Sessions 15 and 16 - glycogen degradation

Question 1

how does glycogen phosphorylase work

Answer 1

it cleaves glucosyl residues from the nonreducing side of a glycogen chain by adding orthophosphate (Pi) to yield glucose 1-phosphate.

Question 2

what can glucose-1 phosphate be readily converted to

Answer 2

glucose 6-phosphate, an important metabolic intermediate, by the enzyme phosphoglucomutase

Question 3

is phorphorolytic cleavage of glycogen energetically advantageous

Answer 3

yes it is energetically advantageous because the released sugar is already phosphorylated. in contrast a hydrolytic cleavage would get glucose which would then need to be phosphorylated.

Question 4

when does glycogen phosphorylase run into problems

Answer 4

it stops cleaving a, 1-4 linkages when it reaches a residue four residues away from a branch point (a, 1-6 linkage).

Question 5

what is required to overcome the branching issue

Answer 5

a transferase that shifts a block of three glucosyl residues from one outer branch to another that exposes a single residue joined by a,1-6 linkage. a,1-6 glucosidase aka debranching enzyme then hydrolyzes the 1-6 bond releasing a free glucose molecule.

Question 6

what is a major biochemical function of the liver

Answer 6

to maintain a nearly constant concentration of glucose in the blood

Question 7

how does liver released glucose contrast to glucose from glycogen breakdown

Answer 7

the phosphorylated glucose from glycogen breakdown doesn’t leave the cell. but the liver contains glucose 6-phosphatase that enables glucose to leave the liver by cleaving the phosphoryl group to form free glucose and orthophosphate.

Question 8

general overview of phorphorylase regulation

Answer 8

it is regulated by several allosteric effectors that signal the energy state of the cell, as well as by reversible phosphorylation, which is responsive to hormones such as epinephrine, glucagon, and insulin.

Question 9

compare liver use of glucose to skeletal muscle use of glucose

Answer 9

the liver maintains glucose homeostasis of the organism as a whole. whereas the muscle uses glucose to produce energy for itself

Question 10

describe activity of phosphorylase a in the liver

Answer 10

the default state of liver phosphorylase a is that glucose is to be generated unless the enzyme is signaled otherwise. glucose binding to the active site shifts the a form from R state to T state. so essentially the enzyme reverts to T state only when there is enough glucose

Question 11

how is phosphorylase a different from phosphorylase b

Answer 11

phosphorylase a equilibrium is in favor of the R state while phosphorylase b equilibrium favors the T state so it is usually inactive.

Question 12

where will you find phosphorylase b primarily

Answer 12

in the muscles because phosphorylase is primarily needed only during contraction

Question 13

what activates phosphorylase b

Answer 13

high concentrations of AMP, which binds to a nucleotide binding site and stabilizes the R state.

Question 14

describe the regulators of phosphorylase b and their effects on its primary configuration

Answer 14

the transition of phosphorylase b between R and T state is controlled by the energy charge of the cell (activated by AMP and inhibited by ATP)

Question 15

does a’ 1-6 glucosidase form glucose or glucose 1-phosphate

Answer 15

just glucose so hexokinase has to transform it to glucose 1-phosphate

Question 16

what is phosphoglucomutase

Answer 16

it moves the phosphate from 1st carbon to 6th. the enzyme contains a pre-phosphorylated serine residue that gives the 6th carbon the phosphoryl group making glucose 1-6 biphosphate. then the phosphoryl group on 1st carbon goes back to the serine.

Question 17

what does phosphorylase kinase do

Answer 17

phosphorylates the two 14-serine residues using 2 ATP to convert phosphorylase b to phosphorylase a.

Question 18

what happens to phosphorylase kinase when the muscle undergoes sudden and strenuous activity

Answer 18

hormones like epinephrine are released and stimulate phorphorylase kinase so that there will be more phosphorylase a

Question 19

describe regulators in exercising skeletal tissues

Answer 19

in exercising tissue there will be a low energy state so high AMP concentrations which shifts equilibrium of phosphorylase b towards the R-state. and hormones will cause there to be more phosphorylase a which already exists predominantly in the R state

Question 20

describe regulators in resting skeletal tissues

Answer 20

ATP will be high which shifts equilibrium in phosphorylase b to the T state. there will also be high levels of glucose 6-phosphate which also helps to stabilize T state of phosphorylase b.

Question 21

what is one difference between phosphorylase in liver and skeletal tissue

Answer 21

in the liver the phosphorylase is sensitive to glucose. glucose inhibits phosphorylase by stabilizing the T-state. so when blood glucose is high (after a meal) it allosterically inhibits. in low blood glucose the glucose leaving the active sites causes the phosphorylase to change to the R state

Question 22

describe phosphorylase b in liver

Answer 22

it doesn’t respond to glucose and it also doesn’t respond to energy change because the energy charge in the liver remains mainly constant.

