry out glycogen breakdown?
- Glycogen phosphorylase
- Debranching enzyme
- major breakdown of glycogen is carried out in three steps by two enzymes
- the 2nd and 3rd steps are catalyzed by the debranching enzyme
enzyme that cleaves glucose residues one at a time by phosphorolysis from the end of an alpha (1-->4) linked glycogen chain
- bond cleavage by addition of phosphoric acid across the cleaved bond
- the product of each step of phosphorolysis is glucose-1-phosphate
At what point in a glycogen chain can glycogen phosphorylase no longer cleave glucose residues?
- when it comes within 4 residues of a branch point
- it cannot cleave any more glucose residues UNTIL the branch is removed
What kind of enzymatic reaction does glycogen phosphorylase catalyze?
phosphorolysis (glycogen chain breakdown)
What is the product of phosphorolytic cleavage of glucose residues by glycogen phosphorylase?
What are the two activities of debranching enzyme?
- glucan transferase activity
- alpha (1-->6) glucosidase activity
What is the reaction carried out by the glucan transferase activity of debranching enzyme?
- glucan transferase cleaves a trisaccharide fragment from the end of a 4-residue-long branched chain & re-attaches it through an alpha(1-->4) linkage to the end of a different chain
- (where phosphorylase can further work)
What remains attached at the glycogen branch point after action of the glucan transferase activity of debranching enzyme?
a single glucose residue attached to a chain via an alpha(1--> 6) linkage
glucosidase activity of debranching enzyme
- catalyzes the cleavage of alpha (1-->6) linkages at glycogen branch points
- The alpha(1--> 6) glucosidase activity of debranching enzyme
What kind of enzymatic reaction does alpha (1--> 6) glucosidase activity of the debranching enzyme catalyze?
What molecule is released from the hydrolytic cleavage of alpha(1->6) linkages by the glucosidase activity of debranching enzyme?
FREE glucose (rather than G-1-P)
What is the major product of glycogenolysis?
converts the major product of glycogenolysis, glucose-1-phosphate, to glucose-6-phosphate
- catalyzes the conversion of glucose-6-phosphate to free glucose in the liver for free glucose to be released into the blood stream
- MUSCLE DOES NOT HAVE glucose-6-phosphatase
What happens to glucose-6-phosphate in muscle?
- because there is no glucose-6-phosphatase (to make free glucose) in muscle, G-6-P is used for glycolysis
- pyruvate can either be converted into lactate (Cori cycle) or acetyl-CoA (TCA cycle)
Glycogen metabolism in muscle responds to which hormones?
epinephrine and insulin (but NOT glucagon)
Glycogen metabolism in the liver responds to which hormones?
- Epinephrine: favors glycogen breakdown (via cAMP & protein kinase A)
- insulin: favors glycogen synthesis
- glucagon: favors glycogen breakdown
metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as pyruvate, lactate, glycerol, glucogenic amino acids, and odd-chain fatty acids
glycogen synthesis: glucose molecules are added to chains of glycogen for storage
glycogen breakdown: purpose is to release glucose into the bloodstream for uptake by other cells (provides energy)
How does CHRONIC cortisol (corticosteroid) affect blood glucose levels?
- it stimulates glycogenolysis (glycogen breakdown) which leads to an increase in blood glucose
- counteracts insulin
How does fructose-1-phosphate affect glycogen?
it inhibits glycogen breakdown because it itself is an energy source so there's no need to access additional sources of fuel (glucose)
As the particle of glycogen gets bigger, its synthesis:
slows down --> autoregulation
True or False: glycogen phosphorylase is more active when it is NOT phosphorylated, whereas glycogen synthase is more active when it IS phosphorylated
- FALSE the opposite is true
- glycogen phosphorylase is more active when it IS phosphorylated
- glycogen synthase is more active when it is NOT phosphorylated
How do glucagon and epinephrine activate glycogenolysis?
- each hormone combines with a specific cell surface receptor and stimulates the enzyme adenyl cyclase
- adenyl cyclase converts ATP to 3'-5' cyclic AMP
- cAMP within the cytoplasm activates protein kinase A (or cAMP-dependent protein kinase)
- protein kinase A phosphorylates both glycogen synthase (inactivating it) and phosphorylase kinase (activating it)
- activated phosphorylase kinase phosphorylates glycogen phosphorylase, activating it
- now there is glycogen breakdown (glycogenolysis)
How does insulin activate glycogenesis?
