Chapter 21- Glycogen metabolism

Question 1

Why does glucose need to be stored as glycogen?

Answer 1

Glucose is an important fuel and a key precursor for the biosynthesis of many molecules. It can’t be stored because high concentrations of glucose disrupt the osmotic balance of the cell and can cause cell damage or death. Therefore, glucose is stored as glycogen, which is a non osmotically active polymer

Question 2

Glycogen

Answer 2

A non osmotically active and readily mobilized storage form of glucose. It is a large, branched homopolymer of glucose residues that can be broken down to glucose molecules when energy is needed. It is found in the cytoplasm of all tissues and appears as granules

Question 3

How many glucose residues does glycogen contain?

Answer 3

A glycogen molecule contains 12 layers of glucose molecules. It can be as large as 40 nm and contain 55,000 glucose residues

Question 4

What links the glucose residues in glycogen?

Answer 4

Most glucose residues are linked by alpha-1,4-glycosidic bonds. Branches at about every 12 residues are created by alpha-1,6-glycosidic bonds

Question 5

Alpha vs beta glycosidic linkages

Answer 5

Alpha glycosidic linkages form open helical polymers, while beta linkages produce nearly straight strands that form structural fibrils (like in cellulose)

Question 6

Where are the largest stores of glycogen located

Answer 6

In the liver and in skeletal muscle. The concentration of glycogen is higher by weight in the liver, but more glycogen is stored in skeletal muscle overall because of muscle’s greater mass.

Question 7

What is glycogen used for in the liver and muscle?

Answer 7

The liver breaks down glycogen and releases glucose into the blood to provide energy for the brain and red blood cells. Muscle glycogen stores are mobilized to provide energy for muscle contraction

Question 8

Glycogen in a liver cell

Answer 8

At the core of the glycogen molecule is the protein glycogenin. On an electron micrograph, gray lines represent glucose molecules joined by alpha 1,4 glycosidic linkages. The nonreducing ends of the glycogen molecule form the surface of the glycogen granule. Degradation takes place at this surface

Question 9

Why isn’t all excess fuel stored as fatty acids instead of glycogen?

Answer 9

The controlled release of glucose from glycogen maintains blood-glucose concentration between meals. The blood supplies the brain with glucose (its primary fuel) as it circulates. Glucose can also be readily mobilized from glycogen when it is needed as energy for sudden, strenuous activity. Released glucose can be metabolized in the absence of oxygen and can be used for anaerobic activity, unlike fatty acids.

Question 10

Which organisms is glycogen present in?

Answer 10

Storing energy as glucose polymers is common to all forms of life. Glycogen is present in bacteria, archaea, and eukaryotes. Plants store glucose as starch, which is similar

Question 11

Glycogen metabolism

Answer 11

The regulated release and storage of glucose. Includes glycogen degradation and synthesis

Question 12

Steps of glycogen degradation (3)

Answer 12

1. The release of glucose 1-phosphate from glycogen
2. The remodeling of the glycogen substrate to permit further degradation
3. The conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism

Question 13

3 fates of glucose 6-phosphate

Answer 13

1. It can be metabolized by glycolysis- used as fuel for anaerobic or aerobic metabolism
2. It can be converted into free glucose in the liver for release into the bloodstream
3. It can be processed by the pentose phosphate pathway to yield NADPH and ribose derivatives

Question 14

Where is glycogen converted into free glucose?

Answer 14

Occurs mainly in the liver

Question 15

Uridine diphosphate glucose (UDP-glucose)

Answer 15

An activated form of glucose, which is required for glycogen synthesis. It is formed by the reaction of UTP and glucose 1-phosphate. Glycogen must be remodeled to allow continued
synthesis.

Question 16

How are glycogen synthesis and degradation related?

Answer 16

They are reciprocally regulated

Question 17

Glycogen phosphorylase

Answer 17

The key regulatory, dimeric enzyme in glycogen breakdown. It cleaves its substrate by the addition of orthophosphate (Pi) to yield glucose 1-phosphate. It requires pyridoxal phosphate
(PLP) as a cofactor. It is also regulated by multiple allosteric effectors and by reversible phosphorylation

Question 18

Phosphorolysis

Answer 18

The cleavage of a bond by the addition of orthophosphate

Question 19

Nonreducing ends of the glycogen molecule

Answer 19

The ends with a free OH group on carbon 4

Question 20

Glycogen phosphorylase mechanism

Answer 20

It catalyzes the sequential removal of glucosyl residues from the nonreducing ends of the glycogen molecule.Glucose 1-phosphate is released from the terminal alpha 1,4-glycosidic bond. Orthophosphate splits the glycosidic linkage between C-1 of the terminal residue and C-4 of the adjacent one. It cleaves the bond between the C-1 carbon atom and the glycosidic oxygen atom, and the alpha configuration at C-1 is retained.

