Week 3- Glycogen Metabolism Flashcards
What tissue is dependent on glycolylis and ketone bodies to make acetyl CoA for TCA?
Brain
What is completely dependent on glycolyis for ATP?
RBCs
What is biggest?
Preproinsulin
Proinsulin
Insulin
Preproinsulin
Where is proinsulin processed?
ER
Insulin is stored in pancratic beta cell as a…
Hexamer wih Zn
What is removed in converting proinsulin to insulin?
C-peptice
1:1 ration with insulin
The oxidation of odd chain length fatty acids produces succinyl CoA. When it moves into TCA, what are the products?
1 FAD, 1 NAD, GTP, Oxaloacetate
What cells can secrete glucose?
Only hepatic cells…
Other bodily cells cannot…
What is glycogen? What does it do in body?
Glycoge in a glucose storage molecule for most cell types but most important in:
Heart and skeletal muscle - serves as a buffer for glucose 6 phosphate for cellular use (energy)
In liver it serves as a glucose buffer for blood
What is glycogen?
Storage molecule for glucose
What does glycogen do in liver and in heart and skeletal muscles
Serves as a buffer for glucose 6-phosphate for use within the cell
What are symptoms of glycogen metabolism defects?
fasting hypoglycemia
muscle pain during exercise
Chemical structure of glucose?
What bonds make linear chains?
What bonds make branch points?
Two types of carbon – carbon bonds in glycogen:
1: 4 Bonds between the and 4 carbons make linear chains
1: 6 Bonds between the 1 and 6 carbons make branch points
What are the substrates for glycogen synthesis?
Charged glucose.. must by phosphorylated…
G6P to G1P to UDP-Glucose
What is UDP-glucose?
Glucose coiled on spring (energized)
Also has nucleotide handle for transport…
When the body make phospholipids, what is is simlar to? (process)
Similar to the process of creating UDP glucose
Structure of UDP-Glucose
Basid structure of glycogen?
Glycogenen has serine OH groups on sides.. second sugar added through 1-4 linkage
It is a puff ball of branched glucoses…
What is the process for creating glycogen?
What is the enzyme for creating the long main chains?
Insulin signaling activates protein phosphatase-1, which dephosphorylates glycogen synthase, activating the enzyme.
In the absence of insulin, glycogen synthase kinase-3 is active, which phosphorylates and inactivates glycogen synthase.
This continues for 11 (or so) units of glucose
Elongation happens towards 4 carbon so always in 1 to 4 direction
Glycogen synthase adds UDP glucose to the linear chain
What is the branching enzyme for glycogen production?
glycosyl 4-6 transferase
Branching enzyme (glycosyl 46 transferase) then cleaves a piece of the chain off, and attaches it to the chain in a 1:6 glycosidic linkage. Both branches then can be extended with 1:4 bonds.
What does glycosyl 4-6 transferase do?
Adds 6 UDP glucoses to a branched chain
Draw branching of glycogen production rxn
What are key enzymes in glycogen synthesis (glycogenogensis)?
glycogen synthase
4-6 transferase
What do the key enzymes do in glycogenogensis?
Glycogen synthase adds a UDP glucose to a branched chain
then 4:6 glucose transferase transferes branched chains to main string of glucoses
What is GSD 0
Defect in glycogen synthase… pts will ahve no glycogen production
Mutation in Glycogen Synthase
What is GSD IV, Anderson disease?
Mutation in 4:6 transferase
The branched chains wnt get moved down to main linear chain..
What does GSD 0 cause?
Glycogen synthase deficiency
Rare (?) autosomal recessive
Normal glucose tolerance; variable clinical presentation of exercise intolerance, cardiac and muscle hypertrophy.
What is GSD IV?
Deficiency of branching enzyme, 4:6-transferase.
Failure to thrive, hepatomegaly, liver failure. Fatal.
So when have abundant carbs/glucose what happens?
Glycogen production
Glycogen is a what?
puffball of glucose…
It is a branched polymer
not linear
Why is it an advantage of glycogen to be branched? not linear?
Key: because it is branched.. multiple enzymes can chop it down much faster and at the same time so glucose can be made form glycogen VERY fast.. much faster than if it were a long chain. Multiple binding points for enzymes
It is a short term buffer for glucose concentration in blood…
Branching increases solubility (more exposed OH groups)
If we dont have carb in blood? but have glycogen stores within cell what happens:
Glycogen degradation (glycogenolysis)
What product from glycogenolysis?
