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exercise, which would continue to use blood glucose, could normally be supported by breakdown

of liver glycogen. However, glycogen synthesis in his liver was activated, and glycogen

degradation was inhibited by the insulin injection. CLINICAL COM M ENTS

Gretchen C. Gretchen C.’s hypoglycemia illustrates the importance of glycogen stores in the

neonate. At birth, the fetus must make two major adjustments in the way fuels are used: It must

adapt to using a greater variety of fuels than were available in utero, and it must adjust to intermittent

feeding. In utero, the fetus receives a relatively constant supply of glucose from the maternal circulation

through the placenta, producing a level of glucose in the fetus that approximates 75% of maternal blood

levels. With regard to the hormonal regulation of fuel use in utero, fetal tissues function in an environment

dominated by insulin, which promotes growth. During the last 10 weeks of gestation, this hormonal milieu

leads to glycogen formation and storage. At birth, the infant’s diet changes to one containing greater

amounts of fat and lactose (galactose and glucose in equal ratio), presented at intervals rather than in a

constant fashion. At the same time, the neonate’s need for glucose is relatively larger than that of the adult

because the newborn’s ratio of brain to liver weight is greater. Thus, the infant has even greater difficulty

maintaining glucose homeostasis than the adult.

At the moment that the umbilical cord is clamped, the normal neonate is faced with a metabolic

problem: The high insulin levels of late fetal existence must be quickly reversed to prevent hypoglycemia.

This reversal is accomplished through the secretion of the counterregulatory hormones epinephrine and

glucagon. Glucagon release is triggered by the normal decline of blood glucose after birth. The neural

response that stimulates the release of both glucagon and epinephrine is activated by the anoxia, cord

clamping, and tactile stimulation that are part of a normal delivery. These responses have been referred to

as the “normal sensor function” of the neonate.

Within 3 to 4 hours of birth, these counterregulatory hormones reestablish normal serum glucose

levels in the newborn’s blood through their glycogenolytic and gluconeogenic actions. The failure of

Gretchen’s normal “sensor function” was partly the result of maternal malnutrition, which resulted in an

inadequate deposition of glycogen in Gretchen’s liver before birth. The consequence was a serious degree

of postnatal hypoglycemia.

The ability to maintain glucose homeostasis during the first few days of life also depends on the

activation of gluconeogenesis and the mobilization of fatty acids. Fatty acid oxidation in the liver not onlypromotes gluconeogenesis (see Chapter 28), it also generates ketone bodies. The neonatal brain has an

enhanced capacity to use ketone bodies relative to that of infants (4-fold) and adults (40-fold). This

ability is consistent with the relatively high fat content of breast milk.

Jim B. attempted to build up his muscle mass with androgens and with insulin. The anabolic

(nitrogen-retaining) effects of androgens on skeletal muscle cells enhance muscle mass by

increasing amino acid flux into muscle and by stimulating protein synthesis. Exogenous insulin has the

potential to increase muscle mass by similar actions and also by increasing the content of muscle

glycogen.

The most serious side effect of exogenous insulin administration is the development of severe

hypoglycemia, such as occurred in Jim’s case. The immediate adverse effect relates to an inadequate flow

of fuel (glucose) to the metabolizing brain. When hypoglycemia is extreme, the patient may suffer a

seizure and, if the hypoglycemia worsens, irreversible brain damage may occur. If prolonged, the patient

will lapse into a coma and die. B IOCHEM ICAL COM M ENTS

Glycogen Synthase Kinase-3. It should be clear that the regulation of glycogen metabolism is

quite complex. Recent work has indicated that certain enzymes involved in regulating glycogen

synthase activity also have far-reaching effects on other aspects of cell metabolism, such as cell structure,

motility, growth, and survival.

