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.pdfepithelium (RPE) and the choriocapillaris epithelium. The photoreceptor/retinal pigment complex
is exposed to sunlight, it is bathed in near-arterial levels of oxygen, and the membranes contain
high concentrations of polyunsaturated fatty acids, all of which are conducive to oxidative
damage. Lipofuscin granules, which accumulate in the RPE throughout life, may serve as
photosensitizers, initiating damage by absorbing blue light and generating singlet oxygen (an
energetically excited form of oxygen) that forms other radicals. Dark sunglasses are protective.
Epidemiologic studies showed that the intake of lutein and zeaxanthin in dark-green leafy
vegetables (e.g., spinach, collard greens) also may be protective. Lutein and zeaxanthin
accumulate in the macula and protect against free-radical damage by absorbing blue light and
quenching singlet oxygen.
4. Other Dietary Antioxidants
Flavonoids are a group of structurally similar compounds that contain two spatially separate aromatic
rings and are found in red wine, green tea, chocolate, and other plant-derived foods. Flavonoids have
been hypothesized to contribute to our free-radical defenses in several ways. Some flavonoids inhibit
enzymes responsible for superoxide anion production, such as xanthine oxidase. Others efficiently chelate
Fe and Cu, making it impossible for these metals to participate in the Fenton reaction. They also may act
as free-radical scavengers by donating electrons to superoxide or lipid peroxy radicals, or they may
stabilize free radicals by complexing with them.
It is difficult to tell how much dietary flavonoids contribute to our free-radical defense system; they
have a high pro-oxidant activity and are poorly absorbed. Nonetheless, we generally consume large
amounts of flavonoids (~800 mg/day), and there is evidence that they can contribute to the maintenance of
vitamin E as an antioxidant. 5. Endogenous Antioxidants
Several compounds that are synthesized endogenously for other functions, or as urinary excretion
products, also function nonenzymatically as free-radical antioxidants. Uric acid is formed from the
degradation of purines and is released into extracellular fluids, including blood, saliva, and lung lining
fluid. Together with protein thiols, it accounts for the major free-radical trapping capacity of plasma. It is
particularly important in the upper airways, where there are few other antioxidants. It can directly
scavenge hydroxyl radicals, oxyheme oxidants formed between the reaction of hemoglobin and peroxy
radicals, and peroxy radicals themselves. Having acted as a scavenger, uric acid produces a range of
oxidation products that are subsequently excreted.
Melatonin, which is a secretory product of the pineal gland, is a neurohormone that functions in
regulation of our circadian rhythm, light–dark signal transduction, and sleep induction. In addition to these
receptor-mediated functions, it functions as a nonenzymatic free-radical scavenger that donates an
electron (as hydrogen) to “neutralize” free radicals. It also can react with ROS and RNOS to form
addition products, thereby undergoing suicidal transformations. Its effectiveness is
related to both its lackof pro-oxidant activity and its joint hydrophilic/hydrophobic nature, which allows it to pass through membranes and the blood–brain barrier.
CLINICAL COM M ENTS
Les G. has “primary” parkinsonism. The pathogenesis of this disease is not well established and
may be multifactorial (Fig. 25.16). Recent work has identified several genes, which, when mutated
and inactive, lead to rare familial Parkinson disease and others that affect the risk for Parkinson disease.
The major clinical disturbances in Parkinson disease are a result of dopamine depletion in the
neostriatum, resulting from degeneration of dopaminergic neurons whose cell bodies reside in the
substantia nigra pars compacta. The decrease in dopamine production is the result of severe degeneration
of these nigrostriatal neurons. Although the agent that initiates the disease is unknown, a variety of studies
support a role for free radicals in Parkinson disease (mitochondrial dysfunction), along with alterations in
the ubiquitin–proteasome pathway of protein degradation. Within these neurons, dopamine turnover is
increased, dopamine levels are lower, glutathione is decreased, and lipofuscin (Lewy bodies) is
increased. Iron levels are higher, and ferritin, the storage form of iron, is lower. Furthermore, the disease
is mimicked by the compound 1-methyl-4-phenylpyridinium (MPP+), an inhibitor of NADH:CoQ
oxidoreductase that increases superoxide production in these neurons and decreases ATP production.