Question 21

Phosphoglucomutase

Answer 21

Converts the glucose 1-phophate released from glycogen into glucose 6-phosphate by shifting a phosphoryl group. A phosphoryl group is transferred from the enzyme to the substrate, and a different phosphoryl group is transferred back to restore the enzyme to its initial state. Glucose 6-phosphate is an important metabolic intermediate, and glucose 1-phosphate has to be phosphorylated to enter the metabolic mainstream. No ATP is used in this reaction

Question 22

How is the phosphorlytic cleavage of glycogen energetically advantageous?

Answer 22

Because the released sugar is already phosphorylated. In contrast, a hydrolytic cleavage would yield glucose. ATP would then have to used to phosphorylate the glucose so it could enter the glycolytic pathway. Also, in muscle cells, no transporters exist for glucose 1-phosphate. Glucose 1-phosphate is negatively charged and can’t be transported or diffuse out of the cell.

Question 23

How does glycogen phosphorylase exclude water from the active site?

Answer 23

Phosphorylase must cleave glycogen phosphorolytically rather than hydrolytically to save ATP. Therefore, water has to be excluded from the active site. Phosphorylase is a dimer and contains 2 identical subunits. Each substrate is folded into an amino-terminal domain that contains a glycogen binding site and a carboxyl-terminal domain. The catalytic site in the subunit is located in a crevice formed by residues from both domains. The substrates bind synergistically, which causes the crevice to narrow and exclude water.

Question 24

Pyridoxal phosphate (PLP)

Answer 24

A cofactor/coenzyme required for glycogen phosphorylase. It is a derivative of pyridoxine (vitamin B6). The aldehyde group of the coenzyme forms a Schiff-base linkage with a specific lysine side chain of the enzyme

Question 25

Mechanism- phosphorolytic
cleavage of glycogen (4 steps)

Answer 25

1. PLP forms a Schiff base with a
   lysine residue at the active site of the phosphorylase.
2. The phosphate substrate promotes cleavage of an α-1,4-
   linkage in glycogen by donating a proton to the departing glucose.
3. This results in the formation of a carbocation intermediate.
4. The carbocation and phosphate combine to form glucose 1-phosphate.

Question 26

Structure of glycogen phosphorylase

Answer 26

The enzyme forms a homodimer. Each catalytic site includes a PLP group, linked to lysine 680 of the enzyme. The catalytic site lies between the C-terminal domain and the glycogen-binding site. A narrow crevice that binds 4 or 5 glucose units of glycogen connects the two sites. The separation of the catalytic sites allows the catalytic site to phosphorolyze several glucose units before the enzyme has to rebind the glycogen substrate.

Question 27

Schiff bases

Answer 27

Also called imines- a compound containing a carbon-nitrogen double bond with the nitrogen atom bonded to an organic compound. A Schiff base is formed by the reaction of a primary amine with an aldehyde or a ketone. A PLP group forms a Schiff base with a lysine residue at the active site of phosphorylase, where is functions as a general acid-base catalyst

Question 28

Glycogen phosphorylase mechanism (3)

Answer 28

1. A bound hydrogen phosphate (HPO4) group favors the cleavage of the glycosidic bond by donating a proton to the C-4 oxygen of the departing glycosyl group
2. This reaction results in the formation of the carbonium ion, and is favored by the transfer of a proton from the protonated phosphate group of the bound PLP group
3. The carbonium ion and the orthophosphate combine to form glucose 1-phosphate

Question 29

Why is the glycogen binding site separated from the catalytic site of glycogen phosphorylase?

Answer 29

The large separation between the 2 sites enables the enzyme to phosphorolyze many residues without having to dissociate and reassociate after each catalytic cycle. Therefore, the enzyme is considered processive

Question 30

Processive enzyme

Answer 30

An enzyme that can catalyze many reactions without having to dissociate and reassociate after each catalytic step. This is a property of enzymes that synthesize and degrade large polymers

Question 31

Limitation of glycogen phosphorylase

Answer 31

Acting alone, glycogen phosphorylase can only degrade glycogen to a limited extent. It breaks α-1,4-glycosidic bonds on glycogen branches, but the α-1,6-glycosidic bonds at the branch points aren’t susceptible to cleavage by the phosphorylase, so the phosphorylase stops cleaving the 1,4 linkages when it reaches a terminal residue 4 residues away from a branch point. 1 in 12 residues are branched, so without other enzymes, the phosphorylase would stop working after 8 glucose molecules had been released from a branch. For these reasons, 2 other enzymes are required (transferase and α-1,6- glucosidase)

Question 32

Transferase

Answer 32

One of the enzymes that remodel the glycogen for continued degradation by the phosphorylase. The transferase shifts a block of 3 glucosyl residues from one outer branch to another. The transfer exposes a single glucose residue joined by an α-1,6-glycosidic linkage, making the glucose moieties accessible to the phosphorylase

Question 33

α-1,6-glucosidase

Answer 33

Also called the debranching enzyme- hydrolyzes the α-1,6-glycosidic bond exposed by the transferase, and releases a free glucose molecule

Question 34

What happens to the free glucose molecule released by α-1,6-glucosidase?

