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92 Cards in this Set
- Front
- Back
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What is glycogen?
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readily mobilized storage form of glucose.
large polymer of glucose residues that can be broken down when energy is needed |
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Since glycogen is not as reduced as fatty acids why use this less energy rich storage system?
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maintains blood sugar levels between meals
good source for sudden strenuous activity can provide energy in the absence of O2 |
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Where is glycogen mainly stored?
What's the difference between how these tissues utilize glycogen? |
liver--breaks down glycogen to meet the needs of the whole organism
muscles--uses glycogen for that specific muscle's purposes |
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Where does the conversion of free glucose take place?
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liver
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How is the regulation of glycogen degradation and synthesis handled?
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NEEDS OF CELLS
allosteric enzymes responding to metabolites (indicators of a cell's need for energy) NEEDS OF ENTIRE ORGANISM hormones initiating signal cascades ( |
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For glycogen degradation what roles do the 4 necessary enzymes play?
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1-degrade
GLYCOGEN PHOSPHORYLASE 2-remodel TRANSFERACE & a-1,6-GLUCOSIDASE 1-convert degradation product into metabolically useful form PHOSPHOGLUCOMUTASE |
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What does Glycogen Phosphorylase do and what is the product?
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cleaves glycogen by adding adding a Pi (phosphorolysis)
glucose 1-Phosphate |
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Where does phosphorolase cleave the glycogen?
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between C-1 of terminal glucose and C-4 of adjascent one.
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What happens to the cleaved, phosphorylated Glucose 1-Pi?
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phosphoglucomutase converts it to glucose
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Because energy transfer potential that exists between glycosidic bond and phosphoryl ester bond is almost equal, how is the break down of glycogen favored?
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[Pi] / [glucose 1 Pi] is greater than 100, the breakdown reaction is more favored due to the increased concentration of Pi favoring Phosphorolysis
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Why is phosphorylis favored over a hydrolytic cleavage of glycogen?
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Because Glucose 1 Pi is already phosphorylated and you don't have to use ATP in order to get it in a ready state for glycolysis.
Also, this is good for muscles because there is no glucose 1-Pi transporter so the energy stays right there in the cell. |
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which bonds on glycogen are not susceptible to cleavage by phosphorylase?
So what 2 enzymes fix this problem? |
a-1,6 glycosidic bonds
transferase and a-1,6-glucosidase |
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How does the transferase work?
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shifts a block of three glucosyl residues from one outer branch to the other
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What does a-1,6-glucosidase do?
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hydrolyzes the a-1,6 glycosidic bond and releases a glucose (which gets phos'd by hexokinase
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How does the Pi in Glucose 1 Pi get shifted to Glucose 6-pi for glycolytic pathway?
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phosphoglucomutase
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What does the catalytic site of an activated mutase have?
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a phosphorylated serine residue
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How does phosphoglucomutase work?
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transfers the phosphoryl group from it's Ser residue to Glucose 1-Pi creating Glucose 1,6-bisphosphate.
Then the Pi from #1 goes onto the Ser viola! |
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what is a major function of the liver?
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maintain a nearly constant level of glucose in the blood.
It is releasing glucose in between meals and during muscular activity. |
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What does Glucose 6-phosphotase do?
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cleaves the phosphoryl group from Glucose 6-Pi so glucose can leave the liver
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Describe glucose 6- phosphotase
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dimer
each dimer has PLP (pyridoxal phosphate group) on Lys 680 excludes H2O because needs to phospholyse and not hydrolyze to save the ATP. |
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Describe how PLP works to exclude water from the active site of Glucose Phosphorylase
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PLP donates a proton to the leaving glucose and creates a carbocation on the remaining glucose.
Pi then comes in and attaches at carbocation site to make glucose-1-pi |
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where is the catalytic site of Phosphorylase relative to glycogen binding site?
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30 A away but there is a narrow crevice where 4-5 glucose units can fit.
This distance allows many phosphorylations without have to detach and reattach |
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What does a processive enzyme mean?
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has a large distance between it's binding and catalytic sites and therefore allows for activity of many units without having to dissociate and reassociate
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What are the 2 forms of skeletal muscle phosphorylase?
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usually active phosphorylase a
usually inactive phosphorylase b |
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When in muscle usually inactive phosphorylase b activated?
what does this substrate do to the enzyme? |
when large accumulations of intracellular AMP are there.
AMP binds to usually inactive phosphorylase b and stabilizes it in the R state |
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Describe how ATP is an allosteric effector for phosphorylase a and b in muscle cells
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ATP competes with AMP to keep phosphorylase b inactive.
Therefore, if there is ATP in the cell, it will cause phosphorylase b to stay in T state and thus no cleavage of glycogen is going to happen. |
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Name 3 allosteric effectors for phosphorylase b in muscle cells.
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AMP
ATP Glucose 6-Pi |
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How is phosphorylase b converted to phosphorylase a in muscles?
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Ser 14 gets Pi'd which is initiated by hormones
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How does epi transition phosphorylase b to a in muscle cells?
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epi excites cell and via phosphorylase kinase, Pi's phosphorylase b to make it phosphorylase a
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What is the allosteric effector for liver phosphorylase?