Analysis of mitochondria from patients with Parkinson disease indicate a 30% to 40% reduction in
complex I activity. The reduced ATP levels may affect the ubiquitin–proteasome pathway negatively,
reducing protein degradation and linking these two pathways, which can lead to Parkinson disease. Even
so, it is not known whether oxidative stress makes a primary or secondary contribution to the disease
process.Drug therapy is based on the severity of the disease. Several options are available. In the early phases
of the disease if symptoms are mild, a monoamine oxidase B inhibitor can be used that inhibits dopamine
degradation and decreases hydrogen peroxide formation. In later stages of the disease or more
symptomatic stages, patients are treated with levodopa (L-DOPA), a precursor of dopamine, sometimes in
combination with the monoamine oxidase B inhibitor.
Cora N. experienced angina caused by severe ischemia in the ventricular muscle of her heart. The
ischemia was caused by clots that formed at the site of atherosclerotic plaques within the lumen of
the coronary arteries. When TPA was infused to dissolve the clots, the ischemic area of her heart was
reperfused with oxygenated blood, resulting in ischemia–reperfusion injury. In her case, the reperfusion
injury resulted in some short runs of ventricular tachycardia.
During ischemia, several events occur simultaneously in cardiomyocytes. A decreased O2 supply
results in decreased ATP generation from mitochondrial oxidative phosphorylation and inhibition of
cardiac muscle contraction. As a consequence, cytosolic AMP levels increase, activating anaerobic
glycolysis and lactic acid production. If ATP levels are inadequate to maintain Na+,K+-ATPase activity,
intracellular Na+ increases, resulting in cellular swelling, a further increase in
H+ concentration, andincreases of cytosolic and subsequently mitochondrial Ca2+ levels. The decrease in ATP and increase in
Ca2+ may open the mitochondrial permeability transition pore, resulting in permanent inhibition of
oxidative phosphorylation. Damage to lipid membranes is further enhanced by Ca2+ activation of
phospholipases.
Reperfusion with O2 allows recovery of oxidative phosphorylation, provided that the mitochondrial
membrane has maintained some integrity and the mitochondrial transition pore can close. However, it also
increases generation of free radicals. The transfer of electrons from CoQ• to O2 to generate superoxide is
increased. Endothelial production of superoxide by xanthine oxidase also may increase. These radicals
may go on to form the hydroxyl radical, which can enhance the damage to components of the ETC and
mitochondrial lipids as well as activate the mitochondrial permeability transition. As macrophages move
into the area to clean up cellular debris, they may generate nitric oxide and superoxide, thus introducing
peroxynitrite and other free radicals into the area. Depending on the route and timing involved, the acute
results may be cell death through necrosis, with slower cell death through apoptosis in the surrounding
tissue.
Currently, an intense study of ischemic insults to a variety of animal organs is underway, in an effort to
discover ways of preventing reperfusion injury. These include methods designed to increase endogenous
antioxidant activity, to reduce the generation of free radicals, and, finally, to develop exogenous
antioxidants that, when administered before reperfusion, would prevent its injurious effects.
Preconditioning tissues to hypoxia is also a viable option to reducing reperfusion injury. Each of these
approaches has met with some success, but their clinical application awaits further refinement. With the
growing number of invasive procedures aimed at restoring arterial blood flow through partially
obstructed coronary vessels, such as clot lysis, balloon or laser angioplasty, and coronary artery bypass
grafting, development of methods to prevent ischemia–reperfusion injury will become increasingly urgent.
