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
17
Q
What situations lead to increase in glycogenolysis?
A
- physiological increase in blood glucose utilization
- exercise
- pathological result of blood loss
- psycological response to acute and chronic stress
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
Her's disease? symptoms? (25)
- 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
Cori/ Forbes disease (GDS III)? symptoms? treatment? (25)
- 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
Fate of G1P in liver? (33)
1. G1P which is generated from the breakdown of glycogen is converted to G6P by phosphoglucomutase
2. G6P is converted to glucose by G-6-phosphatase, then glucose can go into the blood stream
3. 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
Fate of G1P in muscle? (32)
1. G1P from the breakdown of glycogen is converted to G6P by phosphoglucomutase
2. there is no G-6-phosphatase in muscle so G6P goes through glycolysis/TCA for energy
29
Hormonal regulation of glycogenolysis?
- under stress body must maintain blood glucose levels
- when glucose is low in blood stream, insulin is decreased and glucagon is increased (fasting)
- increased epinephrine (acute stress) and kinase enzymes active
- hormones do not act directly on glycogen, but act through series of signals initiated when they bind to specific cell receptors
- binding of glucagon and epinephrine to receptors activates cAMP (2nd messenger)
30
What is the glucagon effect on enzymes related to glycogen?
- glycogen synthase is inactivated by phosphorylation
- protein kinase A targets these enzymes:
- glycogen phosphorylase is activated by phosphorylation
- glycogen is broken down to glucose for the blood stream
31
What hormones does the liver have receptors for? muscle?
- liver: epinephrine, glucagon, insulin
- muscle: epinephrine, insulin
- insulin- inhibition
- glucagon,epinephrine- rapid activation
32
Regulation of glycogenolysis in liver? (37)
1. glucagon signals low blood glucose levels
2. glucagon activates cAMP which activates protein kinase A
3. glycogen synthase is inactivated by phosphorylation
4. glycogen phosphorylase is activated by phosphorylation
5. net result is inactivation glycogenesis, activation of glycogenolysis and glucose enters blood
33
Regulation of glycogenolysis in muscle? (38)
1. hormonal regulation by epinephrine via cAMP in the same way as glucagon in liver
2. 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
34
Why are the muscle glycolytic enzymes active during glycogenolysis?
1. hexokinase- in muscle, is the first regulatory enzyme and is constitutive, so it expressed at all times
2. phosphofructokinase-1 (PFK-1)- is second regulatory enzyme in glycolysis
- during muscle contraction, myosin ATPase increases AMP levels from hydrolysis of ATP to ADP, this increases AMP levels allosterically to stimulate glycogenolysis
- AMP is an allosteric activator of PFK-1 so glycolysis is stimulated too
35
PFK-2 in liver vs muscle? (41)
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
36
What are the regulatory implications for the cells with regard to ATP and AMP, given that ATP is usually high and AMP is low?
- ATP (5-10mM)
- AMP (0.1mM)
- AMP is a much more sensitive indicator of a cell's energetic state
- small changes in ATP concentration are amplified into large changes in AMP concentration
37
Hormonal effects on pyruvate kinase in muscle?
- pyruvate kinase doesnt get phosphorylated
- even though the hormonal effects of epinephrine are the same as glucagon, it doesnt affect the pyruvate kinase in the muscle and pyruvate kinase remains unphosphorylated and active
38
Overall allosteric regulation of glycogenesis and glycogenolysis? (42, 43)
see pics
39
Overall review of clinical cases of GSD? (45)
- GSD primarily affects liver, muscle, RBC, or all
- if liver is affected, hypoglycemia is common with hepatomegaly
40
GSD charts? (51, 52)
see charts
41
Case 1: Mcardles disease Subjective:
CC: 14 year old male, nonsmoker; easily fatigued, experiencing muscle cramps after windsprints and calisthenics in high school gym class.
HPI: Generally sedentary habits; avoided physical activity throughout grade school and junior high school.
Noticed that exercise "hurt", so tended to avoid it if at all possible.
Objective: PE: About 10 pounds overweight.
Pathology: No gross abnormalities noted.
Questions:
1. What is the deficient enzyme?
2. What are the biochemical consequences of a deficiency in its activity?
3. Explain why this patient complains that it "hurts" when he exercises. Why he is easily fatigued?
4. As alternative causes, could this disease also be caused by a deficiency in phosphorylase kinase? Could it be caused by excessive activity by protein phosphatase?
1. deficient in glycogen phosphorylase in skeletal muscle (myopathic)
2. inability to break down glycogen
3. hard for body's muscles to draw on glycogen as a quick source of energy and other sources of glucose must be utilized instead, so sudden demands for energy can cause painful cramps or weakness
4. glycogen phosphorylase kinase catalyzes the reaction to transfer a phosphate, and protein phosphatase catalyzes the dephosphorylation. -glycogen phosphorylation needs to be phosphorylated to break down glycogen
42
Case 2: von gierkes disease (GSD 1) Subjective:
ID/CC: 6 year old boy with frequent episodes of weakness
HPI: Weakness accompanied by sweating, feeling of dizziness; weakness had been noticed since about age 4, but had become more noticeable when child entered school and was challenged by other children during recess.
Objective:
PE: Enlarged abdomen, due to grossly enlarged liver. Kidneys also enlarged. Poor musculature. Normal heart.
Labs (Fasting blood): view slides 49/50
Questions:
1. What is the enzyme defect here?
2. Why is the liver enlarged?
3. Why did the child complain of weakness?
4. What is the significance of the fasting blood sample test results?
5. Why is blood pH on the acidic side? Is this related to the serum CO2 level? If so, how? If not, why not?
6. What is the significance of the high levels of glycogen in the liver biopsy test results?
7. What do the enzyme test results tell you about this patient?
8. What therapy do you recommend for this patient?
1. deficient in G-6-phosphatase- the enzyme that removes phosphate groups from glucose and permits it to be released from the cell
2. glycogen is not being broken down in the liver and it is accumulated, enlarging the liver
3. glycogen cannot be mobilized as glucose into the bloodstream for needed energy, result is sever hypoglycemia and weakness
4. all numbers are off
5. body is using other forms of energy such as fatty acids and ketone bodies, so elevated levels of triglycerides, fatty acids, and ketones in blood, coupled with metabolic acidosis
6. glycogen was accumulating in the liver, unable to be released as glucose
7. low G6Pase could not remove phosphate to make glucose
8. frequent consumption of carbs
MBM
flashcards
Decks in class (24)
# Cards
-
DNA Replication110
-
RNA and Protein Synthesis98
-
Regulation of Gene Expression133
-
DNA Repair79
-
Genetics 1165
-
Genetics 217
-
Proteins83
-
Hormones 161
-
Hormones 263
-
Energy Production and Utilization88
-
ATP Synthesis78
-
Carbohydrates 182
-
Carbohydrates 225
-
Glycogen42
-
Gluconeogenesis/Ketogenesis49
-
Lipids138
-
Fatty Acid Oxidation62
-
Fatty Acid Synthesis47
-
Lipoproteins65
-
Dietary Proteins 180
-
Dietary Proteins 246
-
Hemoglobin92
-
Hemostasis63
-
Nutrition38
