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Prion diseases are categorized as transmissible spongiform encephalopathies, which are
neurodegenerative diseases characterized by spongiform degeneration and astrocytic gliosis
in the central nervous system. Frequently, protein aggregates and amyloid plaques are seen. These
aggregates are resistant to proteolytic degradation.The prion protein is normally found in the brain and is encoded by a gene that is a normal component
of the human genome. The disease-causing form of the prion protein has the same amino acid composition
but is folded into a different conformation that aggregates into multimeric protein complexes resistant to
proteolytic degradation (Fig. 7.26). The normal conformation of the prion protein has been designated
PrPc and the disease-causing form as PrPSc (Sc for the prion disease known as scrapie in sheep).
Although PrPSc and PrPc have the same amino acid composition, the PrPSc conformer is substantially
enriched in β-sheet structure compared with the normal PrPc conformer, which has little or no β-sheet
structure and is approximately 40% α-helix. This difference favors the aggregation of PrPSc into
multimeric complexes. These two conformations presumably have similar energy levels. Fortunately,
spontaneous refolding of PrP proteins into the PrPSc conformation is prevented by a large activation
energy barrier that makes this conversion extremely slow. Thus, very few molecules of PrPSc are
normally formed during a lifetime.
The infectious disease occurs with the ingestion of PrPSc dimers in which the prion protein is already
folded into the high β-structure. These PrPSc proteins are thought to act as a template to lower the
activation energy barrier for the conformational change, causing native proteins to refold into the PrPSc
conformation much more rapidly (much like the role of chaperonins). The refolding initiates a cascade as
each new PrPSc formed acts as a template for the refolding of other molecules. As the number of PrPSc
molecules increases in the cell, they aggregate into a multimeric assembly that is resistant to proteolytic
digestion. Once an aggregate begins to form, the concentration of free PrPSc decreases, thereby shifting the
equilibrium between PrP and PrPSc to produce more PrPSc. This leads to further aggregate formation
through the shift in equilibrium.
Familial prion diseases are caused by point mutations in the gene encoding the Pr protein
(point mutations are changes in one base in the DNA nucleotide sequence). The diseases
have a various names related to the different mutations and the clinical syndrome (e.g.,
Gerstmann-Straüssler-Scheinker disease and fCJD). fCJD arises from an inherited mutation and
has an autosomal dominant pedigree. It typically presents in the fourth decade of life. The mutationlowers the energy required for the protein to fold into the PrPSc conformation; thus, the conversion
occurs more readily. It is estimated that the rate of generating prion disease by refolding of PrPc in
the normal cell is about 3,000 to 4,000 years. Lowering of the activation energy for refolding by
mutation presumably decreases this time to the observed 30to 40-year prodromal period.
Sporadic CJD may arise from somatic cell mutation or rare spontaneous refoldings that initiate a
cascade of refolding into the PrPSc conformation. The sporadic form of the disease accounts for
85% of all cases of CJD. CLINICAL COM M ENTS
Will S. Will S. continues to experience severe low back and lower extremity pain for many hours
after admission. The diffuse pains of sickle cell crises are believed to result from occlusion of
small vessels in a variety of tissues, thereby depriving cells of oxygen and cause ischemic or anoxic
damage to the tissues. In a sickle cell crisis, long hemoglobin polymers form, causing the red blood cells
to become distorted and change from a biconcave disc to an irregular shape, such as a sickle (for which
the disease was named) or a stellate structure (Fig. 7.27). The aggregating Hb polymers damage the red
blood cell membrane and promote aggregation of membrane proteins, leading to increased permeability
of the red blood cell and dehydration. Surface charge and antigens of red blood cells are carried on the
transmembrane proteins glycophorin and band 3 (the erythrocyte anion exchange channel, see Chapter 10).
Hemoglobin S binds tightly to the cytoplasmic portion of band 3, contributing to further polymer
aggregation and uneven distribution of negative charge on the sickle cell surface. As a result, the affected
cells adhere to endothelial cells in capillaries, occluding the vessel and decreasing blood flow to the
distal tissues. The subsequent hypoxia in these tissues causes cellular damage, severe ischemic pain, and
even death.
The sickled cells are sequestered and destroyed mainly by phagocytic cells, particularly those in the
spleen. An anemia results as the number of circulating red blood cells decreases and bilirubin levels risein the blood as hemoglobin is degraded.