Question 23

how do you activate glucose for glycogen synthesis

Answer 23

UDP-glucose pyrophosphorylase. it takes UTP and adds uridine phosphate to glucose 1-phosphate making UDP-glucose. this makes the phosphoryl bond to glucose more active. a by-product is pyrophosphate

Question 24

what is the coupled reaction to make glucose activation more product favorable

Answer 24

when pyrophosphate is in water it spontaneously splits into 2 orthophosphate groups. this is coupled with UDP–glucose pyrophosphorylase to make it more energetically favorable

Question 25

what is glycogen synthase

Answer 25

it takes glucose molecule from UDP-glucose and attaches it to growing glycogen chain by the free hydroxyl group on the end of the glycogen chain attacks the newly activated ester bond making a a, 1-4 glycosidic bond. it can only add glucose molecules onto a chain consisting of more than four residues so a primer is necessary

Question 26

what is glycogenin

Answer 26

before glycogen synthase can begin glycogen synthesis glycogenin must create a primer. the primer is a short sequence of glucose residues connected by a 1-4 glycosidic bonds. is is a dimer with 2 identical subunits that creates primer using UDP-gucose molecules. upon synthesis of the primer, glycogen synthase resumes glycogen synthesis

Question 27

why are glycogen branches beneficial

Answer 27

increases the solubility of glycogen inside the cytoplasm (stored in granules). it also increases the terminal (nonreducing) glucose residues, which raises the rate of glycogen synthesis and breakdown.

Question 28

how are branches formed

Answer 28

glycogen branching enzyme detaches a group of seven or more residues containing a terminal group and attaches the group via a 1-6 bond at another location.

Question 29

what does branching enzyme require

Answer 29

that the original glycogen chain is 11+ residues in length. that the group is placed at least 4 residues away from a pre-existing branch point.

Question 30

describe the structure of phosphorylase kinase

Answer 30

it consists of four types of subunits: a, b, y, and d. each type has four subunits as well. the y subunits are the catalytic subunits while the others are regulatory. the beta and delta are ultimately responsible for activating phosphorylase kinase

Question 31

how are beta units activated

Answer 31

hormones are released during times of stress or exertion and phosphorylate the beta units.

Question 32

how are delta subunits activated

Answer 32

when skeletal muscle tissue contracts the calcium ions stored in sarcoplasmic reticulum and binds to the delta subunits. once this happens the phosphorylase kinase is now fully activated (since beta units were already activated)

Question 33

what does glucagon do

Answer 33

when blood glucose levels are low the a-cells of the pancreas release a peptide hormone called glucagon. glucagon initiates a signal transduction pathway within liver cells that ultimately begins glycogen breakdown

Question 34

describe the glucagon signal transduction pathway

Answer 34

glucagon binds to 7TM receptor. the GDP is expelled from cytplasmic side of 7TM receptor and GTP binds which activates the protein. once activated GTP dissociates and activates adenylate cyclase. this causes ATP to be transformed into cAMP. cAMP binds to inactive PKA. this activates PKA which phosphorylates phosphorylase kinase. once phosphorylase kinase is phosphorylated calcium binds to the phosphorylated phosphorylase kinase fully activating it. which goes on to activate glycogen phosphorylase

Question 35

how does epinephrine play in this glucagon pathway

Answer 35

epinephrine releases the calcium required to fully activate phosphorylase kinase

Question 36

how do liver cells shut down glycogen breakdown

Answer 36

glucagon is no longer released. G-proteins have an intrinsic GTPase activity. (so it self hydrolizes GTP back into GDP). cAMP is converted into AMP by phosphodiesters. PKA phosphorylates a-units of phosphorylase kinase, which makes it a good substrate for protein phosphatase 1 (PP1). PP1 removes the phosphoryl groups from the b-units which deactivates the kinase.

Question 37

describe insulin pathway

Answer 37

insulin binds to IRS which self phosphorylates to become active. IRS activates protein kinases. once they're activated they inactivate glycogen synthase kinase. this keeps glycogen synthase a from being inactivated into glycogen synthase b.

Question 38

how is glycogen synthase b converted back into glycogen synthase a after insulin pathway has started

Answer 38

liver cells must initiate glycogenesis so PP1 must be activated. it is bound to phosphorylase a in R-state which causes it to be inactive. glucose (abundant in liver because of insulin spike) binds to phosphorylase a inactivating it thus making PP1 active. as soon as PP1 dissociates from phosphorylase a it converts glycogen synthase b into glycogen synthase a. PP1 also dephosphorylates phosphorylase a in the T-state making it phosphorylase b so that it doesnt try to re-bind PP1.