Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism

Glycogen Degradation
I. Know how the structure of glycogen is optimized
a. Based on chain branching and length of branches
b. Found primarily in liver and muscle
c. Structure optimized
i. Ability to store and deliver energy quickly
ii. Deliver energy for longest amount of time
iii. Key is average chain length of branches –13 residues
d. Glucose can be released from multiple branch points simultaneously, which is not possible w/ a linear polymer.
II. Know how degradation of glycogen differs in muscle and liver
a. Why is this significant?
i. In Muscle, G­6­P obtained from glycogen breakdown enters glycolysis at Step 2
1. It skips Step 1, so investment is ­1 ATP
a. To supply its own energy needs – only used by muscle tissue.
ii. Liver glycogen breaks down to glucose­6­phosphate, hydrolyzed to give glucose
1. Requires G6P phosphatase (gluconeogenesis), rendering free glucose.
2. Free glucose is exported to supply needs of other cells
a. Liver is the primary storage facility for glycogen.
III. Know the reactions of glycogen breakdown
a. First reaction catalyzed by glycogen phosphorylase
i. Know the overall reaction –
1. Catalyzed by glycogen phosphorylase
a. Cleaves the α(1 → 4) linkages in glycogen
2. G ly c o g e n
G l y c o g e n + P i  ph o s ph o r yl a s e G l u c o s e - 1 - p h o s p h a t e + R e m a i n d e r o f
g ly c o g e n
Cleavage reaction is one of phosphorolysis rather than hydrolysis
a.
No ATP cost – a phosphoryl group is added instead to break the bond rather than water.
b.
i. Product is glucose­1­phosphate
b. Second reaction catalyzed by phosphoglucomutase
i. Know the overall reaction
1. Phosphoglucomutase moves the phosphoryl group from #1 C to #6 carbon

a.
2. Branching of glycogen contains α(1 → 6) linkages at branch points –
a. Complete breakdown requires debranching enzymes that degrade α(1 → 6) linkages
c. Debranching enzyme
i. Transfers 3 glucose residues (limit branch) from the end of one chain to the end of another branch
1. These three residues are referred to as the limit branch.
ii. Glycogen phosphorylase removes glucose residues one at a time from the new end point
iii. Debranching enzymes hydrolyze α(1 → 6) bond of last glucose at branch point
IV. What is the preferred fuel with the following conditions?
a. Low intensity exercise – jogging or running? Fat
b. As intensity of exercise increases, muscle and liver glycogen become critical.

Glycogen Synthesis
I. Glycogen synthesis requires energy, provided by UTP hydrolysis
II. Know the two stages of glycogen production
a. Stage 1 – formation of UDP­glucose
i. G­1­P reacts with UTP to produce UDP­glucose and pyrophosphate (PPi)
1. Catalyzed by UDP­glucose pyrophosphorylase
a. What’s the mechanism? It adds a YMP molecule to G1P by splitting out pyrophosphate.
b. What makes this energetically favorable?

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
i. Hydrolysis of PPi makes glycogen formation energetically favorable; irreversible
b. Stage 2 – Addition of glucose to chain
i. UDPG added to growing chain of glycogen
1. Catalyzed by glycogen synthase
ii. Glycogen synthase forms new α(1 → 4) linkage, and must add to existing chain
1. Know the glycosidic linkage
c. Know the role of glycogenin
i. Where is first glucose added?
ii. In the 1st stage of glycogen synthesis, glucose
residue is attached to ­OH of a Tyr residue on
glycogenin.
1. Starts the chain until ~8 residues
a. Glycogen synthase takes over
after the addition of 8 residues.
d. Branching enzyme – to generate branch points
i. Transfers 7­residue segment from the end of one
growing chain to branch point of another
ii. Know the nature of the linkage at the branch point
1. It catalyzes the formation of alpha(16)
branch point

Control of Glycogen Metabolism

I. Glycogen phosphorylase
a. Know that this is major controlling factor in synthesis and breakdown of glycogen
i. Subject to allosteric control and covalent modification
b. Know that it has both T and R forms
i. Dimer in quaternary structure that exists in inactive T (taut) form and active R (relaxed) form
c. Know how covalent modification relates to regulation of T form
i. ONLY T FORM is subject to phosphorylation
1. Phosphorylation converts glycogen phosphorylase b to glycogen phosphorylase a
ii. Unphosphorylated form is the b form.
iii. Phosphorylation is the major control mechanism for enzyme activity

