Glycogen Flashcards
1
Q
Sources of blood glucose in a 24 hour period? (2)
A
- one hour after meals, blood glucose spikes and this is the glucose that our body uses
- in between meals, we get glucose from glycogenolysis
- at night, while fasting, we get glucose from gluconeogenesis
2
Q
Why is glycogen stored in liver?
A
- stored in the fed state to maintain blood glucose when needed
- gets depleted during a fasted state after 12-18 hours
3
Q
Why is glycogen stored in liver? affected by fasting?
A
- stored in the fed state to maintain blood glucose when needed
- gets depleted during a fasted state after 12-18 hours
4
Q
Why is glycogen stored in muscle? affected by fasting?
A
- glycogen is stored to provide energy during prolonged exercise
- not affected by short periods of fasting (days) and depleted in prolonged fasting (weeks)
5
Q
Tissue distribution of energy reserves (70Kg adult)? (4)
A
- we have a higher percentage of mass of glycogen in liver
- there is a greater total of glycogen in muscle because there is more muscle mass in a person
- regulation of glycogen is different in liver and muscle which reflects the different purposes for them
6
Q
General structure of glycogen? linkages? (5)
A
- glycogen is a branched molecule of hundreds of glucose linked together
- alpha 1, 4 linkages are for linear strands of glycogen and alpha 1, 6 linkages are where branching occurs
- anchored to glycogenin
- more branching in glycogen than starch
- having branching allows several glucose molecules to be added or removed from glycogen simultaneously
7
Q
Initiation of glycogen synthesis?
A
- lengthening the polysaccharide chains of pre existing glycogen molecules
- using protein glycogenin which serves as a primer by glucosylating itself (autoglucosylation), glycogenin makes a bond to glucose via OH groups of tyrosine
8
Q
Reducing and non reducing ends of glycogen? (7)
A
- glycogenin makes a glycosidic bond via the amino acid tyrosine to a glucose reducing end via autoglycosylation
- reducing end binds to nonreducing end to form glycogen
- all end branches of glycogen are nonreducing ends
9
Q
What is the biological advantage of synthesizing glycogen with many branches?
A
- highly branched glycogen is more soluble than unbranched glycogen
- both glycogen synthase and glycogen phosphorylase act at the nonreducing ends of glycogen chains
- branched glycogen has far more ends for enzymes to work on that would the equivalent amount of linear glycogen chains
- having more ends increases the concentration of substrate for the enzymes, thereby increasing rate of glycogen synthesis and breakdown
10
Q
What enzyme activates glycogen synthesis? inactivates it? (9)
A
- activating- glycogen synthase
- inactivating- glycogen phosphorylase via glycogen kinase
11
Q
Steps of Glycogenesis? (11)
A
- glycogen synthesis begins with conversion of glucose to G6P
- G6P to G1P by phosphoglucomutase
- G6P is an intermediate in glycolysis, PPP, and gluconeogenesis
- excess glucose going through glycolysis can be diverted into glycogen storage in response to insulin - high energy form of glucose is formed
- glycogen synthesis is catalyzed by UDP glucose pyrophosphorylase that convert G1P to a high energy form, UDP glucose - alpha 1, 4 linkages are formed
- the enzyme glycogen synthase transfers the glucose in UDP glucose to one of the growing glycogen branches
- released UDP can be reconverted to UTP by a reaction with
ATP UDP + ATP UTP + ADP (nucleoside diphosphate kinase)
- branches are formed
- when about 11 growing glucose molecules are added to one growing chain of glycogen, a branching enzyme, 4:6 (glucosyl) transferase moves a chain of 6-8 glucose molecules to form a new branch chain starting with an alpha 1, 6 linkage
12
Q
Glycogen storage disease (GSD 0)? symptoms? treatment?
A
- deficiency in glycogen synthase
- low amounts of glycogen in liver (fasting hypoglycemia)
- symptoms develop when a baby no longer gets fed during the night (late infancy)
- early in infancy, usually no symptoms
- slower than expected growth (mild growth delay)
- when exercising, become tired more quickly, have muscle cramps
- ketones in urine
- genetic DNA testing performed on blood sample is available
- affects both males and females
- autosomal recessive
- treatment: prevent hypoglycemia by avoiding fasting
- frequent meals and snacks can be given every 3-4 hours during the day
- uncooked starch can act as a slow release form of glucose for the body
- diet high in protein may help with cramping, tiredness, and fatigue
- testing for GSD 0 recently became available
13
Q
Anderson’s disease (GSD IV)? symptoms? treatments?
