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.pdfOnly the three β- and α1-receptors are discussed here. The three β-receptors work through the adenylate
cyclase–cAMP system, activating a Gs-protein, which activates adenylate cyclase, and eventually PKA.
The β1-receptor is the major adrenergic receptor in the human heart and is primarily stimulated by
norepinephrine. On activation, the β1-receptor increases the rate of muscle contraction, in part because of
PKA-mediated phosphorylation of phospholamban (see Chapter 45). The β2-receptor is present in liver,
skeletal muscle, and other tissues and is involved in the mobilization of fuels (such as the release of
glucose through glycogenolysis). It also mediates vascular, bronchial, and uterine smooth muscle
contraction. Epinephrine is a much more potent agonist for this receptor than norepinephrine, whose
major action is neurotransmission. The β3-receptor is found predominantly in adipose tissue and to a
lesser extent in skeletal muscle. Activation of this receptor stimulates fatty acid oxidation and
thermogenesis, and agonists for this receptor may prove to be beneficial weight-loss agents. The α1-
receptors, which are postsynaptic receptors, mediate vascular and smooth muscle contraction. They workthrough the PIP2 system (see Chapter 11, Section III.B.2) via activation of a Gq-protein, and
phospholipase Cβ. This receptor also mediates glycogenolysis in liver. Deborah S., a patient with type 2 diabetes mellitus, is experiencing insulin resistance. Her
levels of circulating insulin are normal to high, although inappropriately low for her
elevated level of blood glucose. However, her insulin target cells, such as muscle and fat, do not
respond as those of a nondiabetic subject would to this level of insulin. For most type 2 patients,
the site of insulin resistance is subsequent to binding of insulin to its receptor; that is, the number
of receptors and their affinity for insulin is near normal. However, the binding of insulin at these
receptors does not elicit most of the normal intracellular effects of insulin discussed previously.
Consequently, there is little stimulation of glucose metabolism and storage after a highcarbohydrate meal and little inhibition of hepatic gluconeogenesis.
CLINICAL COM M ENTS
Deborah S. has type 2 diabetes mellitus, whereas Dianne A. has type 1 diabetes mellitus. Although
the pathogenesis differs for these major forms of diabetes mellitus, both cause varying degrees of
hyperglycemia. In type 1 diabetes mellitus, antibodies directed at a variety of proteins within the β-cells
gradually destroy the pancreatic β-cells. As insulin-secretory capacity by the β-cells gradually diminishes
below a critical level, the symptoms of chronic hyperglycemia develop rapidly. In type 2 diabetes
mellitus, these symptoms develop more subtly and gradually over the course of months or years. Eightyfive percent or more of type 2 patients are obese and, like Ivan A., have a high waist–hip ratio with
regard to adipose tissue disposition. This abnormal distribution of fat in the visceral (peri-intestinal)
adipocytes is associated with reduced sensitivity of fat cells, muscle cells, and liver cells to the actions
of insulin outlined previously. This insulin resistance can be diminished through weight loss, specifically
in the visceral depots. The development of type 2 diabetes mellitus, coupled with obesity and high blood
pressure, can lead to the metabolic syndrome, a common clinical entity that is
discussed in more detail in Section IV of the text.
Connie C. underwent an ultrasonographic (ultrasound) study of her upper abdomen, which showed
a 2.6-cm mass in the midportion of her pancreas. With this finding, her physicians decided that
further noninvasive studies would not be necessary before surgery and removal of the mass. At the time of
surgery, a yellow-white 2.8-cm mass consisting primarily of insulin-rich β-cells was resected from her
pancreas. No cytologic changes of malignancy were seen on microscopic examination of the surgical
specimen, and no evidence of malignant behavior by the tumor (such as local metastases) was found.
Connie had an uneventful postoperative recovery and no longer experienced the signs and symptoms of
insulin-induced hypoglycemia.