Answer 34

It is phosphorylated by hexokinase (a glycolytic enzyme) so the glucose can be processed by glycolysis or the pentose phosphate pathway

Question 35

Glycogen remodeling

Answer 35

The transferase and α-1,6-glucosidase convert the branched structure of glycogen into a linear one, which allows for additional cleavage by phosphorylase. α-1,6-glucosidase removes a glucose residue, which leaves a linear chain with all α-1,4 linkages

Question 36

Phosphoglucomutase mechanism (4)

Answer 36

1. The enzyme exchanges a phosphoryl group with the substrate.
2. The catalytic site of an active mutase molecule contains a phosphorylated serine residue. The phosphoryl group is transferred from the serine residue to the C-6 hydroxyl group of glucose 1-phosphate- this forms glucose 1,6-bisphosphate
3. The C-1 phosphoryl group of this G16B intermediate is then shuttled to the same serine residue- this forms glucose 6-phosphate.
4. The phosphoryl group is restored to the enzyme
   with the formation of glucose 6-phosphate- the phosphoenzyme is regenerated

Question 37

Glucose 6-phosphatase

Answer 37

A hydrolytic enzyme found in the liver. It converts glucose 6-phosphate into glucose, so glucose can then leave the liver. The enzyme cleaves the phosphoryl group to form free glucose and orthophosphate

Question 38

Why is glucose 6-phosphatase necessary to the function of the liver?

Answer 38

The main function of the liver is to maintain a nearly constant concentration of glucose in the blood. The liver releases glucose into the blood between meals and also during muscle activity, so it can be taken up my the brain, skeletal muscle, and red blood cells. However, phosphorylated glucose (glucose 6-phosphate) that is produced by glycogen breakdown is not transported out of cells and can not leave the liver

Question 39

Location of glucose 6-phosphatase

Answer 39

On the lumenal side of the smooth endoplasmic reticulum membrane. Glucose 6-phosphate is transported into the endoplasmic reticulum, and glucose and orthophosphate formed by hydrolysis (catalyzed by glucose 6-phosphatase) are then shuttled back into the cytoplasm. Glucose 6-phosphatase is found in the liver and is absent from most other tissues. Muscle tissue retains glucose 6-phosphate to make ATP

Question 40

2 forms of glycogen phosphorylase

Answer 40

1. A form- usually active and phosphorylated
2. B form- usually inactive, not phosphorylated

Question 41

Equilibrium of glycogen phosphorylase

Answer 41

Each of the two forms (A and B) of glycogen phosphorylase exists in equilibrium between an active relaxed (R) state and a less active tense (T) state. The equilibrium for phosphorylase A favors the active R state, while the equilibrium for phosphorylase b favors the less active T state

Question 42

In glycogen phosphorylase, how does the a form differ from the b form?

Answer 42

The A form has a phosphorylated serine residue, and is therefore more active

Question 43

Default state of the glycogen phosphorylase in the liver

Answer 43

The default state of liver phosphorylase is the A form in the R state- the role of the liver is to degrade glycogen and export the resulting glucose to other tissues when the blood glucose concentration is low. The A form is active and the relaxed (R) state is also more active, so glycogen phosphorylase can be thought of as helping to generate glucose until it is signaled otherwise

Question 44

How does glucose regulate glycogen phosphorylase?

Answer 44

Glucose is a negative regulator of liver phosphorylase,
facilitating the transition from the R state to the T (tense, less active) state. The binding of glucose to the enzyme’s active site causes this shift. This means that the enzyme only reverts to the low activity T state when it detects a sufficient amount of glucose. If glucose is present in the diet, there’s no need to degrade glycogen to make glucose. This is a form of allosteric regulation of the phosphorylase

Question 45

Isozymes of glycogen phosphorylase (2)

Answer 45

Liver phosphorylase and muscle phosphorylase

Question 46

Default state of glycogen phosphorylase in the muscle

Answer 46

Muscle phosphorylase’s default is the B form. This is because in muscle, phosphorylase must be active primarily during muscle contraction.

Question 47

How does AMP regulate glycogen phosphorylase in the muscle?

Answer 47

Muscle phosphorylase b is activated by the presence of high concentrations of AMP, which binds to a nucleotide binding site and stabilizes the conformation of phosphorylase b in the active R state. When a muscle contracts and ATP is converted into AMP by myosin and adenylate kinase, the phosphorylase is signaled to degrade glycogen

Question 48

How does ATP regulate glycogen phosphorylase in the muscle?

Answer 48

ATP acts as a negative allosteric effector by competing with AMP.

Question 49

Allosteric definition

Answer 49

Relating to or denoting the alteration of the activity of a protein through the binding of an effector molecule at a specific site

Question 50

How is the state of phosphorylase controlled by the energy charge of the muscle cell?