A
- deficiency in branching enzyme
- characterized by long strands of glycogen molecules, thought to trigger body immune system causing body to attack tissues, causing scarring (cirrhosis) of liver and muscle
- presents in infantile hypotonia and cirrhosis
- normal at birth but fails to thrive, little weight gain, muscles develop poor tone
- death typically occurs by 5 years old
- treatments: liver transplant, muscle and heart disease may still be a problem
14
Q
What are the major principles of metabolic regulation?
A
- maximize efficiency of fuel utilization by preventing simultaneous operation of opposing paths (futile)
- partition metabolites appropriately between alternative paths
- draw on the fuel best suited for immediate needs of organism
- shut down biosynthetic paths when their products accumulate
15
Q
How is glycogen synthesis regulated by hormones (covalent modification)? (18)
A
- insulin is secreted after a meal which stimulates glycogen synthesis, inhibits glucagon
- insulin, via an insulin factor, activates a phosphatase to remove a phosphate group from glycogen phosphorylase (dephosphorylation), inactivating glycogen breakdown
- insulin, also activates phosphatase to remove phosphate groups from glycogen synthase, activating glycogen synthesis
- insulin stimulates uptake of glucose by muscle (GLUT4)
16
Q
How is glycogen synthesis regulated allosterically? (18)
A
- in a fed state, G6P is elevated which allosterically activates glycogen synthase which was inactive because of phosphorylation
- inactivation of glycogen synthase by phosphorylation is partially overcome by G6P
- G6P is an intermediate in glycolysis
- if glucose levels are really high, glycolysis/TCA are going at top speed, but not keeping up with demand, G6P levels increase and a backup occurs at glycogen synthase
- some G6P is diverted into glycogen for storage, so high levels of G6P directly activate storage
18
Q
Steps of glycogenolysis? (20)
A
- glycogen phosphorylase removes one glucose molecule at a time and converts it to G1P
- glycogen phosphorylase breaks alpha 1, 4 linkages
- no energy requirement, product G1P is phosphorylated - glycogen phosphorylase cannot remove glucose within 4 residues of a branch point so debranching enzymes (4:4 transferase and alpha 1, 6 glucosidase) convert the branched structure into a linear one which paves the way for further cleavage by glycogen phosphorylase
19
Q
Function of 4:4 transferase? (21)
A
- transferase (glucosyl transferase) enzyme removes three glucose residues (as a trisaccharide) adjacent to the branch point (alpha 1, 6 linkage) and transfers them to the end of another row
- breaks an alpha 1, 4 bond and forms another alpha 1, 4 bond
20
Q
Function of 1:6 glucosidase? (21)
A
- debranching enzyme that removes the alpha 1, 6 glycosidic bond to release one glucose molecule as glucose (not G1P) at the branch point
- some energy is needed to utilize glucose
21
Q
Lysosomal degradation of glycogen? (23)
A
- 1 to 3% of glycogen is degraded by lysosomal enzyme alpha 1, 4 glucosidase (acid maltase or acid glucosidase)
- in lysosomes, normal enzyme is involved in debranching and hydrolysis of both alpha 1, 4 and alpha 1, 6 glucosidic linkages at acidic pH of 5 and necessary to break down glycogen
22
Q
Pompe disease (GSD II)? (23)
A
- a deficiency of alpha 1, 4 glucosidase (lysosomal acid glucosidase or acid maltase)
- deficiency in this enzyme results in accumulation of excess amounts of glycogen (normal structure)
- in certain tissues, muscle, excessive accumulated glycogen impairs ability to function normally
- massive cardiomegaly- early death from heart failure
- normal blood glucose levels
- diagnosed by enzyme assay
- Myozyme (alglucosidase alfa)- future gene therapy
23
Q
McArdles disease (GSD V)? symptoms? (25)
A
- deficiency in muscle phosphorylase
- most common types of GSD (1 in 100,00)
- symptoms:
- temporary weakness of exercising skeletal muscle, intolerance with myalgia, early fatigue, painful cramps
- myoglobinuria (myoglobin in urine resulting from serious muscle damage)