BIOCHEM ICAL COM M ENTSActions of Insulin. One of the important cellular responses to insulin is the reversal of glucagonstimulated phosphorylation of enzymes. Mechanisms proposed for this action include the inhibition
of adenylate cyclase, a reduction of cAMP levels, the stimulation of phosphodiesterase, the production of
a specific protein (insulin factor), the release of a second messenger from a bound glycosylated
phosphatidylinositol, and the phosphorylation of enzymes at a site that antagonizes PKA phosphorylation.
Not all of these physiologic actions of insulin occur in each of the insulin-sensitive organs of the body.
Insulin also is able to antagonize the actions of glucagon at the level of specific induction or
repression of key regulatory enzymes of carbohydrate metabolism. For instance, the rate of synthesis of
messenger RNA (mRNA) for phosphoenolpyruvate carboxykinase, a key enzyme of the gluconeogenic
pathway, is increased severalfold by glucagon (via cAMP) and decreased by insulin. Thus, all of the
effects of glucagon, even the induction of certain enzymes, can be reversed by insulin. This antagonism is
exerted through an insulin-sensitive hormone response element (IRE) in the promoter region of the genes.
Insulin causes repression of the synthesis of enzymes that are induced by glucagon. The general stimulation of protein synthesis by insulin (its mitogenic or growth-promoting effect)
appears to occur through a general increase in rates of mRNA translation for a broad spectrum of
structural proteins. These actions result from a phosphorylation cascade initiated by autophosphorylation
of the insulin receptor and ending in the phosphorylation of subunits of proteins that bind to and inhibit
eukaryotic protein synthesis initiation factors (eIFs). When phosphorylated, the inhibitory proteins are
released from the eIFs, allowing translation of mRNA to be stimulated. In this respect, the actions of
insulin are similar to those of other hormones that act as growth factors and that also have receptors with
tyrosine kinase activity.
In addition to signal transduction, activation of the insulin receptor mediates the internalization of
receptor-bound insulin molecules, increasing their subsequent degradation. Although unoccupied
receptors can be internalized and eventually recycled to the plasma membrane, the receptor can be
irreversibly degraded after prolonged occupation by insulin. The result of this process, referred to as
receptor downregulation, is an attenuation of the insulin signal. The physiologic
importance of receptor
internalization on insulin sensitivity is poorly understood but could lead eventually to chronic
hyperglycemia. KEY CONCEPTS
Glucose homeostasis is directed toward the maintenance of constant blood glucose levels.
Insulin and glucagon are the two major hormones that regulate the balance between fuel mobilization
and storage. They maintain blood glucose levels near 80 to 100 mg/dL, despite varying
carbohydrate intake during the day.
If dietary intake of all fuels is in excess of immediate need, it is stored as either glycogen or fat.
Conversely, appropriately stored fuels are mobilized when demand requires. Insulin is released in response to carbohydrate ingestion and promotes glucose use as a fuel and
glucose storage as fat and glycogen. Insulin secretion is regulated principally by blood glucose
levels.
Glucagon promotes glucose production via glycogenolysis (glycogen degradation) and gluconeogenesis (glucose synthesis from amino acids and other noncarbohydrate precursors).Glucagon release is regulated principally through suppression by rising levels of glucose and rising
levels of insulin. Glucagon levels decrease in response to a carbohydrate meal and increase during
fasting. Increased levels of glucagon relative to insulin stimulate the release of fatty acids from
adipose tissue.
Glucagon acts by binding to a receptor on the cell surface, which stimulates the synthesis of the
intracellular second messenger, cAMP.
cAMP activates PKA, which phosphorylates key regulatory enzymes, activating some and inhibiting
others.
Insulin acts via a receptor tyrosine kinase and leads to the dephosphorylation of the key enzymes
phosphorylated in response to glucagon.
Hormones that antagonize insulin action, known as insulin counterregulatory hormones, include
glucagon, epinephrine, and cortisol.