Answer 50

The transition of phosphorylase b between the active R state and the less active T state is controlled by the energy charge. If ATP isn’t available, glucose 6-phosphate can bind at the ATP-binding site and stabilize the less active site of phosphorylase b. In resting muscle, phosphorylase b isn’t active because of the inhibitory effects of ATP and glucose 6-phosphate. However, phosphorylase A is fully active regardless of the concentration of AMP, ATP, and glucose 6-phosphate.

Question 51

How does AMP regulate glycogen phosphorylase in the liver?

Answer 51

The liver phosphorylase is insensitive to regulation by AMP, because the liver doesn’t have dramatic changes in energy like muscle does.

Question 52

What stabilizes the T state of glycogen phosphorylase?

Answer 52

ATP and glucose 6-phosphate

Question 53

Allosteric regulation of muscle phosphorylase

Answer 53

A low energy charge, represented by high concentrations of AMP, favors the transition to the R state. ATP and glucose 6-phosphate stabilize the T state

Question 54

3 fiber types of skeletal muscle

Answer 54

1. Type 1 (slow twitch muscle)
2. Type 2b (fast twitch fibers)
3. Type 2a- have properties intermediate between the other 2 fiber types

Question 55

Type 1 skeletal muscle fibers

Answer 55

They rely primarily on cellular respiration to derive energy. The respiration of the fibers is powered by fatty acid degradation. Type 1 fibers are rich in mitochondria (the site of fatty acid degradation and the citric acid cycle). Generating ATP from fatty acids is slower than from glycogen. However, glycogen is not an important fuel for type 1 fibers, so the amount of glycogen phosphorylase is low. Type 1 fibers power endurance activities and are known as slow twitch muscle fibers

Question 56

Type 2b skeletal muscle fibers

Answer 56

These fibers use glycogen as their main fuel. They generate energy by aerobic glycolysis and perform little cellular respiration. Therefore, glycogen and glycogen phosphorylase are abundant. They also contain a lot of glycolytic enzymes, which are needed to process glucose quickly in the absence of oxygen and poor in mitochondria. They power burst activities like sprinting and weight lifting, and are known as fast twitch muscle fibers

Question 57

Properties of type 1 muscle fibers

Answer 57

High fatigue resistance and mitochondrial density. Oxidative metabolism (cellular respiration). Myoglobin content is high, glycogen content is low, and triacylglycerol content is low.

Question 58

Which enzymes are active in type 1 muscle fibers?

Answer 58

The rate of citrate synthase activity is high. The rate of glycogen phosphorylase and phosphofructokinase activity is low

Question 59

Properties of type 2b muscle fibers

Answer 59

Fatigue resistance and mitochondrial density are intermediate. Metabolic type is oxidative/glycolytic (main energy source is aerobic glycolysis, little cellular respiration). Myoglobin, glycogen, and triacylglycerol content is all intermediate

Question 60

Which enzymes are active in type 2b muscle fibers?

Answer 60

The activity of glycogen phosphorylase, phosphofructokinase, and citrate synthase is all intermediate

Question 61

Properties of type 2a muscle fibers

Answer 61

Fatigue resistance and mitochondrial density is low. Metabolic type is glycolytic. Glycogen content is high, but myoglobin and triacylglycerol content is low.

Question 62

What enzymes are active in type 2b muscle fibers?

Answer 62

Glycogen phosphorylase and phosphofructokinase activity is high, citrate synthase activity is low

Question 63

Phosphofructokinase (PFK)

Answer 63

An enzyme that sets the pace of glycolysis. It catalyzes the second phosphorylation of stage 1 of glycolysis. One molecule of ATP is used to phosphorylate fructose 6-phosphate to fructose 1,6-bisphosphate. This reaction is irreversible to prevent the reformation of glucose 6-phosphate

Question 64

Citrate synthase

Answer 64

Catalyzes the condensation of oxaloacetate (4 carbon unit) and the acetyl group of acetyl CoA (2 carbon unit) in the citric acid cycle. It catalyzes this reaction by bringing the substrates into close proximity, orienting them, and polarizing certain bonds.

Question 65

Phosphorylase kinase

Answer 65

The regulatory enzyme that
converts glycogen phosphorylase b to phosphorylase a with the addition of a phosphate (in both the liver and muscle). This covalent modification removes a peptide loop from the active site of the b form, rendering the enzyme more active.

Question 66

What initiates the activation of glycogen phosphorylase?

Answer 66

Hormones. Low blood concentration of glucose leads to the secretion of the hormone glucagon. The rise in glucagon concentration results in phosphorylation of the enzyme, converting it to the phosphorylase A form in the liver. Additionally, when the concentration of epinephrine increases, it will bind to receptors in the muscle and liver, again inducing the phosphorylation of phosphorylase B to phosphorylase A

Question 67

Structure of phosphorylase kinase

Answer 67

The subunit composition of
phosphorylase kinase in skeletal muscle is (αβγδ)4. It consists of 2 (αβγδ)2 lobes that are joined by a β4 bridge that is the core of the enzyme and serves as a scaffold for the remaining subunits. The γ subunit is the active site, while the other subunits play regulatory roles. The δ subunit is calmodulin. The α and β subunits are targets of protein kinase A. The β subunit is phosphorylated first, followed by the phosphorylation of the α subunit.