- insulin activates a phosphatase which remove phosphates attached to glycogen synthase
- it also prevents phosphorylation of glycogen synthase at sites that block its ability to function
- in response to a rise in blood glucose concentration,
- insulin binds to its membrane receptor which has protein kinase activity (sets off signaling cascades)
The binding of glucagon and epinephrine to specific cell surface receptors leads to the cAMP-dependent activation of which enzyme involved in the regulation of glycogen metabolism?
protein kinase A (cAMP-dependent protein kinase)
What is the effect of glucagon on the activity of glycogen synthase and glycogen phosphorylase?
glucagon decreases the activity of glycogen synthase and increases the activity of glycogen phosphorylase
What is the effect of insulin on the activity of glycogen synthase and glycogen phosphorylase?
insulin increases the activity of glycogen synthase and decreases the activity of glycogen phosphorylase
What is the effect of elevated glucose and fructose-1-phosphate on glycogen synthase and glycogen phosphorylase?
glucose and fructose-1-phosphate decrease glycogen breakdown by favoring the inactivation of glycogen phosphorylase and the activation of glycogen synthase
What is the effect of elevated glucose-6-phosphate on glycogen metabolism?
glucose-6-phosphate stimulates glycogen synthesis
How does glucose-6-phosphate stimulate glycogen synthesis?
- glucose-6-phosphate INHIBITS the protein kinase that phosphorylates glycogen synthase
- this maintains glycogen synthase in its active form, favoring glycogen synthesis
How does glycogen limit its own synthesis?
- glycogen accumulation inhibits protein phosphatase
- this prevents glycogen synthase from being activated while maintaining glycogen phosphorylase in its active form
- activates glycogen phosphorylase to release glucose-1-phosphate from glycogen
- phosphorylase kinase is active when phosphorylated
- phosphorylase kinase is inactive when dephosphorylated
How does calcium activate phosphorylase kinase without it's usual activators cAMP & protein kinase A?
- calcium binds to calmodulin, a subunit of phosphorylase kinase
- this binding induces a conformational change that activates the kinase
- phosphorylase kinase can now phosphorylate/active glycogen phosphorylase, promoting glycogenolysis
In contrast to neuronal calcium signals, epinephrine stimulation of muscle results in:
the cyclic AMP-dependent system phosphorylation of enzymes
glycogen storage diseases (7):
- going 2 penny farthing andrea musters her tolerance
- I G-6-Phosphatase deficiency
- II Pompe
- III Forbes/Cori
- IV Andersen
- V McArdle
- VI Hers
- VII Tauri
- glucose-6-phosphate cannot be converted to free glucose
- prevents the release of glucose from the liver --> hypoglycemia between meals
Which glycogen storage disease is characterized by hypoglycemia between meals, hyperlipidemia, acidosis, and poor growth?
- Type I, glucose-6-phosphatase deficiency
- hepatomegaly (enlarged liver), growth retardation, hyperlipidemia, gout, renal disease
Which glycogen storage disease is characterized by the accumulation of glycogen within lysosomes, particularly in muscle cells?
Type II Pompe (lysosomal acid maltase deficiency)
acid maltase deficiency - Pompe
- acid maltase is an alpha (1-->4) glycosidase that hydrolytically cleaves glycogen in the lysosome
- if deficient, glycogen accumulates in lysosomes, particularly in those of muscle cells
- leads to rigid cells and tissues and interference with heart muscle function (cardiomegaly)
Which glycogen storage disease indicates that some glycogen must normally be broken down in lysosomes?
Type II Pompe: acid maltase deficiency
Debranching enzyme deficiency results in which glycogen storage disease?
Type III (Forbes/Cori)
debranching enzyme deficiency - Forbes/Cori
- release of glucose from glycogen is limited to the straight chain portions at the periphery of the glycogen molecules (only regions that can be attacked by phosphorylase in the absence of debranching enzyme)
- less severe hypoglycemia, abnormal glycogen, hepatomegaly
Which glycogen storage disease is characterized by deposits of abnormal glycogen in the liver, leading to progressive liver cirrhosis and death by the second year?
Type IV (Anderson: branching enzyme deficiency)
branching enzyme deficiency - Anderson
- abnormal (insoluble, not spherical) glycogen is formed with little branching
- it's treated as a foreign body & resulting inflammation and scarring damages the liver
- progressive liver cirrhosis leads to death by the second year (fatal, hepatosplenomegaly)
Which glycogen storage disease is characterized by muscle cramps during vigorous exercise, lack of lactate after vigorous exercise, and higher amounts of normal-structured glycogen?
Type V (McArdle: muscle phosphorylase deficiency)
muscle phosphorylase deficiency - McArdle
- glucose-1-phosphate cannot be provided quickly from muscle glycogen stores
- cramps occur during strenuous exercise
- characterized by a lack of lactate
- liver phosphorylase functions normally in this disease
liver phosphorylase or phosphorylase kinase deficiency - Hers
deficiency of liver phosphorylase kinase has the same biochemical consequences as a lack of liver phosphorylase: not severe b/c glucose can still be supplied by gluconeogenesis
Which glycogen storage diseases emphasize that different genes encoding distinct phosphorylases are expressed in liver and muscle?
type V (muscle, McArdle) and VI (Hers)
Which glycogen storage disease is characterized by muscle cramping and exercise intolerance and also sometimes associated with hemolytic anemias?
Type VII (Tarui: muscle phosphofructokinase deficiency)
muscle phosphofructokinase deficiency - Tarui
- generation of ATP from glucose or G-1-P is inhibited, and there is an increase in muscle glycogen
- similar but more severe consequences than type V
- exercise intolerance, and hemolytic anemia (RBCs)
- *eating fructose helps
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