G1P Glucose 1 phosphate
What are three enzymes in glycogenolysis?
Glycogen phosphorylase
Makes the 1-4 cuts…
But, when it gets to a branchpoint it is sterrically hindered and cant act..
So 4:4 transferase moves it to end of chain
Then alpha 1,6 glucosidase removes the single G1P
Then glycogen phosphorylase breaks of the remaining glucose from chain..
What enzyme can cut 1-4 bond and is not sterically hindered?
4-4 transferase
What does alpha 1,6 glucosidase do?
Cuts one molecule of glucose from glycogen core
Defect in glycogen degredation or one of key enzymes?
Can store glycogen but it wont be able to degredate it so you would see an increase in glycogen in tissues…
What is 4:4 transferase?
Moves three glucoses to end of main glycogen chain when glycogen phosphorylase becomes sterically hindered..
What is glygcogen phosphorylase?
Enzyme to cleaves glucose from glycogen chains and adds inorganic phosphate to make G1P
What is alpha 1,6 glucosidase?
Enzyme that hydrolyzes the remaining glucose after 4:4 transferase removes the previous 3..
Probs resulting form glycogen storage degredation disiease
Fasting hypoglycymia
Liver failure
GSD V (Mcardles disease)
Caused by mutation in muscle glycogen phosphorylase
GSD VI (Hers Disease)
Mutation in liver glycogen phosphorylase
GSD III disease
Deficiency in 1,6 glucosidase activity
High levels of single glucoses on the glycogen core..
How is glycogen metabolism regulated?
Which is faster? A or B?
There are two forms of glycogen phosphorylase: A and B
Shown is a Lineweaver-Burke plot (a.k.a. double reciprocal plot) of initial reaction velocities with different concentrations of substrate (glycogen) for phosphorylase A and phosphorylase B.
B form has higher 1/Vmax, therefore lower Vmax.
B form has higher (or less negative) 1/km, therefore Km is higher.
FED vs FAST state and glycogen metabolism
Glycogen metabolism is controlled by phosphorylation of glycogen phosphorylase and glycogen synthase.
In the fed state, phosphorylase is inactive and glycogen synthase is active. Both are unphosphorylated.
In the fasted state, phosphorylase is active and glycogen synthase is inactive. Both are phosphorylated.
Draw general lineweaver burk plot. Where is 1/vmax, 1/km
hj
What is glycogen metabolism controlled by?
Phosphorylation of glycogen phosphorylase and glycogen synthase
Glycogen metabolism in fasted state
Look at picture, draw it out..
What inhibits and activates glycogen synthase?
Epinepherine and glucagon
activates inhibits glycogen phosphorylase?
Glucagon and Ca++
Protein phosphatase 1
activated by insulin (inactive in fasted)
PLC (phosph lipase C)
Epinepherin ..
DAG
PKC
IP3
diacyl glycerol
phosphoskinase C
inositol 3 phosphate
Glycogen synthase is phosphorylated (deactivated) by what?
Epinepherine and glucagon
What phosphorylizes glycogen phosphoylase kinase?
Glucagon (through PKA) adn Ca++
What phosphorylates glycogen phophorylase?
Ca++ and PKA
Draw glycogen metabolism in FED state in hepatocyte.
What inhibits protein phosphatase 1?
Insulin
what inhibits glycogen synthase kinase 3?
PKB (Akt) through insulin
Role of protein phosphatase?
When active, its role is to remove phosphates from glycogen synthase and glycogen phosphorylase
Difference in kinases and phosphatases in regards to Pi and ATP..
….
Cytoplasmic concentration of Ca?
Extremely Low
But waves of Ca come in from ER or Sarcoplatic Reticulum
Know what epinephrine does… Ca calmudulin to kinase etc…
kj
Whaere is Glucose 6 phosphatase found?
Take Phos off of G6P to put glucose in blood… ONLY IN LIVER. why is it critical?
(only in liver_not skel musc)
What does wave of Ca do in muscle
Stimulates muscle contraction.. Then Ca goes to phosphorylate glycogen phosphorylase kinase.. This activateds glycogen phosphorylase KNow fasted vs fed state of this
Glucose 6 phosphate in liver vs skeletal muscle…
lkj
Draw glycogen metabolism in Fasted state in skeletal muscle
What does AMP to do AMP-K (kinase) and to glycogen phosphorylase?
lkj
GSD 0
Glycogen synthase deficiency
Reduced glycogen storage efficiency
GSD V
Deficiency of muscle glycogen phosphorylase.