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism

1.
a. A phosphorylase kinase transfers the phosphoryl to each of the 2 subunits.
b. Dephosphorylation is catalyzed by a phosphatase
2. Both phosphorylated and unphosphorylated forms exists in T form.
II. Because glycogen phosphorylase exists in two different forms – a and b – they can be regulated by different allosteric effectors.
a. Know the allosteric regulators of the phosphorylated form – glycogen phosphorylase a
i. High [Glucose] is an allosteric inhibitor of A form in the liver.
1. Glucose converts glycogen phosphorylase A from the R form to T form
a. Makes it more subject to dephosphorylation to the B form –
i. If [glucose] is high, there is no need to get any from glycogen, turning the enzyme off
b. Know the allosteric regulators of the unphosphorylated form – glycogen phosphorylase b
i. In muscle:
1. High [AMP] converts it to active R form
a. AMP signals that the cell needs energy– there is a need to retrieve stored glucose to make energy
ii. High [ATP] or [G6P] converts to inactive T form
1. ATP and G6P signal that energy needs are low – no need to retrieve glucose from glycogen
III. Glycogen synthase
a. Subject to same type of covalent modification as phosphorylase but in opposite way
i. The phosphorylation of glycogen synthase inactivates it.
b. Phosphorylation – deactivation – is stimulated by hormonal signals
i. In what way is it stimulated and why?
1. Hormones that phosphorylate and therefore inactivate glycogen synthase – Glucagon or epinephrine
a. Operate via cAMP­dependent protein kinase
b. Hormone signals need to retrieve energy source
c. Signalling systems co­ordinately regulate glycogen synthesis and breakdown.
i. If the signal initiates phosphorylation, BOTH enzymes are phosphorylated.
1. Thus, this activates one while deactivating the other, preventing futile cycling.
d. Understand method of allosteric control
i. The enzymes responsible for reversible phosphorylation are themselves subject to covalent modification and allosteric
control
1. Glycogen synthase is subject to allosteric control –
a. Inhibited by ATP – ATP activates phosphorylase kinase
b. This inhibition can be overcome by the activator, glucose­6­phosphate
i. G6P is the substrate of the synthase reaction – increasing [substrate] favors the reaction

Gluconeogenesis Reactions
I. Know which steps are NOT the reverse of glycolysis and why
o Irreversible reactions include step 1, 3, and 10.
II. Know the names of the enzymes, substrates, and products associated with these steps (NOT structures)
o Step 10 – PEP to pyruvate w/ concomitant generation of ATP
 Catalyzed by pyruvate kinase; irreversible b/c ATP is produced
o Step 3 – fructose­6­phosphate to fructose­1,6­bisphosphate
 Catalyzed by phosphofructokinase; irreversible b/c ATP is used
o Step 1 – glucose to G6P catalyzed by hexokinase
III. Know that the net effect IS the reverse of glycolysis
o 2 Pyruvate is converted to 1 glucose

Pyruvate to Phosphoenolpyruvate

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
I. The 1st part requires reversing pyruvate kinase w/ two steps involing 2 different enzymes:
a. Carboxylase reaction and phosphoenolpyruvate carboxykinase
i. Step 1 – Pyruvate carboxylated to oxaloacetate, catalyzed by pyruvate carboxylase
1. Pyruvate carboxylase is an example of a ligase enzyme
2. Know how and why it is activated by acetyl­CoA
a. Allosterically activated by acetyl­CoA (citric acid cycle)
b. Pyruvate a precursor of acetyl­CoA
3. Requires energy from hydrolysis of ATP as driving force
a. A magnesium cofactor is also involved.
4. Know the two stages of the reaction and the role of biotin cofactor
a. A molecule of bicarbonate is first activated by phosphorylation – minus 1 ATP
b. The Biotin nucleophile attacks the carbonyl carbon of carboxy phosphate
i. Biotin carries a nucleophilic Nitrogen atom
c. This covalently attaches the carboxyl group and releases phosphate
d. The carboxyl group is transferred to pyruvate to form oxaloacetate
i. CO2 transferred from biotin to pyruvate.
5. Step 2 ­ Conversion of oxaloacetate to phosphoenolpyruvate
a. Catalyzed by phosphoenolpyruvate carboxykinase (PEPCK)
b. Involves GTP hydrolysis – energetically equivalent to ATP
II. Know the net reaction and energetic cost of net conversion to phosphoenolpyruvate
a. Two steps are both close to equilibrium
b. Driven by law of mass action
i. Equilibrium shifts based on relative concentrations of reactants/products
c. Net reaction:
i.
P y ru v a te + A T P + G T P  P h o s p h o e n o lp y ru v a te + A D P + G D P + P i
1. $$ of converting pyruvate to PEP is 1 ATP and 1 GTP – requires 2 steps to reverse 1 step in glycolysis