Diseases discussed in this chapter are summarized in Table 19.4. REVIEW QUESTIONS—CHAPTER 19
1.A patient with type 1 diabetes mellitus takes an insulin injection before eating dinner but then gets
distracted and does not eat. Approximately 3 hours later, the patient becomes shaky, sweaty, and
confused. These symptoms have occurred because of which one of the following? A. Increased glucagon release from the pancreas
B. Decreased glucagon release from the pancreasC. High blood glucose levels D. Low blood glucose levels
E. Elevated ketone-body levels
2.Concerning our patient in question 19.1, if the patient had fallen asleep before recognizing the
symptoms, the patient could lose consciousness while sleeping. If that were to occur and paramedics
were called to help the patient, the administration of which one of the following would help to
reverse this effect? A. Insulin
B. Normal saline C. Triglycerides D. Epinephrine
E. Short-chain fatty acids
3.Caffeine is a potent inhibitor of the enzyme cAMP phosphodiesterase. Which one of
the following
consequences would you expect to occur in the liver after drinking two cups of strong espresso
coffee?
A.A prolonged response to insulin
B.A prolonged response to glucagon
C.An inhibition of PKA
D.An enhancement of glycolytic activity
E.A reduced rate of glucose export to the circulation
4.Assume that an increase in blood glucose concentration from 5 to 10 mM would result in insulin
release by the pancreas. A mutation in pancreatic glucokinase can lead to MODY because of which
one of the following within the pancreatic β-cell? A. A reduced ability to raise cAMP levels
B. A reduced ability to raise ATP levels
C. A reduced ability to stimulate gene transcription D. A reduced ability to activate glycogen degradation
E. A reduced ability to raise intracellular lactate levels
5.Which one of the following organs has the highest demand for glucose as a fuel? A. Brain
B. Muscle (skeletal) C. Heart
D. Liver E. Pancreas
6.Glucagon release does not alter muscle metabolism because of which one of the following?
A. Muscle cells lack adenylate cyclase. B. Muscle cells lack PKA.
C. Muscle cells lack G-proteins. D. Muscle cells lack GTP.
E. Muscle cells lack the glucagon receptor.
7.A male patient with fasting hypoglycemia experiences tremors, sweating, and a rapid heartbeat.These symptoms have been caused by the release of which one of the following hormones?
A. Insulin
B. Epinephrine C. Cortisol D. Glucagon
E. Testosterone
8.A patient has tried many different “fad” diets to lose weight. Which one of the following meals
would lead to the lowest level of circulating glucagon shortly after the meal? A. High-fat meal
B. Low-protein meal C. Low-fat meal
D. Low-carbohydrate meal E. High-carbohydrate meal
9.A 45-year-old patient was admitted to the hospital in a coma caused by severe hyperglycemia and
was treated with insulin and fluids. He has been placed on longand short-acting insulin injected
daily to control his blood glucose levels. What test could be ordered at this point to determine if the
patient has type 1 versus type 2 diabetes? A. C-peptide level
B. Insulin level
C. Insulin antibodies D. Proglucagon level E. Glucagon level
10.The patient in the previous question had very high blood glucose levels, and his urine also contained
high blood glucose levels. The high blood glucose levels can lead to cerebral dysfunction owing to
which one of the following?
A.Dehydration
B.Reduced lipid concentrations in the blood
C.Increased lipid concentrations in the blood
D.Hyperhydration
E.High ammonia levels
Low ammonia levels
ANSWERS TO REVIEW QUESTIONS
1. The answer is D. Once insulin is injected, glucose transport into the peripheral tissues will be
enhanced. If the patient does not eat, the normal fasting level of glucose will drop even further
resulting from the injection of insulin, which increases the movement of glucose into muscle and
fat cells. The patient becomes hypoglycemic, as a result of which epinephrine is released from the
adrenal medulla. This, in turn, leads to the signs and symptoms associated with high levels of
epinephrine in the blood. Answers A and B are incorrect because as glucose levels drop,
glucagon will be released from the pancreas to raise blood glucose levels, which would alleviate
the symptoms. Answer E is incorrect because ketone body production does not producehypoglycemic symptoms, nor would ketone bodies be significantly elevated only a few hours after
the insulin shock the patient is experiencing.