The best example of this is glycogen synthase kinase-3 (GSK-3). The enzyme was first identified as

being an inhibitor of glycogen synthase. GSK-3 refers to two isozymes: GSK3α and GSK3β. GSK-3 has

been identified as a kinase that can phosphorylate >60 different proteins, including a large number of

transcription factors. GSK-3 activity is also itself regulated by phosphorylation. GSK-3 activity is reduced by phosphorylation of a serine residue near its amino terminus. PKA, Akt,

and protein kinase C can all catalyze this inhibitory phosphorylation event. GSK-3 is most active on

protein substrates that have already been phosphorylated by other kinases (the substrates are said to be

primed for further phosphorylation events). For example, GSK-3 will add phosphates to glycogen

synthase but only after glycogen synthase had been phosphorylated by PKA. GSK-3 binds to several proteins that sequester GSK-3 in certain pathways. This includes the Wnt

signaling pathway, disruption of which is a significant component of colon cancer, the Patched–

Smoothened signal transduction pathway (see Chapter 18), and the phosphorylation of microtubuleassociated proteins, which leads to altered cell motility. Activation of GSK-3 has also been linked to

apoptosis, although GSK-3 activity is also required for cell survival.

One of the effects of insulin is to phosphorylate GSK-3, via activation of Akt, rendering the GSK-3

inactive. Loss of activity of GSK-3 will lead to activation of glycogen synthase activity and the pathways

of energy storage. In animal models of type 2 diabetes, there is a loss of inhibitory control of GSK-3,

leading to greater-than-normal GSK-3 activity, which antagonizes insulin action (promoting insulin

resistance, a hallmark of type 2 diabetes). Studies in rats have shown that inhibitors of GSK-3 lowered

blood glucose levels and stimulated glucose transport into muscles of insulin-resistant animals.

Inappropriate stimulation of GSK-3 has also been implicated in Alzheimer disease.Current research concerning GSK-3 is geared toward understanding all of the roles of GSK-3 in cell

growth and survival and to decipher its actions in the multitude of multiprotein complexes with which it is

associated. Inhibitors of GSK-3 are being examined as possible agents to treat diabetes, but interpretation

of results is difficult because of the multitude of roles GSK-3 plays within cells. It is possible that in the

future, such drugs will be available to treat type 2 diabetes. KEY CONCEPTS

Glycogen is the storage form of glucose, composed of glucosyl units linked by α-1,4-glycosidic

bonds with α-1,6-branches occurring about every 8 to 10 glucosyl units. Glycogen synthesis requires energy.

Glycogen synthase transfers a glucosyl residue from the activated intermediate UDP-glucose to the

nonreducing ends of existing glycogen chains during glycogen synthesis. The branching enzyme

creates α-1,6-linkages in the glycogen chain.

Glycogenolysis is the degradation of glycogen. Glycogen phosphorylase catalyzes a phosphorolysis

reaction, using exogenous inorganic phosphate to break α-1,4-linkages at the ends of glycogen

chains, releasing glucose 1-phosphate. The debranching enzyme hydrolyzes the α-1,6-linkages in

glycogen, releasing free glucose. Liver glycogen supplies blood glucose.

Glycogen synthesis and degradation are regulated in the liver by hormonal changes that signify

either a deficiency of or an excess of blood glucose.

Lack of dietary glucose, signaled by a decrease of the insulin/glucagon ratio, activates liver

glycogenolysis and inhibits glycogen synthesis. Epinephrine also activates liver glycogenolysis.

Glucagon and epinephrine release lead to phosphorylation of glycogen synthase (inactivating it) and

glycogen phosphorylase (activating it).

Glycogenolysis in muscle supplies glucose 6-phosphate for ATP synthesis in the glycolytic pathway.

Muscle glycogen phosphorylase is allosterically activated by AMP as well as by phosphorylation.

Increases in sarcoplasmic Ca2+ stimulates phosphorylation of muscle glycogen phosphorylase.

Diseases discussed in this chapter are summarized in Table 26.4.REVIEW QUESTIONS—CHAPTER 26

1.Under conditions of glucagon release, the degradation of liver glycogen normally produces which

one of the following?

A. More glucose than glucose 1-P B. More glucose 1-P than glucose

C. Equal amounts of glucose and glucose 1-P D. Neither glucose nor glucose 1-P

E. Only glucose 1-P

2.A patient has large deposits of liver glycogen, which, after an overnight fast, had shorter-than-normal

branches. This abnormality could be caused by a defective form of which one of the following

proteins or activities? A. Glycogen phosphorylase B. Glucagon receptor

C. Glycogenin

D. Amylo-1,6-glucosidase E. Amylo-4,6-transferase

3.An adolescent patient with a deficiency of muscle phosphorylase was examined while exercising her

forearm by squeezing a rubber ball. Compared with a normal person performing the same exercise,

this patient would exhibit which one of the following? A. Exercise for a longer time without fatigue

B. Have increased glucose levels in blood drawn from her forearm C. Have decreased lactate levels in blood drawn from her forearm

D. Have lower levels of glycogen in biopsy specimens from her forearm muscle E. Hyperglycemia

4.In a glucose tolerance test, an individual in the basal metabolic state ingests a large amount of

glucose. If the individual is normal, this ingestion should result in which one of the following?