- Rhabdomyolysis (muscle cells breakdown)
- no rise in lactate during strenuous exercise
- normal renal and hepatic development
- high levels of glycogen with normal structure in muscle
24
Q
Von Gierkes disease (GSD I)? symptoms? treatment? (25)
A
- deficiency in G-6-phosphatase
- liver, kidney, intestine, hepatomegaly (fatty liver), progressive renal disease
- abnormal accumulation of glycogen (normal structure) in kidney and liver cells, causing clinically important end organ disease and morbidity
- diagnosis by DNA testing, enzyme assay and physical exam
- kidney or liver biopsy may be needed for confirmation
- fasting hypoglycemia due to inability of liver to produce glucose
- hyperlacticacidemia (G6P is high, muscle glycogenolysis high and including lactate)
- hyperuricemia
- treated with nocturnal gastric infusions of glucose or uncooked cornstarch and frequent consumption of carbs
25
Q
Her’s disease? symptoms? (25)
A
- deficiency in liver phosphorylase
- high levels of glycogen with normal structure in liver
- clinically similar to von gierke disease but typically milder
- hepatomegaly due to glycogen accumulation
- decreased glycogenolysis
26
Q
Cori/ Forbes disease (GDS III)? symptoms? treatment? (25)
A
- deficiency of debranching enzyme
- characterized by shorter branches in glycogen
- affects both muscle and liver
- diagnosed by liver biopsy
- mild hypoglycemia and hepatomegaly
- treatment: liver transplant
27
Q
Fate of G1P in liver? (33)
A
- G1P which is generated from the breakdown of glycogen is converted to G6P by phosphoglucomutase
- G6P is converted to glucose by G-6-phosphatase, then glucose can go into the blood stream
- in can also go through glycolysis/TCA for energy or to create lactate from pyruvate
- in liver, glycogen is located near folds of smooth ER and G6P is translocated to the SER because G-6-phosphatase is highly hydrophobic enzyme embedded in the SER
28
Q
Fate of G1P in muscle? (32)
A
- G1P from the breakdown of glycogen is converted to G6P by phosphoglucomutase
- there is no G-6-phosphatase in muscle so G6P goes through glycolysis/TCA for energy
32
Q
Regulation of glycogenolysis in liver? (37)
A
- glucagon signals low blood glucose levels
- glucagon activates cAMP which activates protein kinase A
- glycogen synthase is inactivated by phosphorylation
- glycogen phosphorylase is activated by phosphorylation
- net result is inactivation glycogenesis, activation of glycogenolysis and glucose enters blood
33
Q
Regulation of glycogenolysis in muscle? (38)
A
- hormonal regulation by epinephrine via cAMP in the same way as glucagon in liver
- allosteric regulation:
- increased AMP levels activate the inactive form of glycogen phosphorylase
- increased calcium ions further activate the inactive form of glycogen phosphorylase kinase
- notes:
- this allosteric path is used for immediate energy to muscle
- initially most enzymes are not phosphorylated, increased AMP and Ca2+ will signal to become phosphorylated, until all enzymes are phosphorylated, then increased AMP levels are no longer needed
- in contracting muscle, Ca2+ needs to be pumped back into SR
35
Q
PFK-2 in liver vs muscle? (41)
A
Liver:
- low blood sugar stimulates cAMP synthesis, activating protein kinase A (PKA) to phosphorylate PFK-2 (inactivating) and FBPase-2 (activating)
- this results in lower levels of F2,6BP
- in absence of F2,6BP, activity of PFK-1 is reduced, inhibiting glycolysis -activity of FBPase-1 is enhanced, stimulating gluconeogenesis
- liver replenishes blood glucose
Muscle:
- PFK-2 has no phosphorylation site, and is regulated by substrate availability (F6P)
- when F6P is abundant, PFK-2 is active to produce F2,6BP which allosterically activates PFK-1 to activate glycolysis
- F2,6BP is always present in skeletal muscle
38
Q
Overall allosteric regulation of glycogenesis and glycogenolysis? (42, 43)
A
see pics
39
Q
Overall review of clinical cases of GSD? (45)
A
- GSD primarily affects liver, muscle, RBC, or all
- if liver is affected, hypoglycemia is common with hepatomegaly
40
Q
GSD charts? (51, 52)
A
see charts