2. The answer is D. When the patient took the insulin, the hormone stimulated glucose transport into
the muscle and fat cells. This had the effect of lowering blood glucose levels, and, by not eating,
the patient became severely hypoglycemic to the point that the blood glucose levels were below
the K
m for the glucose transporters for the nervous system. The administration of epinephrine will
stimulate the liver to release glucose, via glycogenolysis and gluconeogenesis, and will raise
blood glucose levels sufficiently to overcome the insulin-induced hypoglycemia. The addition of
insulin would only exacerbate the problem. Addition of triglycerides will not aid the nervous
system because the fatty acids cannot cross the blood–brain barrier. Normal saline will not add
nutrients for the nervous system. Short-chain fatty acids also cannot enter the nervous system.
3. The answer is B. When glucagon binds to its receptor, the enzyme adenylate cyclase is eventually
activated (through the action of G-proteins), which raises cAMP levels in the cell. The cAMP
phosphodiesterase opposes this rise in cAMP and hydrolyzes cAMP to 5′-AMP. If the phosphodiesterase is inhibited by caffeine, cAMP levels would stay elevated for an extended
period of time, enhancing the glucagon response. The glucagon response in liver is to export
glucose (thus, E is incorrect) and to inhibit glycolysis (thus, D is incorrect). cAMP activates PKA,
making answer C incorrect as well. The effect of insulin is to reduce cAMP levels (thus, A is
incorrect).
4. The answer is B. Insulin release is dependent on an increase in the ATP/ADP ratio within the
pancreatic β-cell. In MODY, the mutation in glucokinase results in a less active glucokinase at
glucose concentrations that normally stimulate insulin release. Thus, higher concentrations of
glucose are required to stimulate glycolysis and the TCA cycle to effectively raise the ratio of
ATP to ADP. Answer A is incorrect because cAMP levels are not related to the mechanism of
insulin release. Answer C is incorrect because initially transcription is not involved because
insulin release is caused by exocytosis of preformed insulin in secretory vesicles. Answer D is
incorrect because the pancreas will not degrade glycogen under conditions of high blood glucose,
and answer E is incorrect because lactate does not play a role in stimulating insulin release.
5.The answer is A. The brain requires glucose because fatty acids cannot readily cross the blood–
brain barrier to enter neuronal cells. Thus, glucose production is maintained at an adequate level
to allow the brain to continue to burn glucose for its energy needs. The other organs listed as
possible answers can switch to the use of alternative fuel sources (lactate, fatty acids, amino
acids) and are not as dependent on glucose for their energy requirements as is the brain.
6.The answer is E. Muscle does not express glucagon receptors, so they are refractory to the
actions of glucagon. Muscle does, however, contain GTP (made via the TCA cycle), G-proteins,
PKA, and adenylate cyclase (epinephrine stimulation of muscle cells raises cAMP levels and
activates PKA).
7.The answer is B. Insulin does lower blood glucose and cause hypoglycemia, but this would
produce symptoms of fatigue, confusion, and blurred vision. When hypoglycemia is present, the
body releases glucagon, cortisol, epinephrine, and norepinephrine to raise blood glucose levels.
Epinephrine causes tremors, sweating, and elevated pulse rate (fight-or-flight response).Testosterone is not involved.
8.The answer is E. Carbohydrates are more rapidly absorbed and have the greatest and most rapid
influence on elevating blood glucose levels, which stimulates insulin production and reduces
glucagon secretion from the pancreas. In addition, both elevated blood glucose and elevated
insulin levels suppress glucagon release. Many amino acids stimulate glucagon release, and a
low-protein diet would still lead to glucagon secretion from the pancreas to a greater extent than a
high-carbohydrate diet. Highor low-fat diets will not stimulate insulin release, and because
gluconeogenesis is required to synthesize glucose under such diets, glucagon secretion would still
be occurring.