After a few days of treatment, Will’s crisis was resolved. In the future, should Will S. suffer a
cerebrovascular accident (stroke) as a consequence of sickle cell disease causing damage to one of the
large cerebral arteries, or have recurrent life-threatening episodes of generalized vaso-occlusion in
microvessels, a course of long-term maintenance blood transfusions to prevent cerebrovascular accidents
may be indicated. Iron chelation would likely have to accompany such a program to prevent or delay the
development of iron overload. Although a few individuals with this disease have survived into the sixth
decade, mean survival is probably into the fourth decade. Death usually results from infection, renal
failure, and/or cardiopulmonary disease.
Anne J. Mrs. J.’s diagnosis of an acute MI was partly based on measurements of cTnT (the cardiac
isozyme of TnT, a subunit of the regulatory protein troponin). Early diagnosis is critical for a
decision on the type of therapeutic intervention to be used. Serum cTnT is a highly specific marker of
myocardial injury. It is typically detected in an acute MI within 3 to 5 hours after onset of symptoms, is
positive in most cases within 8 hours, and approaches 100% sensitivity at 10 to 12 hours. It remains
elevated for 5 to 10 days.
Mrs. J. stayed in the hospital until she had recovered from her catheterization and was stable on her
medication. She was discharged on a low-fat diet and medications for her heart disease and was asked to
participate in the hospital’s cardiac rehabilitation program for patients recovering from a recent heart
attack. Her physician scheduled regular examinations for her.
Troponin is a heterotrimeric protein involved in the regulation of striated and cardiac
muscle contraction. Most troponin in the cell is bound to the actin–tropomyosin complex in
the muscle fibril. The three subunits of troponin consist of TnC, TnT, and TnI, each with a specific
function in the regulatory process. TnT and TnI exist as different isoforms in cardiac and skeletal
muscle (sequences with a different amino acid composition), thus allowing the development of
specific antibodies against each form. As a consequence, either cTnT or cTnI may be rapidly
measured in blood samples by immunoassay with a high degree of specificity.
Amy L. Amy L. has amyloidosis/AL, which is characterized by deposition of amyloid fibers
derived principally from the variable region of λ- or κ-immunoglobulin light chains. Increased
amounts of the fragments of the light chains called Bence-Jones proteins appeared in her urine. Fibril
deposition in the ECM of her kidney glomeruli has resulted in mild renal failure. Deposition of amyloid in
the ECM of her heart muscle resulted in thickened heart muscle seen on an echocardiogram. In addition to
other signs of right-sided heart failure, she had peripheral edema. The loss of weight may have been
caused by infiltrations of amyloid in the gastrointestinal tract or by constipation and diarrhea resulting
from involvement of the autonomic nervous system. Treatment may be directed against the plasma cell
proliferation and against the symptomatic results of organ dysfunction and is only partially successful. The
most effective approach involves the use of stem cell transplantation in concert with melphalan (an
antineoplastic agent). If the patient is not a candidate for transplantation, then melphalan with
dexamethasone (a steroid) can be used. Renal transplantation and cardiac transplantation have beenperformed in patients with renal and cardiac amyloidosis, respectively, with some success.
During Amy’s evaluation, she developed a cardiac arrhythmia that was refractory to treatment. The
extensive amyloid deposits in her heart had disrupted the flow of electrical impulses in the conduction
system of the heart, ultimately resulting in cardiac arrest. On autopsy, amyloid deposits were found within
the heart, tongue, liver, adipose tissue, and every organ examined except the central nervous system,
which had been protected by the blood–brain barrier.
Dianne A. Dianne A.’s HbA1c of 8.5% was above the normal level of <6.0% of total hemoglobin.
Glycosylation is a nonenzymatic reaction that occurs with a rate directly proportionate to the
concentration of glucose in the blood. In the normal range of blood glucose concentrations (~80 to 140
mg/dL, depending on time after a meal), up to 6% of the hemoglobin is glycosylated to form HbA1c.
Hemoglobin turns over in the blood as red blood cells are phagocytosed and their hemoglobin degraded
and new red blood cells enter the blood from the bone marrow. The average lifespan of a red blood cell
is 120 days. Thus, the extent of hemoglobin glycosylation is a direct reflection of
the average serum
glucose concentration to which the cell has been exposed over its 120-day lifespan. Dianne A.’s elevated
HbA1c indicates that her average blood glucose level has been elevated over the preceding 3 to 4 months.