A. An enhanced glycogen synthase activity in the liver

B. An increased ratio of glycogen phosphorylase a to glycogen phosphorylase b in the liver

C. An increased rate of lactate formation by red blood cells D. An inhibition of PP-1 activity in the liver

E. An increase of cAMP levels in the liver

5.Consider a person with type 1 diabetes who has neglected to take insulin for the past 72 hours and

also has not eaten much. Which one of the following best describes the activity level of hepatic

enzymes involved in glycogen metabolism under these conditions?6. Assume that an individual carries a mutation in muscle PKA such that the protein is refractory to high

levels of cAMP. Glycogen degradation in the muscle would occur, then, under which one of the

following conditions?

A. High levels of intracellular calcium B. High levels of intracellular glucose

C. High levels of intracellular glucose 6-P D. High levels of intracellular glucose 1-P E. High levels of intracellular magnesium

7.Without a steady supply of glucose to the bloodstream, a patient would become hypoglycemic and, if

blood glucose levels get low enough, experience seizures or even a coma. Which one of the

following is necessary for the maintenance of normal blood glucose? A. Muscle glucose 6-P

B. Liver glucose 6-P

C. Glycogen in the heart D. Glycogen in the brain E. Glycogen in the muscle

8.Glycogen is the storage form of glucose, and its synthesis and degradation is carefully regulated.

Which one statement below correctly describes glycogen synthesis and/or degradation? A. UDP-glucose is produced in both the synthesis and degradation of glycogen.

B. Synthesis requires the formation of α-1,4 branches every 8 to 10 residues. C. Energy, in the form of ATP, is used to produce UDP-glucose.

D. Glycogen is both formed from and degrades to glucose 1-P.

E. The synthesis and degradation of glycogen use the same enzymes, so they are reversible

processes.

9.Mutations in various enzymes can lead to the glycogen storage diseases. Which one statement is true

of the glycogen storage diseases?

A. All except type O are fatal in infancy or childhood. B. All except type O involve the liver.

C. All except type O produce hepatomegaly. D. All except type O produce hypoglycemia.

E. All except type O produce increased glycogen deposits.

10.A baby weighing 7.5 lb was delivered at 40 weeks of gestation by normal spontaneous vaginal

delivery. At 1 hour, the baby’s blood glucose level was determined to be 50 mg/dL and at 2 hourspost-birth was 80 mg/dL. These glucose numbers indicate which process? A. Maternal malnutrition

B. Glycogen storage disease C. Normal physiologic change

D. Insulin was given to the baby.

E. IV dextrose 50 was given to the baby. ANSWERS TO REVIEW QUESTIONS

1.The answer is B. Glycogen phosphorylase produces glucose 1-P; the debranching enzyme

hydrolyzes branch points and thus releases free glucose. Ninety percent of the glycogen contains

α-(1,4)-bonds, and only 10% are α-(1,6)-bonds, so more glucose 1-P will be produced than

glucose.

2.The answer is D. If, after fasting, the branches were shorter than normal, glycogen phosphorylase

must be functional and capable of being activated by glucagon (thus, A and B are incorrect). The

branching enzyme (amylo-4,6-transferase) is also normal because branch points are present within

the glycogen (thus, E is incorrect). Because glycogen is also present, glycogenin is present in

order to build the carbohydrate chains, indicating that C is incorrect. If the debranching activity is

abnormal (the amylo-1,6-glucosidase), glycogen phosphorylase would break the glycogen down

up to four residues from branch points and would then stop. With no debranching activity, the

resultant glycogen would contain the normal number of branches, but the branched chains would

be shorter than normal.

3.The answer is C. The patient has McArdle disease, a glycogen storage disease caused by a

deficiency of muscle glycogen phosphorylase. Because she cannot degrade glycogen to produce

energy for muscle contraction, she becomes fatigued more readily than a normal person (thus, A is

incorrect), the glycogen levels in her muscle will be higher than normal as a result of the inability

to degrade them (thus, D is incorrect), and her blood lactate levels will be lower because of the

lack of glucose for entry into glycolysis. She will, however, draw on the glucose in her circulation

for energy, so her forearm blood glucose levels will be decreased (thus B is incorrect), and

because the liver is not affected, blood glucose levels can be maintained by liver glycogenolysis

(thus, E is incorrect).