Question 68

Calmodulin

Answer 68

A calcium binding protein that acts as a calcium sensor. It stimulates many enzymes in eukaryotes

Question 69

How is phosphorylase kinase activated?

Answer 69

Phosphorylase kinase itself is activated first by Ca2+ binding to the δ subunit. Activation is maximal when the β and α subunits are phosphorylated in response to hormonal signals. Phosphorylase kinase is phosphorylated by protein kinase A. When active, the enzyme converts phosphorylase b into phosphorylase a.

Question 70

Brain isozyme of glycogen phosphorylase

Answer 70

Recently, an isozyme of glycogen phosphorylase was identified that is expressed in the brain. Like muscle phosphorylase, the brain isoform is stimulated by AMP. It is also regulated by a redox switch- two cysteines that form a disulfide bond. Reactive oxygen species like hydrogen peroxide act as a signal molecule that lead to the formation of the disulfide bond. The disulfide bond prevents AMP activation of enzyme but does not change its regulation of phosphorylation.

Question 71

Thiram

Answer 71

A pesticide that is a dithiocarbonate. Brain glycogen phosphorylase may be a target of dithiocarbonates. Thiram has been linked to neurotoxic poisoning. It is believed to disrupt the functioning of the redox switch, explaining its neurotoxic side effects

Question 72

Which hormones affect glycogen metabolism? (2)

Answer 72

Epinephrine and glucagon trigger the breakdown of glycogen

Question 73

Epinephrine

Answer 73

Muscular activity or the anticipation of activity leads to the release of epinephrine. It is a catecholamine derived from tyrosine, which is released from the adrenal medulla. Epinephrine stimulates glycogen breakdown in muscle to provide fuel for muscle contraction. It has an effect, to a lesser extent, in the liver

Question 74

Glucagon

Answer 74

A polypeptide hormone secreted by the α cells of the pancreas when the blood sugar concentration is low. Glucagon signals the starved state to the body. The liver is most responsive to glucagon, and muscle glycogen breakdown is not sensitive to glucagon

Question 75

How do hormones trigger the breakdown of glycogen?

Answer 75

They initiate a cyclic AMP signal transduction cascade. Binding events of epinephrine and glucagon activate a G protein that transmits the signal for glycogen breakdown.

Question 76

Where do epinephrine and glucagon bind?

Answer 76

Epinephrine and glucagon bind to specific seven-transmembrane (7TM) receptors in the plasma membranes of target cells. Epinephrine binds to the β-adrenergic receptor in muscle, glucagon binds to the glucagon receptor in the liver.

Question 77

Cyclic AMP signal transduction cascade for glycogen breakdown

Answer 77

1. When epinephrine binds (in the muscle) and glucagon binds (in the liver), the binding events activate the Gs protein.
2. The GTP-bound subunit of Gs activates the transmembrane protein adenylate cyclase. This enzyme catalyzes the formation of the second messenger cAMP from ATP.
3. The elevated cAMP concentration activates protein kinase A.
4. Protein kinase A phosphorylates phosphorylase kinase, which activates glycogen phosphorylase, leading to glycogen degradation.

Question 78

Adenylate cyclase

Answer 78

This enzyme catalyzes the formation of the second messenger cAMP from ATP.

Question 79

cAMP regulation of protein kinase A

Answer 79

When cAMP binds to inhibitory regulatory subunits of protein kinase A, it triggers their dissociation from the catalytic subunits. The free catalytic subunits are now active. Therefore, elevated cAMP concentration activates protein kinase A

Question 80

Why must glycogen breakdown be rapidly turned off?

Answer 80

Glycogen breakdown must be able to be terminated quickly to prevent the wasteful depletion of glycogen after energy needs have been met. When glucose needs have been satisfied, phosphorylase kinase and glycogen phosphorylase are dephosphorylated and inactivated. Simultaneously, glycogen synthesis is activated

Question 81

Mechanisms turning off glycogen degradation (4)

Answer 81

1. The signal transduction pathway shuts down when the hormones that stimulate glycogen breakdown (epi and glucagon) are no longer present.
2. The inherent GTPase activity of the Gα subunit inactivates G protein signaling.
3. Phosphodiesterase converts cAMP into AMP, which does
   not stimulate protein kinase A.
4. Protein phosphatase 1 removes phosphoryl groups from phosphorylase kinase and glycogen phosphorylase, thereby inactivating the enzymes by converting them into the inactive b form

Question 82

Glycogen degradation yields

Answer 82

Glucose 1-phosphate

Question 82

Uridine diphosphate glucose (UDP-glucose)

Answer 82

An activated form of glucose that acts as the glucose donor in the biosynthesis of glycogen. UDP-glucose is the monomer that is used to extend the glycogen chain in synthesis. The C-1 carbon atom of the glucosyl unit of UDP-glucose is activated because its hydroxyl group is esterified to the diphosphate component of UDP

Question 83

UDP-glucose is synthesized from which molecules? (2)

Answer 83

It’s synthesized from glucose 1-phosphate and uridine triphosphate (UTP). The reaction releases the outer 2 phosphoryl residues of UTP as pyrophosphate

Question 84

UDP-glucose pyrophosphorylase

Answer 84

Catalyzes the synthesis of UDP-glucose from glucose 1-phosphate and UTP. This reaction is readily reversible and releases pyrophosphate

Question 85

What drives the synthesis of UDP-glucose?