An increase of Dianne A.’s insulin dosage would decrease her hyperglycemia and, over time, decrease
her HbA1c level. BIOCHEM ICAL COM M ENTS
The Basics of Hemoglobin Cooperativity. Using X-ray diffraction to study both the oxygenated
and deoxygenated forms of hemoglobin, it is now possible to describe the change in conformation
at the molecular level when oxygen binds to hemoglobin. We will present a simplistic approach here,
looking at interactions that the β-subunit experiences and having oxygen bind initially to one of the two β-
subunits in the hemoglobin tetramer. All of the subunits of hemoglobin contain eight helices, labeled A
through H, with A representing the helix at the amino-terminal end. The deoxygenated form of hemoglobin
is stabilized by the following interactions, which are also depicted in Figure 7.28:1. Asp94 (of the F helix of the β-chain), through its carboxylate side chain, forms a salt bridge (ionic
interaction) with the charged imidazole group of His146, which is the carboxy-terminal amino acid
in the β-chain. Part of the Bohr effect is realized through this interaction because as the pH is
reduced, the possibility that His146 is protonated is increased.
2.The carbonyl carbon of Val98 forms a hydrogen bond with the tyrosine hydroxyl group at position
145(the next-to-last amino acid in the β-chain). The effect of these first two interactions is to
position helices F and H in close proximity to each other.
3.The free carboxylate group of His146 (of the β-chain) forms a salt bridge with the ε-amino group of
the side chain of Lys40 of the corresponding α-chain. This salt bridge allows communication
between these two subunits and places the β-chain H helix close to the α-subunit. In the β-chain, the proximal His92 (the eighth amino acid of the F helix [F8]) forms a coordinate
covalent bond with the iron in heme and, in so doing, pulls the iron slightly out of the plane of the heme
ring. These interactions are all occurring in the deoxygenated state.
So what happens when oxygen binds to a β-subunit? Oxygen binds to the iron in a bent conformation.
The binding event triggers the movement of the iron into the plane of the heme ring. Because the iron is
also covalently linked to histidine F8, the entire F helix, and the FG corner (where the F and G helices
meet), also move.
1.Asp94 is in the F helix. As it is moved (because of the movement of the F helix), it can no longer
form a salt bridge with the imidazole of His146, which weakens the interactions between the F and
H helices.
2.Valine 98 is in the FG corner of the β-subunit, so as that moves, the hydrogen bond formed between
Val98 and Tyr145 (at the end of the H helix) is also broken.3. Due in part to the loss of interactions between the F and H helices, the H helix moves and, in so doing, breaks the ionic interaction between His146 and Lys40 of the α-subunit. This, along with the
steric hindrance of the heme ring and His92, leads to a rotation of one αβ-dimer relative to the other
αβ-dimer and will allow oxygen to bind more readily to the other subunits. The
rotation of dimers
also forces 2,3-BPG to leave its binding site on hemoglobin, which will favor oxygen binding.
The disruption of the bonds listed previously has to occur for oxygen to bind. This is why it takes a
high concentration of oxygen to get the first oxygen bound to hemoglobin. At low oxygen levels, the
oxygen can dissociate from the iron, which allows the T form to re-form and allow the salt bridges and
hydrogen bonds, which stabilize the deoxygenated form, to re-form. If the oxygen concentration is high,
such that the iron is continuously occupied with oxygen, the events described earlier are more likely to
occur, and the oxygenation of hemoglobin will occur. KEY CONCEPTS
There are four levels of protein structure:
The primary structure (linear sequence of amino acids within the protein) The secondary structure (a regular, repeating pattern of hydrogen bonds that stabilize a particular
structure)
The tertiary structure (the folding of the secondary structure elements into a three-dimensional
conformation)
The quaternary structure (the association of subunits within a protein)
The primary structure of a protein determines the way a protein folds into a unique threedimensional structure, called its native conformation.
When globular proteins fold, the tertiary structure generally forms a densely packed hydrophobic
core with polar amino acid side chains on the outside, facing the aqueous environment.