9.The answer is A. Type 1 diabetes mellitus is caused by a lack of insulin (therefore, neither
proinsulin nor C-peptide is produced as well), whereas type 2 diabetes mellitus is cellular
resistance to secreted insulin (therefore, endogenous insulin and C-peptide are still produced in
patients with type 2 diabetes). Measurement of an absolute insulin level would not be helpful
because the patient is injecting insulin each day. However, if the patient is still producing insulin,
he would also produce the C-peptide and would be classified as having type 2 diabetes. If Cpeptide levels are not detected, the patient is classified as having type 1 diabetes. Individuals with
type 1 diabetes can have islet cell antibodies in their blood, but not insulin antibodies. The
presence of antibodies against insulin in the blood would lead to a reduced response to insulin, or
a form of type 2 diabetes. The measurement of glucagon or proglucagon levels would not
differentiate type 1 from type 2 diabetes because both glucagon and proglucagon would still be
produced in individuals with diabetes. The levels of glucagon secreted in both types of diabetes is
similar.
10. The answer is A. The elevated glucose in the blood leads to an osmotic diuresis because water
will leave cells to enter the blood and urine in order to reduce the glucose concentration in those
fluids. As the water leaves the tissues and enters the urine, blood volume also decreases, leading
to even higher blood glucose concentrations. The loss of water leads to severe dehydration and to
reduced blood flow to the brain (because of reduced blood volume), which will lead to cerebral
dysfunction. The brain cannot use lipids as an energy source, so altering lipid concentrations in the
blood will not affect cerebral function. The cerebral dysfunction is actually occurring under higher
than normal blood glucose concentrations; it is the reduced blood volume that leads to the
dysfunction. Carbohydrates do not contain a nitrogen group, so they do not produce ammonia. High
levels of ammonia can cause cerebral dysfunction, but it does not come about because of high
blood glucose levels.20
Cellular Bioenergetics: Adenosine Triphosphate and O2
For additional ancillary materials related to this chapter, please visit thePoint. Bioenergetics refers to cellular energy transformations.
The ATP–ADP Cycle. In cells, the chemical bond energy of fuels is transformed into the physiologic
responses that are necessary for life. The central role of the high-energy phosphate bonds of adenosine
triphosphate (ATP) in these processes is summarized in the ATP–ADP (adenosine diphosphate) cycle
(Fig. 20.1). To generate ATP through cellular respiration, fuels are degraded by oxidative reactions that
transfer most of their chemical bond energy to nicotinamide adenine dinucleotide (NAD+) and flavin
adenine dinucleotide (FAD) to generate the reduced form of these coenzymes, NADH and FAD(2H).
When NADH and FAD(2H) are oxidized by oxygen (O2) in the electron-transport chain (ETC), the energy
is used to regenerate ATP in the process of oxidative phosphorylation. Energy available from cleavage
of the high-energy phosphate bonds of ATP can be used directly for mechanical work (e.g., muscle
contraction) or for transport work (e.g., a Na+ gradient generated by Na+,K+-ATPase). It can also be
used for biochemical work (energy-requiring chemical reactions), such as anabolic pathways
(biosynthesis of large molecules such as proteins) or detoxification reactions. Phosphoryl transfer
reactions, protein conformational changes, and the formation of activated intermediates containing
high-energy bonds (e.g., uridine diphosphate [UDP]-sugars) facilitate these energy transformations.
Energy released from foods that is not used for work against the environment is
transformed into heat.ATP Homeostasis. Fuel oxidation is regulated to maintain ATP homeostasis (“homeo,” same; “stasis,”
state). Regardless of whether the level of cellular fuel use is high (with increased ATP consumption) or
low (with decreased ATP consumption), the available ATP within the cell is maintained at a constant
level by appropriate increases or decreases in the rate of fuel oxidation. Problems in ATP homeostasis
and energy balance occur in obesity, hyperthyroidism, and myocardial infarction (MI).