Answer 85

The irreversible hydrolysis of pyrophosphate drives the synthesis of UDP-glucose. Pyrophosphate is rapidly hydrolyzed in vivo to orthophosphate by an inorganic pyrophosphate. This renders the reaction irreversible

Question 86

Glycogen synthase

Answer 86

The key regulatory enzyme in glycogen synthesis. It transfers a glucose moiety from UDP-glucose to the C-4 terminal residue of a glycogen chain to form an α-1,4-glycosidic bond. UDP is displaced by the terminal residue to form the glycosidic bond in this reaction. There are 2 isozymes of glycogen synthase

Question 87

2 isozymes of glycogen synthase

Answer 87

One is specific to the liver, the other is expressed in muscle and other tissues

Question 88

Why does glycogen synthesis require a primer?

Answer 88

Glycogen synthase is part of the large glycosyltransferase family and can only add glucosyl residues to a polysaccharide that contains at least 4 residues. Glycogenin carries out the priming function by catalyzing the formation of α-1,4-glucose polymers. Then, glycogen synthase takes over to extend the glycogen molecule

Question 89

Glycogenin

Answer 89

Carries out the priming function necessary for glycogen synthase function. It requires manganese (Mn 2+) and is a glycosyltransferase dimer. Each subunit of glycogenin catalyzes the formation of α-1,4-glucose polymers that are 10-20 glucosyl units in length. The glucose polymers are synthesized stepwise directly on the phenolic hydroxyl group of a specific tyrosine reside in each glycogenin subunit. UDP-glucose is the donor in this autoglycosylation. This is why glycogen molecules contain glycogenin at their core.

Question 90

Branching enzyme

Answer 90

Glycogen synthase only catalyzes the synthesis of α-1,4 linkages. Another enzyme is required to form the α-1,6 that make glycogen a branched polymer. A branching enzyme generates branches by cleaving an α-1,4-linkage, moving a block of
approximately seven glucoses and synthesizing an α-1,6 linkage. Glycogen synthase can then extend the branched polymer.

Question 91

Why is branching important?

Answer 91

It increases the solubility of glycogen. Branching also creates a large number of terminal residues, which are the sites of action of glycogen phosphorylase and glycogen synthase. Therefore, branching increases the rate of glycogen synthesis and degradation.

Question 92

2 forms of glycogen synthase

Answer 92

Like glycogen phosphorylase, glycogen synthase exists in either an active nonphosphorylated A form or an inactive phosphorylated B form. The interconversion of the 2 forms is regulated by covalent modification mediated by hormones.

Question 93

How is glycogen synthase regulated?

Answer 93

It is regulated by allosteric regulation of the phosphorylated form of the enzyme, glycogen synthase b. Glucose 6-phosphate activates the enzyme and converts the b form in the T state to the active R state

Question 94

Glycogen synthase kinase

Answer 94

Phosphorylates glycogen synthase at multiple sites. It is under the control of insulin and protein kinase A. The function of the multiple phosphorylation sites is unclear. However, phosphorylation has opposite effects on the enzymatic activities of glycogen synthase and glycogen phosphorylase. It maintains glycogen synthase in its phosphorylated, inactive state

Question 95

Why is glycogen considered an efficient storage form of glucose?

Answer 95

Only one molecule of ATP is required to incorporate
glucose 6-phosphate into glycogen. The energy yield from the breakdown of glycogen is highly efficient. The complete oxidation of glucose 6-phosphate derived from glycogen yields about 31 molecules of ATP.

Question 96

How are glycogen breakdown and synthesis reciprocally regulated?

Answer 96

Glycogen synthesis is inhibited by the same glucagon and epinephrine signaling pathways that stimulate glycogen breakdown. They control breakdown and synthesis of glycogen using protein kinase A. Phosphorylation of glycogen synthase a by protein kinase A to form glycogen synthase b inhibits glycogen synthesis, as phosphorylation leads to a decrease in enzymatic activity. Glycogen synthase kinase also phosphorylates and
inhibits glycogen synthase.

Question 97

Protein kinase A

Answer 97

Adds a phosphoryl group to phosphorylase kinase, activating that enzyme and initiating glycogen breakdown

Question 98

Coordinate control of glycogen metabolism

Answer 98

Glycogen metabolism is regulated, in part, by hormone-triggered cyclic AMP cascades. The sequence of reactions leading to the activation of protein kinase A ultimately activates glycogen degradation. At the same time, protein kinase A along with glycogen synthase kinase inactivates glycogen synthase, shutting down glycogen synthesis.