In Cora N.’s case, oxygen was restored before permanent impairment of oxidative phosphorylation
had occurred and the stage of irreversible injury was reached. BIOCHEM ICAL COM M ENTS
Oxidases, the Tricarboxylic Acid Cycle, and Cancer. The advent of whole genome sequencing
(see Chapter 17) has allowed a large number of tumor cells to be analyzed for mutations in the
genome. Surprisingly, certain types of tumors contained mutations in enzymes related to the tricarboxylic
acid (TCA) cycle (see Chapter 23). Enzymes identified include succinate dehydrogenase, which was
found in familial paraganglioma cells (this mutation is a loss of activity, in which succinate will
accumulate); fumarase deficiency was found in multiple cutaneous and uterine leiomyomas and exhibited
autosomal dominant behavior (in this mutation, fumarate will accumulate); and certain isozymes of
isocitrate dehydrogenase, in which a gain of function mutation enables the enzyme to produce 2-
hydroxyglutarate instead of α-ketoglutarate, is found in gliomas and acute myeloid
leukemia (AML). The
accumulation of succinate, fumarate, or 2-hydroxyglutarate, in a manner described in the following
paragraphs, leads to an alteration in gene expression and oxygen sensing, which, in part, leads to tumor
formation.
α-Ketoglutarate, in addition to being a key intermediate in the TCA cycle, is also required for vitaminC–dependent hydroxylation reactions (see Chapter 5). Enzymes catalyzing such reactions include Nmethyllysine hydroxylase (the first step in demethylating histones) and methylcytosine demethylase (the
first step in demethylating 5-methylcytosine, found in the promoter of genes which are usually
inactivated). The reaction catalyzed by these enzymes is oxygen + α-ketoglutarate + substrate to be
hydroxylated yields succinate + CO2 + hydroxylated product.
Isocitrate dehydrogenase exists as three different isozymes: IDH1, IDH2, and IDH3. IDH3 is the
mitochondrial version, requires NAD+, and is part of the TCA cycle. Mutations in IDH3 do not lead to
tumor formation. IDH1 and IDH2 are NADP+-dependent isozymes, with IDH1 being located in the
cytoplasm, and IDH2 in the mitochondria. If IDH1 or IDH2 contains a mutation that alters a key arginine
residue at the active site, the enzyme will use α-ketoglutarate as a substrate (instead of isocitrate) and
generate 2-hydroxyglutarate as the product.
As described in Chapter 16, histone methylation occurs on the N-terminal tails of histones and is a
component of the epigenetic regulation of gene expression. These methylation events can either activate or
inhibit expression of a gene, depending on the gene. The enzyme N-methyllysine hydroxylase is the first
step in the demethylation of the tails. The methyl group becomes hydroxylated, and the carbon is then lost
in the form of formaldehyde, which is picked up by the one carbon carrier tetrahydrofolate. If 2-
hydroxyglutarate has accumulated, it will bind to the active site of N-methyllysine hydroxylase, inhibiting
the enzyme, and not allowing histone demethylation to occur. Similarly, if succinate has accumulated
owing to a mutation in succinate dehydrogenase or fumarase, succinate will inhibit the hydroxylation
reaction because of product inhibition (recall that succinate is a product of the hydroxylase).
In a similar fashion, the removal of methyl groups from cytosine in promoter regions of genes requires
an initial hydroxylation reaction (the enzyme is methylcytosine dioxygenase) which is similarly inhibited
by 2-hydroxyglutarate, succinate, or fumarate. This leads to a constant state of hypermethylation of the
genome, and altered gene expression. In cases of AML the methylation pattern of the genome resembles
that of stem cells and not that of differentiated blood cells.
The mutations in the TCA cycle enzymes and isozymes also affect the degradation of the transcription
factor hypoxia inducible factor (HIF). Under conditions of low oxygen concentration, HIF binds to DNA
regulatory elements to induce genes in response to low-oxygen conditions, such as an increase in
expression of glycolytic enzymes. HIF activity is regulated, in part, by proline hydroxylation (which
requires α-ketoglutarate). An inability to hydroxylate the proline residue (because of 2-hydroxyglutarate,
succinate, or fumarate accumulation) leads to HIF being active for extended period of times, altering gene
transcription and leading to cell proliferation.
Laboratory experiments using inhibitors of the altered IDH molecules are in progress, and drugs have
been developed that are candidates for clinical trials. Some of the drugs developed led to reversal of both
DNA and histone hypermethylation, and induced cellular differentiation, in cultured cells containing
tumor-inducing IDH-2 mutations. KEY CONCEPTS
Oxygen radical generation contributes to cellular death and degeneration in a variety of diseases.
Radical damage occurs via electron extraction from a biologic molecule, creating a chain reactionof radical propagation.