4.The answer is A. After ingestion of glucose, insulin levels rise, cAMP levels within the cell drop

(thus, E is incorrect), and PP-1 is activated (thus, D is incorrect). Glycogen phosphorylase a is

converted to glycogen phosphorylase b by the phosphatase (thus, B is incorrect), and glycogen

synthase is activated by the phosphatase. Red blood cells continue to use glucose at their normal

rate; hence, lactate formation will remain the same (thus, C is incorrect).

5.The answer is F. In the absence of insulin, glucagon-stimulated activities predominate. This leads

to the activation of PKA, the phosphorylation and inactivation of glycogen synthase, the

phosphorylation and activation of phosphorylase kinase, and the phosphorylation and activation of

glycogen phosphorylase.

6.The answer is A. Calcium activates a calmodulin subunit in phosphorylase kinase which will

allow phosphorylase kinase to phosphorylate, and activate, glycogen phosphorylase. Glucose isan allosteric inhibitor of glycogen phosphorylase a in liver but has no effect in muscle. Glucose 1-

P has no effect on muscle phosphorylase, whereas glucose 6-P is an allosteric inhibitor of muscle

glycogen phosphorylase a. The levels of magnesium have no effect on muscle glycogen phosphorylase activity. Normally, glucagon or epinephrine would activate the cAMP-dependent

PKA, but this is not occurring under these conditions.

7.The answer is B. Glycogen in the liver provides glucose for the circulation. Glycogen in the

heart, brain, or muscle cannot provide glucose for the circulation. In the liver, glucose 6-

phosphatase hydrolyzes glucose 6-P to glucose, which is released into the bloodstream. The liver

generates glucose 6-P from either glycogen degradation or gluconeogenesis. Muscle does not

contain glucose 6-phosphatase.

8.The answer is D. Glycogen is both formed from and degrades to glucose 1-P. A high-energy

phosphate bond from UTP is required to produce UDP-glucose in glycogen synthesis, but UDPglucose is not resynthesized when glycogen is degraded. The pathways of glycogen synthesis and

degradation use different enzymes and are not reversible reactions. In this way, the pathways can

be regulated independently.

9.The answer is E. Type O glycogen storage disease is caused by a reduced level of liver glycogen

synthase activity, so in this disease, very little liver glycogen is formed so glycogen deposits

would not be found in the liver. All of the other glycogen storage diseases are characterized by

glycogen deposits. Not all are fatal, some are mild, and some have an adult-onset form. Some

glycogen storage disorders involve the liver, whereas others involve the muscle. Only those

involving the liver will produce hepatomegaly and hypoglycemia.

10.The answer is C. At birth, maternal glucose supply to the baby ceases, causing a temporary

physiologic drop in glucose even in normal healthy infants. This drop signals glycogenolysis in the

newborn liver, returning the blood glucose to normal levels. Exogenous insulin would precipitously drop the blood glucose into hypoglycemic levels, and an exogenous bolus of

dextrose would raise blood glucose levels above normal levels. This physiologic drop does not

necessarily mean maternal malnutrition or evidence of a glycogen storage disease.Pentose Phosphate Pathway and the

Synthesis of Glycosides, Lactose, Glycoproteins, and Glycolipids

For additional ancillary materials related to this chapter, please visit thePoint. Glucose is used in several pathways other than glycolysis and glycogen synthesis. The pentose

phosphate pathway (also known as the hexose monophosphate shunt, or HMP shunt) consists of both

oxidative and nonoxidative components (Fig. 27.1). In the oxidative pathway, glucose 6-phosphate

(glucose 6-P) is oxidized to ribulose 5-phosphate (ribulose 5-P), carbon dioxide (CO2), and reduced

nicotinamide adenine dinucleotide phosphate (NADPH). Ribulose 5-P, a pentose, can be converted to

ribose 5-phosphate (ribose 5-P) for nucleotide biosynthesis. The NADPH is used for reductive

pathways, such as fatty acid biosynthesis, detoxification of drugs by monooxygenases, and the

glutathione defense system against injury by reactive oxygen species (ROS).In the nonoxidative phase of the pathway, ribulose 5-P is converted to ribose 5-P and to intermediates

of the glycolytic pathway. This portion of the pathway is reversible; therefore, ribose 5-P can also be

formed from intermediates of glycolysis. One of the enzymes involved in these sugar interconversions,

transketolase, uses thiamin pyrophosphate as a coenzyme.