Question 99

Protein phosphatase 1 (PP1)

Answer 99

Regulates glycogen metabolism by shifting it from the degradation mode to the synthesis mode. PP1 inactivates glycogen phosphorylase a and phosphorylase kinase by dephosphorylating them. PP1 decreases the rate of glycogen breakdown, and it reverses the effects of the phosphorylation cascade. It also removes phosphoryl groups from glycogen synthase b to convert it into the more active glycogen synthase a form. In this case, PP1 accelerates glycogen synthesis.

Question 100

Regulatory subunits of PP1

Answer 100

A key regulatory subunit is the G subunit. In the skeletal muscle and heart, the most prevalent regulatory subunit is called Gm. In the liver, the most prevalent subunit is GL. The regulatory subunits have modular structures with domains that participate in interactions with glycogen, the catalytic subunit, and with target enzymes. They bind glycogen and the catalytic
subunit, localizing the enzyme with its substrates. The regulatory subunits therefore act as scaffolds that bring together the phosphatase and its substrates on the glycogen particle. A second regulatory subunit, when phosphorylated,
binds to and further inhibits the catalytic subunit.

Question 101

Catalytic subunit of PP1

Answer 101

A single domain protein that is usually bound to one of a family of regulatory subunits. PP1 consists of a catalytic subunit and two regulatory subunits.

Question 102

PP1 regulation in muscle

Answer 102

In muscle, phosphorylation of GM by protein kinase A leads to dissociation of the catalytic subunit from glycogen and reduces its activity. Phosphorylation of the inhibitor subunit by protein kinase A and its subsequent binding by the phosphatase completely inactivates the catalytic subunit of PP1.

Question 103

What prevents the phosphatase activity of PP1 from always inhibiting glycogen degradation?

Answer 103

When glycogen degradation is necessary, epinephrine or glucagon initiates the cAMP cascade that activates protein kinase A. Protein kinase A reduces the activity of PP1 by different mechanisms

Question 104

How does protein kinase A reduce the activity of PP1? (2)

Answer 104

1. In muscle, Gm is phosphorylated in the domain responsible for binding the catalytic subunit. The catalytic subunit is released from glycogen and from its substrates, so its phosphatase activity is greatly reduced
2. Almost all tissues contain small proteins that, when phosphorylated, bind to the catalytic subunit of PP1 and inhibit it. Then, when glycogen degradation is switched on by cAMP, the accompanying phosphorylation of the inhibitors keeps phosphorylase in its active a form and glycogen synthase in its inactive b form

Question 105

How is glycogen synthesis stimulated?

Answer 105

When blood glucose concentration is high, insulin stimulates the synthesis of glycogen by inactivating glycogen synthase kinase

Question 106

Steps in the action of insulin (5)

Answer 106

1. Binds to its receptor- a tyrosine kinase receptor in the plasma membrane
2. The binding of insulin stimulates the tyrosine kinase activity of the receptor so that it phosphorylates insulin-receptor substrates
3. The phosphorylated IRSs trigger signal transduction pathways that eventually lead to the activation of protein kinases that phosphorylate and inactivate glycogen synthase kinase
4. Inactive kinases can’t maintain glycogen synthase in its phosphorylated, inactive state
5. PP1 dephosphorylates glycogen synthase, activating it, and restoring glycogen reserves

Question 107

Insulin

Answer 107

Increases the amount of glucose in the cell by increasing the number of glucose transporters (GLUT4) in the membrane. This allows for increased uptake of
glucose. The net effect of insulin is the replenishment of glycogen stores

Question 108

How does glucose blood concentration regulate glycogen synthesis?

Answer 108

The normal range of glucose in the blood is 4.4-6.7 mM. The liver senses the concentration of glucose in the blood and takes up or releases glucose accordingly. The amount of liver phosphorylase A decreases rapidly when glucose is infused. After a lag period, the amount of glycogen synthase A increases, which results in glycogen synthesis. Glycogen degradation in the liver is inhibited, and glycogen synthesis is stimulated by high blood-glucose levels

Question 109

How does glycogen phosphorylase A act as a glucose sensor?

Answer 109

Phosphorylase A is the glucose sensor in liver cells, and facilitates the switch from degradation to synthesis. The R to T transition of muscle phosphorylase A is unaffected by glucose and is therefore not affected by the rise in blood-glucose concentration- this process senses glucose in the liver. When glucose binds to phosphorylase A, it shifts its allosteric equilibrium from the active R form to the inactive T form. This conformational change makes the phosphoryl group on the enzyme a substrate for PP1.

Question 110

Glycogen phosphorylase A glucose sensor mechanism (5)

Answer 110

1. Glucose binds to phosphorylase A, which shifts its allosteric equilibrium from the active R form to the inactive T form
2. The conformational change makes the phosphoryl group on serine 14 of the enzyme a substrate for PP1.
3. PP1 binds tightly to phosphorylase a only when the
   phosphorylase is in the R state, but PP1 is inactive when bound. 4. When glucose induces the transition to the T form, PP1 and the phosphorylase dissociate from each other and the glycogen particle, and PP1 becomes active, converting phosphorylase a to the b form.
4. PP1 converts glycogen
   metabolism from a degradation mode to a synthesis mode.