Reactive oxygen species (ROS) include superoxide, hydrogen peroxide, and the hydroxyl radical.
ROS can be produced either enzymatically or nonenzymatically.
ROS cause damage by oxidatively damaging DNA, proteins, and lipids, leading to mutations and
cell death.
Other radical species include nitric oxide (NO) and hypochlorous acid (HOCl).
NO reacts with oxygen or superoxide to form a family of reactive nitrogen species (RNOS).
The immune response normally produces radical species (superoxide, HOCl, NO) to destroy
invading microorganisms. Escape of radicals from the immune cells during this protective event can
damage surrounding tissues.
Cellular defense mechanisms against radical damage include defense enzymes, antioxidants, and
compartmentalization of free radicals.
Cellular defense enzymes include superoxide dismutase, catalase, and glutathione peroxidase.
Antioxidants include vitamins E and C and plant flavonoids.
Diseases discussed in this chapter are summarized in Table 25.3.REVIEW QUESTIONS—CHAPTER 25
1.Which one of the following vitamins or enzymes is unable to protect against free-radical damage?
A. β-Carotene
B. Glutathione peroxidase C. SOD
D. Vitamin B6 E. Vitamin C F.
Vitamin E
2.SOD is one of the body’s primary defense mechanisms against oxidative stress. The enzyme
catalyzes which one of the following reactions? A. O2− + e− + 2H+ → H2O2
B. 2O2− + 2H+ → H2O2 + O2
C. O2− + HO• + H+ → CO2 + H2O D. H2O2 + O2 → 4H2O
E. O2− + H2O2 + H+ → 2H2O + O2
3.The mechanism of vitamin E as an antioxidant is best described by which one of the following?
A. Vitamin E binds to free radicals and sequesters them from the contents of the cell.
B. Vitamin E participates in the oxidation of the radicals. C. Vitamin E participates in the reduction of the radicals.
D. Vitamin E forms a covalent bond with the radicals, thereby stabilizing the radical state.
E. Vitamin E inhibits enzymes that produce free radicals.
4.An accumulation of hydrogen peroxide in a cellular compartment can be converted to dangerous
radical forms in the presence of which metal? A. Selenium
B.Iron
C.Manganese
D.Magnesium
E.Molybdenum
5.The level of oxidative damage to mitochondrial DNA is 10 times greater than that to nuclear DNA.
This could be, in part, because of which one of the following? A. SOD is present in the mitochondria.
B. The nucleus lacks glutathione.
C. The nuclear membrane presents a barrier to ROS. D. The mitochondrial membrane is permeable to ROS. E. Mitochondrial DNA lacks histones.
6.A patient with chronic granulomatous disease, who is complaining of fever, dermatitis, and diarrhea,
is seen in your clinic. The genetic form of this disease results in the inability to generate, primarily,
which one of the following? A. Superoxide
B. Hydrogen peroxideC. Reduced glutathione D. Hypochlorous acid
E. Nitric oxide
7.You diagnose a patient with ALS, and you discover that his father also had the disease. The patient
most likely had a mutation that leads to the inability to detoxify which one of the following?
A. Oxidized glutathione B. Hydrogen peroxide C. Nitric oxide
D. Hydroxyl radical E. Superoxide
8.Nitroglycerin and other medications used for treating erectile dysfunction work by forming NO, a
potent vasodilator (in low concentrations). In high concentrations, NO can produce RNOS that are
involved in which one of the following diseases? A. Ischemic heart disease
B. Infertility
C. Viral infections D. Fungal infections
E. Rheumatoid arthritis
9.An individual taking xenobiotics, such as alcohol, medications, and other foreign chemicals, can
increase their risk for free-radical injury through which one of the following mechanisms?
A. Reaction of O2 with CoQ
B. Induction of oxidases in peroxisomes
C. Induction of enzymes containing cytochrome P450 D. Production of ionizing radiation
E. Production of hydrogen peroxide in the manufacturing process, such that hydrogen peroxide is
present in the ingested materials
10.A balanced diet contains antioxidant molecules that help to protect cells from free-radical injury.