The sugars produced by the pentose phosphate pathway enter glycolysis as fructose 6-phosphate

(fructose 6-P) and glyceraldehyde 3-phosphate (glyceraldehyde 3-P), and their further metabolism in the

glycolytic pathway generates NADH, adenosine triphosphate (ATP), and pyruvate. The overall equation

for the conversion of glucose 6-P to fructose 6-P and glyceraldehyde 3-P through both the oxidative and

nonoxidative reactions of the pentose phosphate pathway is

3 Glucose 6-P + 6 NADP+ → 3 CO2 + 6 NADPH + 6 H+ + 2 fructose 6-P + glyceraldehyde 3-P

As had been seen previously in glycogen synthesis, several pathways for interconversion of sugars or

the formation of sugar derivatives use activated sugars attached to nucleotides. Both uridine diphosphate

(UDP)-glucose and UDP-galactose are used for glycosyltransferase reactions in many systems.

Lactose, for example, is synthesized from UDP-galactose and glucose in the mammary gland. UDPglucose also can be oxidized to form UDP-glucuronate, which is used to form glucuronide derivatives of

bilirubin and xenobiotic compounds. Glucuronide derivatives are generally more readily excreted in

urine or bile than the parent compound.

In addition to serving as fuel, carbohydrates are often found in glycoproteins (carbohydrate chains

attached to proteins) and glycolipids (carbohydrate chains attached to lipids). Nucleotide sugars are used

to donate sugar residues for the formation of the glycosidic bonds in both glycoproteins and glycolipids.

These carbohydrate groups have many different types of functions. Glycoproteins contain short chains of carbohydrates (oligosaccharides) that are usually branched.These oligosaccharides are generally composed of glucose, galactose, and their amino derivatives. In

addition, mannose, L-fucose, and N-acetylneuraminic acid (NANA) are frequently present. The

carbohydrate chains grow by the sequential addition of sugars to a serine or threonine residue of the

protein. Nucleotide sugars are the precursors. Branched carbohydrate chains also may be attached to the

amide nitrogen of asparagine in the protein. In this case, the chains are synthesized on dolichol

phosphate and subsequently transferred to the protein. Glycoproteins are found in mucus, in the blood, in

compartments within the cell (such as lysosomes), in the extracellular matrix, and embedded in the cell

membrane with the carbohydrate portion extending into the extracellular space. Glycolipids belong to the class of sphingolipids. They are synthesized from nucleotide sugars that add

monosaccharides sequentially to the hydroxymethyl group of the lipid ceramide (related to sphingosine).

They often contain branches of NANA produced from cytidine monophosphate (CMP)-NANA. They are

found in the cell membrane with the carbohydrate portion extruding from the cell surface. These

carbohydrates, as well as some of the carbohydrates of glycoproteins, serve as cell recognition factors.

THE WAITING ROOM

After Al M. had been released from the hospital, where he had been treated for thiamin deficiency,

he quickly fell off the wagon and injured his arm after falling down in the street while intoxicated.

Two days after hurting his arm, Al’s friends took him to the hospital when he developed a fever of

101.5°F. One of the physicians noticed that one of the lacerations on Mr. M.’s arm

was red and swollen,

with some pus drainage. The pus was cultured and gram-positive cocci were found and identified as

Staphylococcus aureus. Because his friends stated that he had an allergy to penicillin, and because of the

concern over methicillin-resistant S. aureus, Al was started on a course of the antibiotic combination of

trimethoprim and sulfamethoxazole (TMP/sulfa). To his friends’ knowledge, he had never been treated

with a sulfa drug previously.

On the third day of therapy with TMP/sulfa for his infection, Mr. M. was slightly jaundiced. His

hemoglobin level had fallen by 3.5 g/dLfrom its value at admission, and his urine was red-brown

because of the presence of free hemoglobin. Mr. M. had apparently suffered acute hemolysis (lysis or

destruction of some of his red blood cells) induced by his infection and exposure to the sulfa drug.