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glucose binds to enzyme and inactivates it.
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How do muscle and liver phosphorylase a and b differ?
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liver phosphorylase a is most responsive to R-->T transition
liver is not sensitive to AMP levels but rather phosphorylase a is inactivated by the binding of glucose. |
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How does phosphorylase kinase activate phosphorylase b?
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by Pi-ing it.
kinase is activated by phosphorylation (signaled by hormones) and Ca2+ |
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How does exercise effect phosphorylase?
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Increased hormones in system activate b form and phosphorylation of the phosphorylase commences
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What is the main difference between a phosphorylated R state vs. T state phosphorylase?
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In the active a form, regardless of phosphorylation, the rotation has occurred to move the loop out of the way
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In muscle phosphorylase, what does high levels of AMP do?
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stabilizes phosphorylase b in R state
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Is AMP or ATP a negative allosteric effector for Phosphorylase b?
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ATP is negative allosteric effector. It competes with AMP for nucleotide binding spot and if it wins it makes the enzyme T state
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How does glucose 6-Pi effect muscle phosphorylase b?
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negative feedback inhibition. Makes phosphorylase b in T state.
Thus the energy charge of the muscle cell controls the R vs. T state of phosphorylase b |
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How does exercise effect phosphorylase?
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Increased hormones in system activate b form and phosphorylation of the phosphorylase commences
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What is the main difference between a phosphorylated R state vs. T state phosphorylase?
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In the active a form, regardless of phosphorylation, the rotation has occurred to move the loop out of the way
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In muscle phosphorylase, what does high levels of AMP do?
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stabilizes phosphorylase b in R state
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Is AMP or ATP a negative allosteric effector for Phosphorylase b?
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ATP is negative allosteric effector. It competes with AMP for nucleotide binding spot and if it wins it makes the enzyme T state
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How does glucose 6-Pi effect muscle phosphorylase b?
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negative feedback inhibition. Makes phosphorylase b in T state.
Thus the energy charge of the muscle cell controls the R vs. T state of phosphorylase b |
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What is the role of phosphorylase in the liver?
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to break down glycogen to export to body.
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How does the presence of glucose effect phosphorylase in the liver?
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glucose indicates the body has enough glucose so phosphorylase is inactive.
Shifts a from R to T |
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In the liver, is a or b form more sensitive to R-T state transitions?
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in liver, a form is more sensitive to T to R transitions
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How does AMP effect liver phosphorylase?
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It doesn't. Liver does not have energy charge changes.
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Describe the structure of phosphorylase kinase in skeletal muscles.
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(aByd)4 protein
y subunit is a kinase d subunit is a calmodulin |
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What are the dual controls of phosphorylase kinase in skeletal muscles?
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phosphorylation
Ca2+ levels |
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How is maximal activity achieved in phosphorylase kinase in muscles?
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phosphorylation of the B subunit (from Epi and cAMP and PKA activity)
plus Ca2+ binding as it is released from sarcoplasmic reticulum |
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What happens when phosphorylase kinase is fully activated from phosphorylation and calcium binding?
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when fully active the enzyme converts phosphorylase b into phosphorylase a (loop is outta the way)
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What is the target tissue for epi for glycogen breakdown?
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muscle tissue
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What is the target tissue for glucagon for glycogen breakdown?
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liver
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Where does epi come from?
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adrenal medulla hormone
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Where does glucagon come from?
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pancreatic a-cells (secreted when hypoglycemic)
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Explain the cascade from when epi binds to its B-adrenergic 7TM receptor on muscle cells
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activates Ga's
a-GTP activates adenylate cyclase adenylate cyclase increases cAMP cAMP stimulates PKA PKA phosphorylates B subunit of phosphorylase kinase phosphorylase kinase b converted to a form |
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explain how maximum glycogenolysis is obtained in the liver via epi and glucagon
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epi binds to B-adrenergic receptors which does the cAMP, PKA, phosphorylase kinase, b to a cascade
AND binds to a-adrenergic receptors to activate PIP2 breakdown leading to IP3 + DAG which binds to ER and releases Ca2+ which binds to d subunit of phosphorylase kinase |
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What turns off the glycogenolysis process?
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dephosphorylation of phosphorylase kinase and glycogen phosphorylase
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how is desphosphorylation attained?
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once the hormone is not bound a GTPase of the G protein converts GTP to GDP
phosphodiesterase makes cAMP into AMP PKA phosphorylats B subunit and a subunits of Phosphorylase kinase which makes it a better target for PP1 (protein phosphatase 1) |
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What is protein phosphotase 1?
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an enzyme that dephosphorylates glycogen phosphorylase a to make it b form.
It also inactivates phosphorylase kinase |
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In glycogen synthesis, what is the activated glucose donor to get things rolling?
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UDP-glucose
uridine diphosphate glucose |
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What is UDP-glucose?
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activated form of glucose (like ATP or Acetyl CoA are activated)
C-1 position of glucose has esterified hydroxyl bond to diphosphate of UDP |
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How is UDP glucose made?