The tertiary structure of a protein consists of structural domains, which may be similar between
different proteins, and performs similar functions for the different proteins. Certain structural domains are binding sites for specific molecules, called a ligand, or for other
proteins.
The affinity of a binding site for its ligand is quantitatively characterized by an association or
affinity constant, Ka (or dissociation constant, Kd).
Protein denaturation is the loss of tertiary (and/or secondary) structure within a protein, which can
be caused by heat, acid, or other agents that interfere with hydrogen bonding and usually causes a
decrease in solubility (precipitation).
Diseases discussed in this chapter are summarized in Table 7.1.REVIEW QUESTIONS—CHAPTER 7
1.One theory of amyloid fibril formation is that sections of α-helical structure are converted to β-
sheets. Such regions of the amyloid proteins would most likely lack which one of the following
amino acids? A. Cysteine B. Methionine C. Proline D. Leucine E. Isoleucine
2.In order for lipid-based hormones such as testosterone or estrogen to be transported in the
bloodstream, they are bound to and transported by water-soluble proteins. In order to be watersoluble, the transporting protein contains which one of the following amino acids on its surface in
contact with aqueous blood? A. Valine
B. Arginine C. Leucine
D.Isoleucine
E.Phenylalanine
3.A patient has wheezing and shortness of breath, which are his typical asthma symptoms, so he takes a
“rescue inhalant” which is a β2-adrenergic receptor agonist. The active ingredient of the inhalant
relaxes the smooth muscle of the bronchi and allows him to breathe more normally. The receptor to
which the agonist binds can be best described by which one of the following? A. A globular protein
B. A transmembrane protein
C. A protein containing a nucleotide binding fold D. An exclusively β-pleated sheet protein
E. A protein containing an actin fold
4.Autopsies of patients with Alzheimer disease show protein aggregates called neurofibrillary
tangles and neuritic plaques in various regions of the brain. These plaques exhibit the characteristic
staining of amyloid. Which of the following structural features is the most likely characteristic of at
least one protein in these plaques?
A. A high content of β-pleated sheet structure B. A high content of α-helical structure
C. A high content of random coils
D. Disulfide bond cross-links between polypeptide chains E. A low-energy native conformation
5.While studying a novel pathway in a remote species of bacteria, you discover a new globular protein
that phosphorylates a substrate, using ATP as the phosphate donor. This protein most likely contains
which one of the following structures? A. An actin fold
B. An immunoglobulin fold C. A nucleotide binding fold D. A globin fold
E. A β-barrel
6.β2-Adrenergic agonists used as treatments for acute asthma attacks were formulated to have a higher
affinity for the β2-adrenergic receptor than epinephrine. Which one of the following would be true of
the β2-agonist as compared to epinephrine? A. The K
a of the agonist is higher than that of adrenaline. B. The K
a of the agonist is lower than that of adrenaline. C. The K
a of the agonist is the same as adrenaline.
D. The Kd of the agonist is higher than that of adrenaline.E. The Kd of the agonist is equal to adrenaline.
7.A patient is exposed to hepatitis A and as a preventative measure is given hepatitis A immune
globulin to prevent the patient from contracting the disease. The vaccine is an IgG immunoglobulin
specific for coat proteins of the hepatitis A virus. The target of the immunoglobulin binds to which of
the following locations in the immunoglobulin? Choose the one best answer. A. A site consisting of the constant regions of the heavy chains
B. A site consisting of the constant regions of the light chains C. A site consisting of the variable regions of the light chains D. A site consisting of the variable regions of the heavy chains
E. A site consisting of variable regions of both the light and heavy chains
8.Each IgG molecule (like hepatitis A immunoglobulin) contains two light and two heavy chains,
which can be separated by the loss of which one of the following types of interactions?
A.Hydrogen bonds
B.Disulfide bonds
C.Ionic bonds
D.Van der Waals interactions
E.The hydrophobic effect
9.A patient with type 1 diabetes was able to lower her HbA1c value from 8.2% to 5.9%. This
occurred because of a reduction of which one of the following processes? A. Enzymatic oxidation
B. Nonenzymatic oxidation C. Enzymatic glycosylation
D. Nonenzymatic glycosylation E. Enzymatic reduction
F.
Nonenzymatic reduction
10.In amyloidosis, α-helices may form alternative β-sheets of amyloid fibrils. The α-helices in these
proteins can be characterized by which one of the following? A. They all have the same primary structure.