To help support herself through medical school, Edna R. works evenings in a hospital blood bank.

She is responsible for ensuring that compatible donor blood is available to patients who need

blood transfusions. As part of her training, Edna has learned that the external surfaces of all blood cells

contain large numbers of antigenic determinants. These determinants are often glycoproteins or

glycolipids that differ from one individual to another. As a result, all blood transfusions expose the

recipient to many foreign immunogens. Most of these, fortunately, do not induce antibodies, or they induce

antibodies that elicit little or no immunologic response. For routine blood transfusions, therefore, tests are

performed only for the presence of antigens that determine whether the patient’s blood type is A, B, AB,

or O and Rh(D)-positive or -negative.

Jay S.’s psychomotor development has become progressively more abnormal (see Chapter 15). At

2 years of age, he is obviously severely developmentally delayed and nearly blind. His muscleweakness has progressed to the point that he cannot sit up or even crawl. As the result of a weak cough

reflex, he is unable to clear his normal respiratory secretions and has had recurrent respiratory infections.

Blood typing in a clinical lab uses antibodies that recognize either the A antigen, the B

antigen, or the Rh(D) antigen. Each antigen is distinctive, in part, because of the different

carbohydrate chains attached to the protein. The blood sample is mixed with each antibody

individually. If cell clumping (agglutination) occurs, the red blood cells are expressing the

carbohydrate that is recognized by the antibody (recall from Chapter 7 that antibodies are

bivalent; the agglutination occurs because one arm of the antibody binds to antigen on one cell,

whereas the other arm binds to antigen on a second cell, thereby bringing the cells together). If

neither the A nor B antibodies cause agglutination, the blood type is O, indicating a lack of either

antigen.

I. The Pentose Phosphate Pathway

The pentose phosphate pathway is essentially a scenic bypass route around the first stage of glycolysis

that generates NADPH and ribose 5-P (as well as other pentose sugars). Glucose 6-P is the common

precursor for both pathways. The oxidative first stage of the pentose phosphate

pathway generates 2 mol

of NADPH per mole of glucose 6-P oxidized. The second stage of the pentose phosphate pathway

generates ribose 5-P and converts unused intermediates to fructose 6-P and glyceraldehyde 3-P in the

glycolytic pathway (see Fig. 27.1). All cells require NADPH for reductive detoxification, and most cells

require ribose 5-P for nucleotide synthesis. Consequently, the pathway is present in all cells. The enzymes

reside in the cytosol, as do the enzymes of glycolysis. A. Oxidative Phase of the Pentose Phosphate Pathway

In the oxidative first phase of the pentose phosphate pathway, glucose 6-P undergoes an oxidation and

decarboxylation to a pentose sugar, ribulose 5-P (Fig. 27.2). The first enzyme of this pathway, glucose 6-P

dehydrogenase, oxidizes the aldehyde at carbon 1 and reduces NADP+ to NADPH. The gluconolactone

that is formed is rapidly hydrolyzed to 6-phosphogluconate, a sugar acid with a carboxylic acid group at

carbon 1. The next oxidation step releases this carboxyl group as CO2, with the electrons being

transferred to NADP+. This reaction is mechanistically very similar to the one catalyzed by isocitrate

dehydrogenase in the tricarboxylic acid (TCA) cycle. Thus, 2 mol of NADPH per mole of glucose 6-P are

formed from this portion of the pathway.NADPH, rather than NADH, is generally used in the cell in pathways that require the input of

electrons for reductive reactions, because the ratio of NADPH/NADP+ is much greater than the

NADH/NAD+ ratio. The NADH generated from fuel oxidation is rapidly oxidized back to NAD+ byNADH dehydrogenase in the electron-transport chain, so the level of NADH in the cell is very low.

NADPH can be generated from several reactions in the liver and other tissues but not red blood cells.

For example, in tissues with mitochondria, an energy-requiring transhydrogenase located near the

complexes of the electron-transport chain can transfer reducing equivalents from NADH to NADP+ to

generate NADPH.

NADPH, however, cannot be oxidized directly by the electron-transport chain, and the ratio of

NADPH to NADP+ in cells is >1. The reduction potential of NADPH, therefore, can contribute to the

energy needed for biosynthetic processes and provide a constant source of reducing power for

detoxification reactions.