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
Role of Sugar Phosphates in Gluconeogenesis –

I. Overview – Pyruvate carboxylase catalyzes a compartmentalized reaction.

a. Pyruvate is converted to oxaloacetate in the mitochondria. Because oxaloacetate cannot be transported
across the mitochondrial membrane, it must be reduced to malate, transported to the cytosol, and then
oxidized back to oxaloacetate before gluconeogenesis can continue.

II. Know the two fates of oxaloacetate in the mitochondrion

a. Oxaloacetate is converted to PEP and transported to cytosol
i. Within the mitochondria, Oxaloacetate is converted to PEP
ii. PEP can leave mitochondria via specific transporter to continue gluconeogenesis in cytosol
b. Oxaloacetate is reduced to malate and transported to cytosol
i. Know the enzyme name – malate dehydrogenase
1. This reaction requires the reduced cofactor NADH, generating NAD+
c. Gluconeogenesis continues in both cases
i. Malate leaves mitochondria
ii. Reaction reversed – malate is oxidized to oxaloacetate by cytosolic malate dehydrogenase
1. This reaction requires an oxidized NAD+ factor, generating a reduced NADH
2. NADH is required for gluconeogenesis and this mechanism is a mechanism of
generating it.
iii. Way to produce NADH in cytosol so gluconeogenesis can continue
III. There are two other reactions – both dephosphorylations –in gluconeogenesis that differ from glycolysis
a. Fructose­1,6­bisphosphatase reaction
i. Know the substrate and product names (not structures)
1. Fructose­1,6­bisphospahte is converted to fructose­6­phosphate (F6P)
a. This is reverse of phosphofructokinase reaction
2. Highly exergonic b/c it involves the hydrolysis of a high energy phosphorylating compound.
ii. Know allosteric regulation – allosteric enzyme strongly inhibited by AMP but stimulated by ATP
1. High [ATP] suggests that energy is available for the pathway – b/c it’s an anabolic pathway
a. It is the control point of the gluconeogenic pathway b/c of allosteric regulation
b. Glucose­6­phosphatase
i. Know the substrate and product names and structures
1. This reaction is highly exergonic and occurs in endoplasmic reticulum
2. G6P is hydrolyzed to form free glucose + phosphate ion.

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism

c. The remaining steps of glycolysis are readily reversible in

gluconeogenesis, requiring the same enzymes as glycolysis

Gluconeogenesis.
I. Anabolic pathway
a. Costs energy
b. Doesn’t operate in all cells
i. Liver uses this to make glucose for other cells
when glycogen stores are depleted.

II. Reversal of glycolysis

a. Conversion of 2 pyruvates to 1 glucose
i. VS 1 glucose = 2 pyruvates in glycolysis
b. Some steps in glycolysis we can reverse (ΔG ≈0)
c. 3 irreversible steps due to large negative ΔG
i. Hexokinase, PFK, pyruvate kinase
1. 4 enzymes needed for these steps

Reciprocal Regulation in Glucose Metabolism

I. Understand the purpose of reciprocal regulation
a. To prevent futile cycle – turn on a pathway while keeping a
different one off.
II. Know how hexokinase and glucose­6­phosphatase reciprocally regulated
a. By [G6P] – if [G6P] is high, phosphatase is favored.
i. At low [G6P], hexokinase reaction is favored.
III. Understand reciprocal regulation of PFK and F­1,6­BPase
a. Phosphofructokinase (PFK) regulation
i. Converts F­6­P  F­1,6­bisphosphate
1. Activated by F­2,6­Bisphosphate and AMP
a. Due to high energy need
2. Inhibited by ATP and citrate
a. Due to low energy need
b. F­1,6­Bisphosphatase reverses PFK in gluconeogenesis
i. Converts F­1,6­bisphosphate  F­6­P
1. Inhibited by F­2,6­BP and AMP
c. Understand how level of F­2,6­BisPhosphate regulated
i. Concentration depends on balance between synthesis and
degradation
1. Synthesized by phosphofructokinase­2 (PFK­2)
2. Degradation or undone: fructose­2,6­
bisphosphatase (FBPase)
ii. Thus, there is a kinase to phosphorylate F6P to F­2,6­
BisPhosphate and a phosphatase to reverse it.
iii. PFK­2 and Fructose­2,6­bisphate are controlled by alternate
phosphorylation/ dephosphorylation mechanism
1. PFK­1 makes fructose­1,6­bisphosphate
2. PFK­2 makes fructose­2,6­bisphosphateA
d. Role of protein kinase
i. Protein kinase plays key role in level of F2,6BP
1. This kinase is a dimeric protein which is also
regulated by phosphorylation
ii. Phosphorylated form activates FBPase and inhibits PFK­2
1. Phosphorylation of kinase
2. Activates FBPase so [F2,6BP] 
3. Inactivates PFK­2 so no more F2,6BP made
a. Glycolysis inhibited and gluconeogenesis favored in response to low blood [glucose]