Energy from Fuel Oxidation. Fuel oxidation is exergonic; it releases energy. The maximum quantity of
energy released that is available for useful work (e.g., ATP synthesis) is called ΔG0ʹ, the change in
Gibbs free energy at pH 7.0 under standard conditions. Fuel oxidation has a negative ΔG0ʹ; that is, the
products have a lower chemical bond energy than the reactants, and their formation is energetically
favored. ATP synthesis from ADP and inorganic phosphate (Pi) is endergonic: It requires energy and has
a positive ΔG0ʹ. To proceed in our cells, all pathways must have a negative ΔG0ʹ. How is this
accomplished for anabolic pathways such as glycogen synthesis? These metabolic pathways incorporate
reactions that expend high-energy bonds to compensate for the energy-requiring steps. Because the ΔG0ʹ
values for a sequence of reactions are additive, the overall pathway becomes energetically favorable.
Fuels are oxidized principally by donating electrons to NAD+ and FAD, which then donate electrons
to O2 in the ETC. The caloric value of a fuel is related to its ΔG0ʹ for transfer of electrons to O2, and its
reduction potential, E0ʹ (a measure of its willingness to donate, or accept, electrons). Because fatty acids
are more reduced than carbohydrates, they have a higher caloric value. The high affinity of O2 for
electrons (a high positive reduction potential) drives fuel oxidation forward, with release of energy that
can be used for ATP synthesis in oxidative phosphorylation. However, smaller amounts of ATP can be
generated without the use of O2 in anaerobic glycolysis.
Fuel oxidation can also generate NADPH, which usually donates electrons to biosynthetic pathways
and detoxification reactions. For example, in some reactions catalyzed by oxygenases, NADPH is the
electron donor and O2 is the electron acceptor. THE WAITING ROOM
Otto S. is a 26-year-old medical student who has completed his first year of medical school. He is
5 ft 10 in tall and began medical school weighing 154 lb, within his ideal weight range (see
Chapter 1). By the time he finished his last examination in his first year, he weighed 187 lb. He had
calculated his basal metabolic rate (BMR) at approximately 1,680 kilocalorie [kcal] and his energyexpenditure for physical exercise equal to 30% of his BMR. He planned on returning to his pre–medical
school weight in 6 weeks over the summer by eating 576 kcal less each day and playing 7 hours of tennis
every day. However, he did a summer internship instead of playing tennis. When Otto started his second
year of medical school, he weighed 210 lb.
Stanley T. is a 26-year-old man who noted heat intolerance, with heavy sweating, heart
palpitations, and tremulousness. Over the past 4 months, he has lost weight in spite of a good
appetite. He is sleeping poorly and describes himself as feeling “jittery inside.” On physical examination, his heart rate is rapid (116 beats/minute) and he appears restless and
fidgety. His skin feels warm, and he is perspiring profusely. A fine hand tremor is observed as he extends
his arms in front of his chest. His thyroid gland appears to be diffusely enlarged and, on palpation, is
approximately three times normal size. Thyroid function tests confirm that Mr. T.’s thyroid gland is
secreting excessive amounts of the thyroid hormones tetraiodothyronine (T4) and triiodothyronine (T3), the
major thyroid hormones present in the blood.
To assess for thyroid function, one must understand how the hormones T3 and T4 are released from the thyroid (see Chapter 41). The hypothalamus and the pituitary gland both
monitor the level of free T3 in the blood bathing them. When the concentration of free T3 in the
blood drops, the pituitary releases thyroid-stimulating hormone (TSH), which stimulates the
thyroid to release T3 and T4. The pituitary is under the control of the hypothalamus, which releases
TSH-releasing hormone (TSHRH) under the appropriate conditions. Thus, if one notices low
serum T3 or T4 levels, it may represent a thyroid or pituitary problem. Understanding the
physiology enables the appropriate tests to be run to determine where the defect lies.
T
3 and T4 are measured using sensitive techniques that involve antibody recognition (radioimmunoassay; see Chapter 41). TSH levels can be determined in a similar fashion using a
sandwich technique (which requires the use of two distinct antibodies that recognize TSH).
Through the appropriate interpretation of these tests, one can determine if thyroid or pituitary
function is impaired and design treatment accordingly.