Question 111

How does glucose binding to glycogen phosphorylase stimulate glycogen synthesis?

Answer 111

The conversion of A into B is accompanies by the release of PP1, which is then free to activate glycogen synthase. The removal of the phosphoryl group of inactive glycogen synthase B converts it into the active A form

Question 112

What accounts for the lag between termination of glycogen degradation and the beginnings of glycogen synthesis?

Answer 112

There are about 10 phosphorylase A molecules per molecule of phosphatase- there are approximately 10 times more copies of phosphorylase a than phosphatase. Therefore, the activity of glycogen synthase begins to increase only after most of phosphorylase A is converted into B. The lag between the decrease in glycogen degradation and the increase in glycogen synthesis prevents the 2 pathways from operating simultaneously.

Question 113

3 elements of the glucose sensing system

Answer 113

1. Communication within phosphorylase between the allosteric site for glucose and the serine phosphate
2. The use of PP1 to inactivate phosphorylase and activate glycogen synthase
3. The binding of the phosphatase to phosphorylase A to prevent the premature activation of glycogen synthase

Question 114

von Gierke disease symptoms

Answer 114

Abdominal distension due to liver enlargement, hypoglycemia between meals, blood glucose concentration does not rise on administration of epinephrine and glucagon. Infants may have seizures

Question 115

Von Gierke disease (type 1)

Answer 115

Glucose 6-phosphatase is missing from the liver. This is an inherited enzyme deficiency. As a result, the glycogen in the liver is normal in structure but is present in abnormally large amounts. The absence of glucose 6-phosphatase causes hypoglycemia because glucose can’t be formed from glucose 6-phosphate. This phosphorylated sugar can’t leave the liver because it can’t cross the plasma membrane. The presence of excess glucose 6-phosphate triggers an increase in glycolysis in the liver, leading to high concentrations of lactate and pyruvate in the blood. Patients with this disease also have an increased dependence on fat metabolism

Question 116

How many glycogen storage diseases have been characterized?

Answer 116

8

Question 117

Pompe disease (type 2)

Answer 117

A glycogen storage diseae- lysosomes become engorged with glycogen because they lack α-1,4-glucosidase. α-1,4-glucosidase is a hydrolytic enzyme that is only found in lysosomes

Question 118

Cori disease (type 3)

Answer 118

Type 3 cannot be distinguished from type 1 by physical examination alone. In type 3a and 3c, the structure of both liver and muscle glycogen is abnormal and the amount is drastically increased. Type 3b and 3d are specific to the liver. In all subtypes, the outer branches of the glycogen are very short. Patients lack the debranching enzyme (α-1,6-glucosidase) so only the outermost branches of glycogen can be effectively utilized. Therefore, only a small fraction of this abnormal glycogen is functionally active as an accessible store of glucose.

Question 119

Andersen disease (type 4)

Answer 119

The defective enzyme is the branching enzyme (alpha 1,4 to alpha 1,6 linkages). The liver and spleen are the organs affected. There is a normal amount of glycogen, but it has very long outer branches. Clinical features- progressive cirrhosis of the liver, and death due to liver failure typically occurs before age 2

Question 120

McArdle disease (type 5)

Answer 120

Phosphorylase is the defective enzyme, and this defect is glycogen metabolism is confined to the muscle only. Since muscle phosphorylase activity is absent, the patient’s capacity to perform strenuous exercise is limited due to painful muscle cramps. Patients also exhibit burgundy-colored urine following an attempt at vigorous exercise. The coloration is due to rhabdomylosis (rapid breakdown of skeletal muscle), which causes release of myoglobin in the blood and urine. Otherwise, the patient appears normal and well developed. This suggests that effective utilization of muscle glycogen isn’t essential for life

Question 121

Hers disease (type 6)

Answer 121

Phosphorylase is the defective enzyme. The liver is the affected organ and there is an increased amount of glycogen. Clinical features- like type 1, but a milder course of symptoms

Question 122

Type 7 glycogen storage disease

Answer 122

Phosphofructokinase is the defective enzyme. Muscle is the affected organ. There is an increased amount of glycogen, but the structure is normal. Clinical features are similar to those of type 5

Question 123

Type 8 glycogen storage disease

Answer 123

Phosphorylase kinase is the defective enzyme, and the liver is the affected organ. There is an increased amount of glycogen, but the structure is normal. Clinical features- mild liver enlargement, mild hypoglycemia

Question 124

What does the muscle cell of a patient with Pompe disease look like?

Answer 124

Glycogen engorged lysosomes are seen throughout the cell, including in the myofibrils. As the disease progresses, lysosomes may rupture, releasing large amounts of glycogen into the cytoplasm. These accumulations of cytoplasmic glycogen are called glycogen lakes.