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
iii. Unphosphorylated form inhibits FBPase and activates PFK­2
1. Inactivates F2,6­BPase so F2,6BP not degraded
2. Activates PFK­2 so [F2,6BP] 
3. This activates PFK­1 and inactivates F1,6­BPase
a. Glycolysis stimulated and gluconeogenesis inhibited in response to high blood [glucose]
IV. Know the effect of high vs. low [F2,6BP]
a. In mammals, as blood glucose , insulin stimulates PFK­2, which activates the  production of fructose­2,6­bisphosphate
i. An  [F­2,5­BP] activates PFK­1, elevating its activity. Thus, more glucose is processed via the glycolytic pathway.
1. Fructose­2,6­bisphosphate allosterically inhibits the opposing reaction enzyme, fructose­1,6­
bisphosphatase
a. Thus, increased [F­2,5­BP] activates PFK­1 and inhibits fructose­1,6­bisphosphatase
i. This reciprocal regulation occurs to prevent futile cycling
b. In bacteria, high [ADP] is an activator of PFK­1
i. High [PEP], from step 9, inhibits PFK­1

Hormonal Regulation in Glycogen Breakdown

I. Know purpose of reciprocal regulation in synthesis and degradation of glycogen
a. Glycogen synthase and glycogen phosphorylase controlled by covalent modification and allosteric control
i. The same system responsible for modification of both
b. Hormonal control essential in synthesis and breakdown of glycogen
II. Know steps of activation of glycogen breakdown
a. Enzymatic cascade triggers activation of glycogen phosphorylase
b. Begins with production of cAMP by adenylate cyclase
i. First reaction in cascade is catalyzed by adenylate cyclase, which uses ATP to form cAMP

ii.
c. cAMP is the second messenger that stimulates a series of phosphorylation events
i. You do NOT need to know individual steps – what about structures?
d. Results in phosphorylation and activation of glycogen phosphorylase b to form active phosphorylase a –
i. High [cAMP] favors glycogen breakdown

Hormonal Regulation in Glycogen Synthesis

I. Insulin is produced in response to high blood glucose, binding to cell surface receptors
a. Insulin starts series of covalent modifications – it occurs in one of two ways:
i. Glycogen synthase kinase (GSK3) phosphorylated and inactivated
ii. Glycogen synthase remains unphosphorylated and active
II. Know the function of glycogen synthase kinase (GDK3)
a. This is the state of the cell in the absence of insulin.
i. GSK3, in its active form, phosphorylates glycogen synthase I to glycogen
synthase D, thereby deactivating it.
1. Dependent on G6P = inactive
a. Glycogen synthase I form = active; independent of its
substrate concentration, [G6P]
2. How is this beneficial? Its only active at high [G6P]
a. The enzyme acts as a sensor of intracellular G6P levels and only active at high [G6P]
III. Know the general cascade of events following insulin binding to receptor

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
a. Binding of insulin to receptor also:
i. Starts another protein kinase cascade; Stimulates translocation of
GLUT4 transporters to the cell surface
1. GLUT4 sequestered inside vesicles
2. Kinase cascade results in incorporation of glucose into
plasma membrane, which facilitates glucose uptake
ii. Insulin stimulates GLUT4 to take up glucose
1. Thus, glucose is converted to G6P to trap it inside
2. High [G6P] activates glycogen synthase D
a. Now, glucose can be stored as glycogen
b. Stimulates a 2nd kinase cascade that phosphorylates and inactivates GSK3
i. This prevents further phosphorylation and inactivation of
glycogen synthase such that it remains in the active I form.
c. Stimulates phosphorylation and activation of phosphoprotein phosphatase­1
i. PP­1 is also phosphorylated and activated by kinase cascade
ii. PP­1 dephosphorylates glycogen synthase from its inactive D to
active I form via hydrolysis of attached phosphoryl groups.

iii.This kinase cascade renders a dual effect –

1. It prevents the phosphorylation of additional molecules of glycogen synthase to keep it active
2. And dephosphorylates those previously inactivated.
d. What are the effects of these responses to insulin? Glucose is stored as glycogen.