The ribulose 5-P formed from the action of the two oxidative steps is isomerized to produce ribose 5-

P(a ketose-to-aldose conversion, similar to fructose 6-P being isomerized to glucose 6-P). The ribose 5-

Pcan then enter the pathway for nucleotide synthesis, if needed, or it can be converted to glycolytic

intermediates, as described in the following section for the nonoxidative phase of the pentose phosphate

pathway. The pathway through which the ribose 5-P travels is determined by the needs of the cell at the

time of its synthesis.

The transketolase activity of red blood cells can be used to measure thiamin nutritional

status and diagnose the presence of thiamin deficiency. The activity of transketolase is

measured in the presence and absence of added thiamin pyrophosphate. If the thiamin intake of a

patient is adequate, the addition of thiamin pyrophosphate does not increase the activity of

transketolase because it already contains bound thiamin pyrophosphate. If the patient is thiamindeficient, transketolase activity will be low, and adding thiamin pyrophosphate will greatly

stimulate the reaction. In Chapter 24, Al M. was diagnosed as having beriberi heart disease,

resulting from thiamin deficiency, by direct measurement of thiamin, which is the more commonly

used test currently.

B. Nonoxidative Phase of the Pentose Phosphate Pathway

The nonoxidative reactions of this pathway are reversible reactions that allow intermediates of glycolysis

(specifically, glyceraldehyde 3-P and fructose 6-P) to be converted to five-carbon sugars (such as ribose

5-P), and vice versa. The needs of the cell determine in which direction this pathway proceeds. If the cell

has produced ribose 5-P but does not need to synthesize nucleotides, then the ribose 5-P is converted to

glycolytic intermediates. If the cell still requires NADPH, the ribose 5-P is converted back into glucose

6-P using nonoxidative reactions (see the next section). And finally, if the cell already has a high level of

NADPH but needs to produce nucleotides, the oxidative reactions of the pentose phosphate pathway are

inhibited, and the glycolytic intermediates fructose 6-P and glyceraldehyde 3-P are used to produce the

five-carbon sugars using exclusively the nonoxidative phase of the pentose phosphate pathway.

How does the net energy yield from the metabolism of 3 mol of glucose 6-P through the

pentose phosphate pathway to pyruvate compare with the yield of 3 mol of glucose 6-Pthrough glycolysis?

The net energy yield from 3 mol of glucose 6-P metabolized through the pentose phosphate

pathway and then the last portion of the glycolytic pathway is 6 mol of NADPH, 3 mol of

CO2, 5 mol of NADH, 8 mol of ATP, and 5 mol of pyruvate. In contrast, the metabolism of 3 mol

of glucose 6-P through glycolysis is 6 mol of NADH, 9 mol of ATP, and 6 mol of pyruvate.

1. Conversion of Ribulose 5-Phosphate to Glycolytic Intermediates

The nonoxidative portion of the pentose phosphate pathway consists of a series of rearrangement and

transfer reactions that first convert ribulose 5-P to ribose 5-P and xylulose 5-phosphate (xylulose 5-P),

and then the ribose 5-P and xylulose 5-P are converted to intermediates of the glycolytic pathway. The

enzymes involved are an epimerase, an isomerase, transketolase, and transaldolase. The epimerase and isomerase convert ribulose 5-P to two other five-carbon sugars (Fig. 27.3). The

isomerase converts ribulose 5-P to ribose 5-P. The epimerase changes the stereochemical position of one

hydroxyl group (at carbon 3), converting ribulose 5-P to xylulose 5-P. Transketolase transfers two-carbon fragments of keto sugars (sugars with a keto group at carbon 2) toother sugars. Transketolase picks up a two-carbon fragment from xylulose 5-P by cleaving the carbon–

carbon bond between the keto group and the adjacent carbon, thereby releasing glyceraldehyde 3-P (Fig.

27.4). The two-carbon fragment is covalently bound to thiamin pyrophosphate, which transfers it to the

aldehyde carbon of another sugar, forming a new ketose. The role of thiamin pyrophosphate here is thus

very similar to its role in the oxidative decarboxylation of pyruvate and α-ketoglutarate (see Chapter 24,

Section III.C). Two reactions in the pentose phosphate pathway use transketolase: In the first, the twocarbon keto fragment from xylulose 5-P is transferred to ribose