Cora N. is a 64-year-old female who had a myocardial infarction (MI; often referred to as a “heart
attack”) 8 months ago. Although she has managed to lose 6 lb since the MI, she remains overweight
and has not reduced the fat content of her diet adequately. The graded aerobic exercise program she
started 5 weeks after her infarction is now followed irregularly, falling far short of the cardiac
conditioning intensity prescribed by her cardiologist. She is readmitted to the hospital cardiac care unit
after experiencing a severe “viselike pressure” in the midchest area while cleaning ice from the
windshield of her car. The electrocardiogram shows evidence of a new anterior wall MI. Signs and
symptoms of left ventricular failure are present.
Cora N. suffered a heart attack 8 months ago and had a significant loss of functional heart
muscle. She occasionally gets pain while walking. The pain she is experiencing is calledangina pectoris and is a crushing or constricting pain located in the center of the chest, often
radiating to the neck or arms (see Ann J., Chapters 6 and 7). The most common cause of angina is
partial blockage of coronary arteries from atherosclerosis. The heart muscle cells beyond the
block receive an inadequate blood flow and oxygen, and they die when ATP production falls too
low.
I. Energy Available to Do Work
The basic principle of the ATP–ADP cycle is that fuel oxidation generates ATP, and
hydrolysis of ATP to
ADP provides the energy to perform most of the work required in the cell. ATP has, therefore, been called
the energy currency of the cells. To keep up with the demand, we must constantly replenish our ATP
supply through the use of oxygen (O2) for fuel oxidation.
The amount of energy from ATP cleavage available to do useful work is related to the difference in
energy levels between the products and substrates of the reaction and is called the change in Gibbs free
energy, ΔG (Δ, difference; G, Gibbs free energy). In cells, the ΔG for energy production from fuel
oxidation must be greater than the ΔG of energy-requiring processes, such as protein synthesis and muscle
contraction, for life to continue.
The heart is a specialist in the transformation of ATP chemical bond energy into mechanical
work. Each single heartbeat uses approximately 2% of the ATP in the heart. If the heart
were not able to regenerate ATP, all its ATP would be hydrolyzed in <1 minute. Because the
amount of ATP required by the heart is so high, it must rely on the pathway of oxidative
phosphorylation for generation of this ATP. In Cora N.’s heart, hypoxia (the lack of oxygen) is
affecting her ability to generate ATP. A. The High-Energy Phosphate Bonds of ATP
The amount of energy released or required by bond cleavage or formation is determined by the chemical
properties of the substrates and products. The bonds between the phosphate groups in ATP are called
phosphoanhydride bonds (Fig. 20.2). When these bonds are hydrolyzed, energy is released because the
products of the reaction (ADP and phosphate) are more stable, with lower bond energies, than the
reactants (ATP and water [H2O]). The instability of the phosphoanhydride bonds arises from their
negatively charged phosphate groups, which repel each other and strain the bonds between them. It takes
energy to make the phosphate groups stay together. In contrast, there are fewer negative charges in ADP to
repel each other. The phosphate group as a free anion is more stable than it is in ATP because of an
increase in resonance structures (i.e., the electrons of the oxygen double bond are shared by all the oxygen
atoms). As a consequence, ATP hydrolysis is energetically favorable and proceeds with release of energy
as heat.In the cell, ATP is not hydrolyzed directly. Energy released as heat from ATP hydrolysis cannot be
transferred efficiently into energy-requiring processes such as biosynthetic reactions or maintenance of an
ion gradient. Instead, cellular enzymes transfer the phosphate group to a metabolic intermediate or protein
that is part of the energy-requiring process (a phosphoryl transfer reaction). B. Change in Free Energy (ΔG) during a Reaction
How much energy can be obtained from ATP hydrolysis to do the work required in the cell? The
maximum amount of useful energy that can be obtained from a reaction is called ΔG— the change in
Gibbs free energy. The value of ΔG for a reaction can be influenced by the initial concentration of
substrates and products, by temperature, pH, and by pressure. The ΔG0 for a reaction refers to the energy
change for a reaction starting at 1 M substrate and product concentrations and proceeding to equilibrium