IV. Know the effects of glucagon and epinephrine on glycogen synthesis and breakdown
a. Glucagon and epinephrine produced when blood [glucose] levels decrease
i. Signal fuel need
ii. Binding of either initiates cascade that:
1. Activates glycogen phosphorylase
2. Inhibits glycogen synthase
3. Shift to energy retrieval rather than storage
4. Series of phosphorylation events amplifies original signal of hormone binding
b. Opposite effects to that of insulin
c. System geared toward retrieval rather than storage

Glycogen Metabolism in Body Organs

I. Understand the concept of substrate cycling – beneficial when part of a larger regulation between tissues.
a. Opposing reaction are catalyzed by different enzymes
i. Know the benefits of this –
1. Opposing reactions can be independently regulated.
a. Thus, they can have different rates; different catalysts allow this
b. The energetic price is ATP hydrolysis
b. Know what this means in terms of energetic cost
i. EX: F6P  fructose­1,6­bisphosphate  F6P is NOT the reverse of each other
1. Both reactions are exergonic yet their net reaction is not energetically equal
II. Know the function and purpose of the Cori cycle
a. An example of substrate cycling between tissues – Cori Cycle
b. Anaerobic glycolysis in muscle to produce lactate –
i. Cycling of glucose b/w glycolysis in muscle tissue and gluconeogenesis in the liver.
1. Glycolysis in a fast­twitch skeletal muscle produces pyruvate, which is converted to lactate to regenerate
NAD+.
a. Lactate is a waste product released into the bloodstream.
i. Liver takes the lactate and oxidizes it to pyruvate to make glucose via gluconeogenesis.
1. Glucose can then be sent back to the muscle.
c. What does this accomplish? remove lactate from muscle and transport it to the liver for gluconeogenesis
d. Know the net cost – hydrolysis of 2 ATP and 2 GTP; 4 total high energy molecules.
i. Glycolysis in muscle generates 2 ATP per glucose, resulting in 2 pyruvates converted to 2 lactates.
ii. In liver, 2 lactates are oxidized back to 2 pyruvates and used to generate 1 molecule of glucose
1. This requires the expenditure of 2 ATP + 4 GTP molecules.

Pentose Phosphate Pathway – carried by ALL living cells for nucleotide synthesis
I. Purpose – production of 5C ribose sugars and NADPH

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
II. Oxidative reactions that produce NADPH and five­carbon sugars
a. Know the net reaction: glucose­6­phosphate  ribulose­5­phosphate
i. Reaction 1: G­6­P oxidized to 6­phosphoglucon
1. Produces NADPH
ii. Reaction 2: 6­phosphogluconate loses carboxyl group as CO2
1. Results in production of five­carbon ketose, ribulose­5­phosphate
2. Required for all nucleotide synthesis
b. Know that it produces 2 NADPH and ribose­5­phoshate
i. Both needed to generate deoxyribonucleotides
c. Know importance of these steps
i. The isomerization of ribulose­5­phosphate to ribose­5­phosphate
1. Results in an aldose rather than ketose.
a. Ribose­5­phosphate needed for synthesis of all nucleotides
ii. Way for all cells to produce NADPH for biosynthesis reactions
1. Cells may need NADPH more than they need Rib­5­Phosphate
a. The buildup of R5P may build up and shut down the pathway –
i. In this case, the cell utilizes nonoxidative reactions to keep the pathway running
d. You do NOT need to know the enzyme names
III. Nonoxidative reactions involving reshuffling of the carbon skeletons of sugars
a. Know how the cell recycles components to continue making NADPH
i. Excess carbons recycled to build glycolytic intermediates
ii. Sugars can then be degraded to pyruvate or used in gluconeogenesis
iii. Readily reversible reactions
1. Interconvert sugars – 3 R5P can be converted into 2 molecules into F6P + 1 G3P
a. The cell can feed these sugars into glycolysis while NADPH can continue to be regenerated via the
oxidative reactions of the pentose phosphate pathway.
b. You do NOT need to know the details of how the saccharides are combined
c. Know that the products of recycling are Frc­6­P and Gly­3­P