Which one of the following foods would contain high levels of an antioxidant? A. Citrus fruits
B. Enriched bread C. Dairy products D. Energy drinks
E. Green leafy vegetables ANSWERS TO REVIEW QUESTIONS
1.The answer is D. Pyridoxal phosphate is a water-soluble vitamin that is important for amino acid
and glycogen metabolism but has no role in protecting against free-radical damage. Ascorbate
(vitamin C), vitamin E, and β-carotene can all react with free radicals to terminate
chain
propagation, whereas SOD uses the superoxide radical as a substrate and converts it to hydrogen
peroxide, and glutathione peroxidase removes hydrogen peroxide from the cell, converting it towater.
2.The answer is B. SOD combines two superoxide radicals to produce hydrogen peroxide and
molecular oxygen. None of the other reactions is correct.
3.The answer is C. Vitamin E donates an electron and proton to the radical, thereby converting the
radical to a stable form (LOO• → LOOH). The vitamin thus prevents the free radical from
oxidizing another compound by extracting an H from that compound and propagating a free-radical
chain reaction. The radical form of vitamin E generated is relatively stable and actually donates
another electron and proton to a second free radical, forming oxidized vitamin E.
4.The answer is B. The Fenton reaction is the nonenzymatic donation of an electron from Fe2+ to
H2O2 to produce Fe3+, the hydroxyl radical, and hydroxide ion. Only Fe2+ or Cu1+ can be used in
this reaction; thus, the other answers are incorrect.
5.The answer is E. Histones coat nuclear DNA and protect it from damage by radicals.
Mitochondrial DNA lacks histones, so when radicals are formed, the DNA can be easily oxidized.
Answers A and B are nonsensical; SOD reduces radical concentrations, so the fact that it is
present in the mitochondria should help to protect the DNA from damage, not enhance it.
Glutathione also protects against radical damage, and if the nucleus lacks it, then one would
expect higher levels of nuclear DNA damage, not reduced levels. ROS can diffuse across
membranes, so answers C and D are incorrect. Other factors that increase mitochondrial DNA
damage relative to nuclear DNA are the proximity of mitochondrial DNA to the membrane, and the
fact that most radical species are formed from CoQ, which is found within the mitochondria.
6.The answer is A. The familial form of chronic granulomatous disease is caused by reduced
activity of NADPH oxidase, which generates superoxide from oxygen during the respiratory burst
in neutrophils, designed to destroy engulfed bacteria. Once superoxide is generated, other oxygen
radicals can be generated (such as hydrogen peroxide), but the generation of superoxide is the
primary event. Hypochlorous acid is also generated during the respiratory burst, but the enzyme
required is myeloperoxidase, which is not defective in chronic granulomatous disease. Nitric
oxide is generated by nitric oxide synthase and is not mutated in chronic granulomatous disease.
Reduced glutathione is the protective form of glutathione and can be generated using glutathione
peroxidase or glutathione reductase, neither of which is defective in chronic granulomatous
disease.
7.The answer is E. The familial form of ALS (Lou Gehrig disease) is caused by an inherited
mutation in SOD. In the absence of SOD, increased oxidative damage is possible to the neurons
because of the accumulation of superoxide, the substrate for SOD. Catalase will reduce hydrogen
peroxide levels, whereas glutathione peroxidase will convert reduced glutathione to oxidized
glutathione, using hydrogen peroxide as an electron donor. Nitric oxide does not accumulate in
Lou Gehrig disease. The hydroxyl radical may accumulate because of the accumulation of
superoxide, but the hydroxyl radical is not the direct cause of the disease. 8. The answer is E. RNOS are involved in neurodegenerative diseases such as Parkinson and in
chronic inflammatory diseases such as rheumatoid arthritis. Although RNOS has a minor role in
neutrophils (bacterial infections), ROS are strongly involved in fungal and viral infections as well
as ischemic heart disease and infertility.9. The answer is C. Most xenobiotics (e.g., alcohol, medications, other chemicals) induce the
cytochrome P450 family of enzymes to metabolize the xenobiotic. During the reactions catalyzed
by this family of enzymes, free radicals are sometimes generated and released from the enzyme