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glucose 1 Pi + UTP ----->UDP glucose + PPi
enzyme is UDP-glucose pyrophosphorylase (releases pyrophosphate from UTP) |
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What happens to the PPi (pyrophosphate) once it is freed from UTP?
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rapidly hydrolyzed
PPi + H20 --> 2 Pi |
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What is the overall stoichiometry of the synthesis of UDP-glucose?
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glucose 1-Pi + UTP + H2O --> UDP-glucose + 2 Pi
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Why is the hydrolysis of PPi important?
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Drives the otherwise readily reversible reaction of UDP-glucose forward
this happens in many biosynthetic reactions |
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What is the enzyme that catalyzes the transfer of glucose from UDP-glucose to the terminal end of a growing glycogen chain?
Where does it add it to? |
glycogen synthase
C-4 of terminal glucose residue on glycogen forms an a-1,4 link |
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What is the key regulatory enzyme in glycogen synthesis
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glycogen synthase
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What is the primer in glycogen synthesis and why is it needed?
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glycogenin
glucose can only be transferred by glycogen synthase to a polysaccharide containing 4 or more residues |
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Describe glycogenin
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homodimer where each dimer has an oligosaccharide of a-1,4 glycosyl units which is an autoglycosylation to get the process started
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Where are the a-1,4 glycosyl units attached on glycogenin?
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C-1 end attached to Tyr-OH of glycogenin
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What are the substrates and the enzyme?
Also, what is the primer for this reaction? |
enzyme is glycogen synthase
primer is glycogenin |
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What types of links does glycogen synthase form?
What enzyme is needed to get the branching we see in glycogen? |
glycogen synthase only makes a-1,4 linkages
need branching enzyme |
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Describe how the branching enyzme works.
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break a a-1,4 link and then on a more interior site it forms an a-1,6-link
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Why is branching important?
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increases the soluability of glycogen
increases the number of non-reducing termini (site of glycogen phosphorylase and synthase) |
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How is glycogen synthase regulated?
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phosphorylation by PKA and glycogen synthase kinase inactivate it
Therefore this is the opposite of what happens in phosphorylase. In glycogen synthase Pi causes the a form to go to b form Now the b form can only be active if the allosteric levels of glucose 6-Pi are high |
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what does nucleoside diphosphokinase do?
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This enzyme puts the Pi back on UDP
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Describe the energetics of how much ATP is used to make glycogen and why this storage method is highly energetically favored.
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It costs 1 ATP to add each glucose 6-Pi to glycogen
90% of the glucose cleaved in the breakdown of glycogen is phosphoretically cleaved requiring no ATP (10% is hydrolyzed and consumes 1 ATP) thus breakdown yields 31 ATP and synthesis requires 1 ATP leading to 97% efficiency |
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How does increased cAMP activity effect glycogen synthase?
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inhibits it
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When glucagon and epi are high is glycogen going to be synthesized?
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No, because those hormones increase cAMP and PKA activity which is inhibitory to glycogen synthase
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What is Gm and G l?
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regulatory subunits that bind to PP1
They act as scaffolds, bringing together the phosphatase and its substrates in glycogen particles |
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How does PKA regulate PP1 activity?
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2 ways
in muscle Gm is phos'd and it releases PP1 which greatly decreases the dephos activity also, most cells have small proteins that get phos'd by the cAMP cycle and they bind to PP1 and inhibit it. Thus phosphorylase stays phos'd and in a form and glycogen synthase is phos'd and remains in inactive b form |
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How does insulin signal the bod to make some glycogen?
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insulin inactivate glycogen synthase kinase (the guy that keeps glycogen synthase phos'd in an inactive b form)
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What does glycogen synthase kinase do?
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phos's glycogen synthase which inactivates it. Phos'ing makes it stay in b form
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What is the normal range for blood glucose levels?
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80-120 mg per 100 mL
4.4-6.7 mM |
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In liver, how does glucose regulate glycogen metabolism?
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glucose binds to phosphorylase a which shifts it from R to T state.
Once a is in T state it's serine phosphoryl group is suddenly a target for PP1 (which is released by the conformational change from R to T) and it gets dephos'd PP1 also is able to dephos glycogen synthase converting it from b to a form. |
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Describe how the lag between breakdown and synthesis occurs?
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as phosphorylase a is being converted to b form via PP1 there are about 10 to every one PP1. Thus it takes awhile for PP1 to dephos the a guys and also to begin to act on glycogen synthase by dephos'ing it as well.
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What is von Gierke disease?
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no glucose 6- phosphatase in liver
causes: large amounts of liver glycogen hypoglycemia increased glycolysis means there is excess pyruvate and lactate in the blood increased dependence of fat metabolism |
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What is Pompe disease?
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lysomal a-1,4-glucosidase is defective
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What is Cori disease?
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muscle and liver debranching enzyme a-1,6-glucosidase is defective
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What is McArdle disease?
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muscle phosphorylase is absent
painful muscle cramps with exercise correlated with high ADP |
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What is Cori disease?
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muscle and liver debranching enzyme a-1,6-glucosidase is defective
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What is McArdle disease?
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muscle phosphorylase is absent
painful muscle cramps with exercise correlated with high ADP |