Review Exercises Recommended: 1,2, 3, 4, 5*,6, 7, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 34, 35, 36, 37,
38, 39, 40, 41, 42,, 43, 46, 53, 54, 55

1. Why is it essential that the mechanisms that activate glycogen synthesis also deactivate glycogen phosphorylase?
a. These two pathways occur in the same cellular compartment, and, if both are on at the same time, a futile ATP hydrolysis cycle
results. Using the same mechanism to turn them on/off or off/on is highly efficient

2. How does phosphorolysis differ from hydrolysis?

a. In phosphorolysis, a bond is cleaved by adding the elements of phosphoric acid across that bond, whereas in hydrolysis, the
cleavage takes place by adding the elements of water across the bond.

3. Why is it advantageous that breakdown of glycogen gives rise to glucose­6­phosphate rather than to glucose?

a. G6P is already phosphorylated. This saves one ATP equivalent in the early stages of glycolysis.

4. Briefly outline the role of UDPG in glycogen biosynthesis.

a. Each glycogen residue is added to the growing glycogen molecule by transfer from UDPG

5. Name two control mechanisms that play a role in glycogen biosynthesis. Give an example of each.

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
a. Synthase is INactivated by phosphorylation and activated by dephosphorylation. It is allosterically inhibited by ATP and
activated by its substrate – glucose­6­phosphate (G6P). To understand the inhibition by ATP, keep in mind that having enough
energy to store glucose isn’t sufficient – the cell must also have a high concentration of G6P.
b. As [ATP] increases, it binds to synthase causes a conformational change, so that a higher concentration of G6P is required.
This mechanism ensures that there is not only sufficient energy for glycogen storage – but also sufficient glucose.

6. Does the net gain of ATP in glycolysis differ when glycogen, rather than glucose, is the starting material? If so, what is the change?

a. There is a net gain of 3 rather than 2.

7. In metabolism, glucose­6­phosphate (G6P) can be used for glycogen synthesis or for glycolysis, among other fates. What does it cost, in
terms of ATP equivalents, to store G6P as glycogen, rather than to use it for energy in glycolysis? Hint: The branched structure of glycogen
leads to 90% of glucose residues being released as glucose­1­phosphate and 10% as glucose.

a. It “costs” one ATP equivalent (UTP to UDP) to add a glucose residue to glycogen. In degradation, about 90% of the glucose
residues do not require ATP to produce glucose­1­phosphate. The other 10% require ATP to phosphorylate glucose. On average,
this is another 0.1 ATP. Thus, the overall “cost” is 1.1 ATP, compared with the three ATP that can be derived from glucose­6­
phosphate by glycolysis.

8. How does the cost of storing glucose­6­ phosphate (G6P) as glycogen differ from the answer you obtained in Question 7 if G6P were used
for energy in aerobic metabolism?

a. ATP cost is the same but more than 30 ATP can be derived from aerobic metabolism.

9. Would eating candy bars, high in sucrose rather than complex carbohydrates, help build up glycogen stores?

a. Sucrose can be hydrolyzed to glucose and fructose, which can both be readily converted to G1P, the immediate precursor of
glycogen.

10. 12) The concentration of lactate in blood rises sharply during a sprint and declines slowly for about an hour afterward. What causes the
rapid rise in lactate concentration? What causes the decline in lactate concentration after the run?
a. The anaerobic sprint produces lactate from glucose. Lactate is recycled back into glucose via gluconeogenesis.
11. Reflect and apply A researcher claims to have discovered a variant form of glycogen. The variation is that it has very few branches (every
50 glucose residues or so) and that the branches are only three residues long. Is it likely that this discovery will be confirmed by later work?
a. No. the highly branched glycogen structure is optimized for glucose release on demand.
12. What is the source of the energy needed to incorporate glucose residues into glycogen? How is it used?
a. Each glucose residue added to a growing phosphate chain comes from uridine diphosphate glucose. The cleavage of the
phosphate ester bond to the nucleotide diphosphate moiety supplies the need for energy.
13. Reflect and apply Why is it useful to have a primer in glycogen synthesis?
a. The enzyme that catalyzes the addition of glucose residues to a growing glycogen chain cannot form a bond between
isolated glucose residue; thus, we need a primer.
14. Reflect and apply Is the glycogen synthase reaction exergonic or endergonic? What is the reason for your answer?
a. Exergonic b/c its coupled w/ phosphate ester hydrolysis.
15. What is the effect on gluconeogenesis and glycogen synthesis of
a. (a) increasing the level of ATP – favors both
b. (b) decreasing the concentration of fructose­1,6­bisphosphate – stimulates glycolysis
c. (c) increasing the concentration of fructose­6­phosphate? NO effect
16. Reflect and apply Briefly describe “going for the burn” in a workout in terms of the material in this chapter.
a. Lactic acid build up from anaerobic metabolism