complex, which can lead to intracellular protein and lipid damage. The ingestion of alcohol,
medications, and other chemicals do not increase the frequency of oxygen reacting with CoQ, nor
do they induce oxidases in peroxisomes or produce ionizing radiation. Hydrogen peroxide is not
produced in the manufacturing of alcohol, most medications, or most chemicals. 10. The answer is A. Vitamins C and E and perhaps A act as antioxidants. Citrus fruits are high in
vitamin C. Enriched bread is high in niacin and folate. Fortified dairy products are high in vitamin
D (although raw milk is not), and green leafy vegetables are high in vitamin K and folate. Energy
drinks usually have sugar, caffeine, and B vitamins.Formation and Degradation of Glycogen 26
For additional ancillary materials related to this chapter, please visit thePoint. Glycogen is the storage form of glucose found in most types of cells. It is composed of glucosyl units
linked by α-1,4-glycosidic bonds, with α-1,6-branches occurring roughly every 8 to 10 glucosyl units
(Fig. 26.1). The liver and skeletal muscle contain the largest glycogen stores. The formation of glycogen from glucose is an energy-requiring pathway that begins, like most of
glucose metabolism, with the phosphorylation of glucose to glucose 6-phosphate. Glycogen synthesis
from glucose 6-phosphate involves the formation of uridine diphosphate glucose (UDP-glucose) and the
transfer of glucosyl units from UDP-glucose to the ends of the glycogen chains by the enzyme glycogen
synthase. Once the chains reach approximately 11 glucosyl units, a branching enzyme moves 6 to 8 unitsto form an α-(1,6)-branch.
Glycogenolysis, the pathway for glycogen degradation, is not the reverse of the biosynthetic pathway.
The degradative enzyme glycogen phosphorylase removes glucosyl units one at a time from the ends of
the glycogen chains, converting them to glucose 1-phosphate without resynthesizing UDP-glucose or
uridine triphosphate (UTP). A debranching enzyme removes the glucosyl residues near each branch
point.
Liver glycogen serves as a source of blood glucose. To generate glucose, the glucose 1-phosphate
produced from glycogen degradation is converted to glucose 6-phosphate. Glucose 6-phosphatase, an
enzyme found only in liver and kidney, converts glucose 6-phosphate to free glucose, which then enters
the blood.
Glycogen synthesis and degradation are regulated in liver by hormonal changes that signal the need
for blood glucose (see Chapter 19). The body maintains fasting blood glucose levels at approximately 80
mg/dL to ensure that the brain and other tissues that are dependent on glucose for the generation of
adenosine triphosphate (ATP) have a continuous supply. The lack of dietary glucose, signaled by a
decrease of the insulin/glucagon ratio, activates liver glycogenolysis and inhibits glycogen synthesis.
Epinephrine, which signals an increased use of blood glucose and other fuels for exercise or emergency
situations, also activates liver glycogenolysis. The hormones that regulate liver glycogen metabolism
work principally through changes in the phosphorylation state of glycogen synthase in the biosynthetic
pathway and glycogen phosphorylase in the degradative pathway.
In skeletal muscle, glycogen supplies glucose 6-phosphate for ATP synthesis in the glycolytic
pathway. Muscle glycogen phosphorylase is stimulated during exercise by the increase of adenosine
monophosphate (AMP), an allosteric activator of the enzyme, and also by phosphorylation. The
phosphorylation is stimulated by calcium released during contraction and by epinephrine, the fight-orflight hormone. Glycogen synthesis is activated in resting muscles by the elevation of insulin after
carbohydrate ingestion.
The neonate must rapidly adapt to an intermittent fuel supply after birth. Once the umbilical cord is
clamped, the supply of glucose from the maternal circulation is interrupted. The combined effect of
epinephrine and glucagon on the liver glycogen stores of the neonate rapidly restores glucose levels to
normal.
THE WAITING ROOM
A newborn baby girl, Gretchen C., was born after a 38-week gestation. Her 36-year-old mother
developed a significant viral infection that resulted in a prolonged severe loss of appetite with
nausea in the month preceding delivery, leading to minimal food intake. Fetal bradycardia (slower than
normal fetal heart rate) was detected at the end of each uterine contraction of labor, a sign of possible
fetal distress, and the baby was delivered emergently.