Late childhood onset of exercise intolerance, myoglobinuria after exercise.
Increased creatine kinase; exagerated increase of creatine kinase and ammonia after exercise.
Treatment: Avoid exercise; try to build tolerance
GSD I
Deficiency in glucose 6-phosphatase.
Fasting hypoglycemia, lactic acidosis. Hepatomegaly due to glycogen accumulation. Hyperuricemia and hyperlipidemia.
Treatment:
Avoid fasting by frequent feeding, uncooked cornstarch
Blue cell and pink cell.. which is hepatocyte and which is muscle cell?
Hepatocyte on right
Can transport glucose out
Has glucose 6 phosphatease
AMP only in muscles
Ca from muscle contraction
Glucagon only acts on hepatocytes (not skeletal muscle)
GLucokinase in liver
Hexokinase in muscle
FASTED STATE
Symptoms of GSD 0?
Glycogen synthase deficiency
Muscle Specific… Skeletal and Cardiac
If in Cardiac it is significant…
Normal glucose tolerance, variable clinical presentation of excercise intolerance…
Cardiac and skeletal muscle hypertrophy
May be cause of SIDS… unknown though
GSD I Symptoms
Glucose 6 phosphatase
Only in liver*
Whole body glucohomeostacis problem…
Fasting hypoglycemia, lactic acidosis
Hepatomegaly due to glycogen accumulation
Hyperuricemia and hyperlipidemia
GSD I Treatment?
Avoid fasting by frequent feeding, eating uncooked corn starch
GSD III symptoms and treatment
Loss of debranching enzyme 1,6 glucosidase
Fasting hypoglycemia, ketoacidosis (starvation response)
Hyperlipidemia
Hepatomegaly with elevated ALT/AST
GSD III a - affects liver and muscle. can cause cardiac issues
GSD III b - affects only the liver
Treatment: frequent high carb meals
GSD IV symptoms
Deficiency of branching enzymes, 4,6 transferase
Glycogen does not branch, justmany long chains
Failure to thrive, hepatomegaly, liver failure, can be fatal
GSD V symptoms
Deficiency of muscle glycogen phosphorylase..
Late childhood onset of exercise intolerance, myoglobinuria after excercise
Increased creatine kinase
Exaggerated increase in ammonia after excercise
Treatment: avoid exercise, try to build tolerance
What is general approach to child with fasting hypoglycemia…
adicocis vs no acidosis.. etc
Clinical case I
8 year old south indian boy…
8 y/o male, died unexplained during excercise
mke card for consaguinous (first cousin parents)
Autopsy showed? Ragged red fibers. Tons of mitochondria and are swollen and nunnomral.. GLycogen depleted..
Sink fibrobalsts.. cultured in vitro in me dia containing. Plotted concentration of lactate vs time.
So muscles are trying to have aerobic production of energy but doesnt have glucose.. so it is producein energy form fatty acids and ketone bodies…
Mitochondria are porliferating to try to increase energy production
Plot.. lactate in control is from glucose stored as glycogten that goes throu anaerobic glycolosis. IN pt lactate is not being produces.. so not getting glucose from glycogen…
glycogen synthase (GYS1) western blot showd no blot for pateint but yes for control.. So pt not making GYS1 protein.. So the mutation prefents GYS1 from being produced. Then add GAPDH and it ensures same abount of protein in each sample..
Summary of pathophysiology of excercise aindused suden cardiac arrest due to inherit4ed deficiency of muscle glycogen synthase
So deficiency in synthase. not able to store glucose as glycogen.. then in fasted state you have no glucose/energy. With no enrgy the muscle tissue compensated and produced many mitochondrial and hypertorphied. breaking up muscle fibers that eventually led to cardiac arrest…
so this boy was 8.. he compenstaed for many years, creating damage all the way along.
If a skin punch would have been done at birth… pt most likely could have been treated (by limited excercise). Is this plausable for every pt tho.. prob not.
Next case.. Patient E..
PAS-pos.. Periotic acid shift stain - identifies sugars
So if take glycogen and incubate with amylase you get G6P..
So pictures show bad disfigureation of muscle
Phosphorylase kinase activity undetectable in heart
look at quiz slides online..
What is different in liver and muscle glycogen phosphorylase?
liver - glucose
muscle - Glucose 6 phosphate