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
17. Reflect and apply Suggest a reason why sugar nucleotides, such as UDPG, play a role in glycogen synthesis, rather than sugar phosphates,
such as glucose­6­phosphate.
a. Sugar nucleotides are diphosphates. The net result is hydrolysis of two phosphate ions, releasing more energy and driving
the addition of glucose residues to glycogen in the direct polymerization

18. Recall What reactions in this chapter require acetyl­CoA or biotin?

a. The carboxylation of pyruvate to oxaloacetate

19. Recall Which steps of glycolysis are irreversible? What bearing does this observation have on the reactions in which gluconeogenesis
differs from glycolysis?

a. They are the production of pyruvate and ATP from phosphoenolpyruvate, the production of fructose­1,6­bisphosphate from
fructose­6­phosphate, and the production of glucose­6­phosphate from glucose. These reactions are bypassed in gluconeogenesis;
the reactions of gluconeogenesis differ from those of glycolysis at these points and are catalyzed by different enzymes.

20. Recall What is the role of biotin in gluconeogenesis?

a. Biotin is the molecule to which CO2 is attached to the process of being transferred to pyruvate. The reaction produces
oxaloacetate, which then undergoes further reactions of gluconeogenesis.

21. Recall How does the role of glucose­6­phosphate in gluconeogenesis differ from that in glycolysis?

a. In gluconeogenesis, G6P is dephosphorylated to glucose in the very last step to make free glucose

b. In glycolysis, G6P isomerizes to fructose­6­phosphate, the second step.

22. Reflect and apply Avidin, a protein found in egg whites, binds to biotin so strongly that it inhibits enzymes that require biotin. What is the
effect of avidin on glycogen formation? On gluconeogenesis? On the pentose phosphate pathway?

a. Pyruvate carboxylase of the gluconeogenic pathway is affected – it catalyzes conversion of pyruvate to oxaloacetate

23. How does the hydrolysis of fructose­1,6­ bisphosphate bring about the reversal of one of the physiologically irreversible steps of
glycolysis?

a. The hydrolysis of fructose­1,6­ bisphosphate is strongly exergonic; the reverse reaction in glycolysis, phosphorylation of F6P, is
irreversible b/c of the energy supplied by ATP hydrolysis.

24. 26. Recall Which reaction or reactions discussed in this chapter re­quire ATP? Which reaction or reactions produce ATP? List the enzymes
that catalyze the reactions that require and that produce ATP.

a. Reactions that require ATP: formation of UDP­glucose from glucose­1­phosphate and UTP (indirect requirement, because ATP
is needed to regenerate UTP), regeneration of UTP, and carboxylation of pyruvate to oxaloacetate.

b. Reactions that produce ATP: none. Enzymes that catalyze ATP­requiring reactions: UDP­glucose phosphorylase (indirect
requirement), nucleoside phosphate kinase, and pyruvate carboxylase.

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
c. Enzymes that catalyze ATP­producing reactions: none.

25. 27. Recall How does fructose­2,6­bisphosphate play a role as an allosteric effector?

a. F­2,5­BP is an allosteric activator of PFK in glycolysis and an allosteric inhibitor of F­1,6­Bisphosphatase in gluconeogenesis

26. 28. Recall How do glucokinase and hexokinase differ in function?

a. Hexokinase can add a phosphate to any group of several six­carbon sugars whereas glucokinase is specific for glucose.

i. Glucokinase has a lower affinity (higher Km) for glucose than hexokinase; it deals w/ excess glucose in the liver.

27. 29. Recall What is the Cori cycle?

a. Cycling of glucose due to muscle glycolysis and gluconeogenesis in the liver.

b. Blood transports lactate from muscle to liver and glucose from liver to muscle.