At birth, Gretchen was cyanotic (a bluish discoloration caused by a lack of adequate oxygenation of
tissues) and limp. She responded to several minutes of assisted ventilation. Her Apgar score of 3 was
low at 1 minute after birth, but it improved to a score of 7 at 5 minutes. The Apgar score is an objective
estimate of the overall condition of the newborn, determined at both 1 and 5 minutes after birth. A scoreof 7, 8, or 9 is normal. The highest score of 10 is less common. Physical examination in the nursery at 10 minutes showed a thin, malnourished female newborn. Her
body temperature was slightly low, her heart rate was rapid, and her respiratory rate of 55 breaths/minute
was elevated. Gretchen’s birth weight was only 2,100 g, compared with a normal value of >2,500 g. Her
length was 47 cm, and her head circumference was 33 cm (low normal). The laboratory reported that
Gretchen’s serum glucose level when she was unresponsive was 14 mg/dL. A glucose value <40 mg/dL
(2.5 mM) is considered to be abnormal in newborn infants.
At 5 hours of age, she was apneic (not breathing) and unresponsive. Ventilatory
resuscitation was
initiated and a cannula placed in the umbilical vein. Blood for a glucose level was drawn through this
cannula, and 5 mL of a 20% glucose solution was injected. Gretchen slowly responded to this therapy.
Jim B., a 19-year-old body builder, was rushed to the hospital emergency department in a coma.
One-half hour earlier, his mother had heard a loud crashing sound in the basement where Jim had
been lifting weights and completing his daily workout on the treadmill. She found her son on the floor
having severe jerking movements of all muscles (a grand mal seizure).
In the emergency department, the doctors learned that despite the objections of his family and friends,
Jim regularly used androgens, other anabolic steroids, and insulin in an effort to bulk up his muscle mass.
On initial physical examination, he was comatose, with occasional involuntary jerking movements of
his extremities. Foamy saliva dripped from his mouth. He had bitten his tongue and had lost bowel and
bladder control at the height of the seizure.
The laboratory reported a serum glucose level of 18 mg/dL (extremely low). The intravenous infusion
of 5% glucose (5 g of glucose per 100 mL of solution), which had been started earlier, was increased to
10%. In addition, 50 g of glucose was given over 30 seconds through the intravenous tubing.
Jim B.’s treadmill exercise and most other types of moderate exercise involving wholebody movement (running, skiing, dancing, tennis) increase the use of blood glucose and
other fuels by skeletal muscles. The blood glucose is normally supplied by the stimulation of liver
glycogenolysis and gluconeogenesis. I. Structure of Glycogen
Glycogen, the storage form of glucose, is a branched glucose polysaccharide composed of chains of
glucosyl units linked by α-1,4-bonds with α-1,6-branches every 8 to 10 residues (see Fig. 26.1). In a
molecule of this highly branched structure, only one glucosyl residue has an anomeric carbon that is not
linked to another glucose residue. This anomeric carbon at the beginning of the chain is attached to the
protein glycogenin. The other ends of the chains are called nonreducing ends (see Chapter 5). The
branched structure permits rapid degradation and rapid synthesis of glycogen because enzymes can work
on several chains simultaneously from the multiple nonreducing ends.
Glycogen is present in tissues as polymers of very high molecular weight (107 to 108 Da) collected
together in glycogen particles. The enzymes involved in glycogen synthesis and degradation and some of
the regulatory enzymes are bound to the surface of the glycogen particles.II. Function of Glycogen in Skeletal Muscle and Liver
Glycogen is found in most cell types, where it serves as a reservoir of glucosyl units for ATP generation
from glycolysis.
Glycogen is degraded mainly to glucose 1-phosphate (glucose 1-P), which is converted to glucose 6-
phosphate (glucose 6-P). In skeletal muscle and other cell types, glucose 6-P enters the glycolytic
pathway (Fig. 26.2). Glycogen is an extremely important fuel source for skeletal muscle when ATP
demands are high and when glucose 6-P is used rapidly in anaerobic glycolysis. In many other cell types,
the small glycogen reservoir serves a similar purpose; it is an emergency fuel