28. 30. Earlier biochemists called substrate cycles “futile cycles.” Why might they have chosen such a name? Why is it a misnomer?

a. Substrate cycling is futile b/c there is no net change except for ATP hydrolysis.

b. However, substrate cycles allow for increased control over opposing reactions when they are catalyzed by different enzymes

29. 31. Why is it advantageous for two control mechanisms—allosteric control and covalent modification—to be involved in the metabolism of
glycogen?

a. Allows for fine­tuning of control and the possibility of amplification. Both are capable of rapid response to conditions in
milliseconds in the case of allosteric control and seconds to minutes in covalent modification.

30. 34) Why would you expect to see that reactions of substrate cycles involve different enzymes for different directions?
a. Enzymes speed up forward and reverse reactions to the same extent. Having different catalysts is the only way to ensure
independent control over the rates of the forward and reverse process.
31. 35. Reflect and apply Suggest a reason or reasons why the Cori cycle takes place in the liver and in muscle.
a. Muscle tissues use large quantities of glucose producing lactate in the process. Liver is an important gluconeogenic site
32. 36. Reflect and apply Explain how fructose­2,6­bisphosphate can play a role in more than one metabolic pathway.
a. F­2,6­BP is an allosteric activator of PFK and inhibitor of fructose­1,6­bisphosphatase. It plays a role in 2 pathways that are not
the exact reverse of each other.
33. 37. Reflect and apply How can the synthesis and breakdown of fructose­2,6­bisphosphate be controlled independently?
a. The concentration of fructose­2,6­bisphosphate in a cell depends on the balance between its synthesis (catalyzed by
phosphofructokinase­2) and its breakdown (catalyzed by fructose­1,6­bisphosphatase). The separate enzymes that control the
formation and breakdown of fructose­2,6­bisphosphate are themselves controlled by a phosphorylation/dephosphorylation
mechanism.
34. 38. How is it advantageous for animals to convert ingested starch to glucose and then to incorporate the glucose into glycogen?
a. Glycogen is more intensively branched than glycogen. It’s a more useful form of storage of glucose – glucose is moblizied more
easily w/ glycogen stores.
35. 39. Recall How does control of the glucose­6­phosphatase reaction differ from that of the fructose­1,6­bisphosphatase reaction?
a. In glucose­6­phosphatase, the concentration of substrate is the main determinant of reaction velocity. In fructose­1,6­
bisphosphatase, allosteric effects are the main reaction velocity determinants.
36. 40. How does the action of allosteric effectors differ in the reactions catalyzed by phosphofructokinase and fructose­1,6 bisphosphatase?

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 Ch 18: Storage Mechanisms and Control in Carbohydrate Metabolism
a. AMP and F­2,6­BP are allosteric activators of PFK; both are also allosteric inhibitors of fructose­1,6­bisphoshatase.
37. 41. Recall Name two forms of control of enzymatic action. Which of the two is more important in control of glycogen breakdown?
a. Allosteric effect and covalent modifications – mostly the latter
38. 42. Recall What role does insulin play in glycogen synthesis? Triggers a series of events that leads to glycogen synthesis
39. 43. What roles do glucagon and epinephrine play in glycogen breakdown? Triggers a series of events that leads to glycogen breakdown

40. 46. Recall What are four possible metabolic fates of glucose­6­ phosphate?

a. G6P  glucose in gluconeogenesis; or glycogen for stores; Pentose phosphates; pyruvate via glycolysis

41. 53. Suggest a reason why a different reducing agent (NADPH) is used in anabolic reactions rather than NADH, which plays a role in
catabolic ones. Keeps them independent – metabolically separate ­ and prevents wasting energy.

42. 54. Explain how the pentose phosphate path­way can respond to a cell’s need for ATP, NADPH, and ribose­5­ phosphate.

a. If a cell needs NADPH, all PPP reactions occur; if the cell only needs ribose sugars, oxidative portion is bypassed.

b. The PPP does not significantly affect the cells ATP supply.

43. 55. Why is it reasonable to expect that glucose­ 6­phosphate will be oxidized to a lactone rather than to an open­chain compound?

a. Glucose­6­phosphate + NADP+ 6­Phosphoglucono­gamma­lactone + NADPH + H+

i. The ester bond is more easily broken than any other bonds that form the sugar ring. Hydrolysis of this bond is the next

step in the pathway

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