B. They are formed principally by hydrogen bonds between a carbonyl oxygen atom in one peptide
bond and the amide hydrogen from a different peptide bond.
C. They are formed principally by hydrogen bonds between a carbonyl atom in one peptide bond
and the hydrogen atoms on the side chain of another amino acid.
D. They are formed by hydrogen bonding between two adjacent amino acids in the primary
sequence.
E. They require a high content of proline and glycine. ANSWERS TO REVIEW QUESTIONS
1.The answer is C. In the α-helix, the oxygen atom of a carbonyl group forms a hydrogen bond with
the nitrogen atom four amino acids farther along the chain. Because proline’s nitrogen is part of its
cyclic structure, when proline is in a peptide bond, its nitrogen group lacks a proton and cannotform a hydrogen bond with the appropriate carbonyl oxygen atom. The bond angles within the
proline ring are also incompatible with α-helix formation, such that proline is known as a “helix
breaker.” None of the other amino acids listed has its nitrogen in a cyclic structure, so all can form
the bond angles and hydrogen bonds necessary for an α-helix.
2.The answer is B. Arginine is a charged polar amino acid and is water-soluble, whereas the others
listed are nonpolar and hydrophobic and are not expected to be on the surface of a protein
exposed to an aqueous environment.
3.The answer is B. The β2-adrenergic receptor is a transmembrane protein that contains seven
membrane-spanning domains and has intracellular and extracellular domains on either side of the
membrane. It is composed primarily of α-helices but not β-sheets. It does not contain an actin fold
and is neither a globular protein nor a protein containing a nucleotide binding fold. The receptor is
coupled to a GTP-binding protein (a G-protein), which does bind GTP or guanosine diphosphate
(GDP). The receptor itself, however, does not bind nucleotides.
4.The answer is A. The characteristic staining of amyloid arises from fibrils of β-pleated sheet
structure perpendicular to the axis of the fiber (thus, B, C, and D are incorrect). The native
conformation of a protein is generally the most stable and lowest energy conformation, and the
lower its energy state, the more readily a protein folds into its native
conformation and the less
likely it will assume the insoluble β-pleated sheet structure of amyloid (thus, E is incorrect).
5.The answer is A. The protein hydrolyzes ATP, which is a characteristic of the actin fold. None of
the other folds described will hydrolyze ATP.
6.The answer is A. The binding affinity is described quantitatively by its association constant, Ka.
The higher the Ka, the higher the affinity. Because Kd is the reciprocal of Ka (1/Ka), the higher the
affinity, the lower the Kd. Because the β-agonist has a higher affinity than adrenaline, its Ka would
be higher and its Kd would be lower than that of adrenaline.
7.The answer is E. The variable regions of the light and heavy chains interact to produce a single
antigen-specific binding site (in this case, for the hepatitis A virus) at each branch of the Y-shaped
immunoglobulin. The constant regions are not involved with specific immunity. The variable
regions are physically separated such that they are not able to interact with each other (variable L
with variable Lor variable H with variable H). The variable region of a light chain is
immediately adjacent to the variable region of a heavy chain, and they interact to form a single
binding site.
8.The answer is B. Each IgG molecule contains two light and two heavy chains joined by disulfide
bonds. Reduction of the disulfide bonds will lead to the separation of the light and heavy chains.
9.The answer is D. In nonenzymatic glycosylation, glucose present in blood binds to amino acids on
hemoglobin forming an irreversible glycosylated protein through the lifetime of that red blood
cell. Because the reaction is nonenzymatic, the rate of glycosylation is proportional to the
concentration of the glucose present. Patients with consistently high blood glucose will have a
high HbA1c, a marker of poor diabetic control. Oxidation and/or reduction is not involved with
the formation of HbA1c.
10.The answer is B. The regular repeating structure of an α-helix is possible because it is formed by
hydrogen bonds within the peptide backbone of a single strand. Thus, α-helices can be formedfrom a variety of primary structures. However, proline cannot accommodate the bends for an α-
helix because the atoms involved in the peptide backbone are part of a ring structure and glycine
cannot provide the space-filling required for a stable structure.8 Enzymes as Catalysts
For additional ancillary materials related to this chapter, please visit thePoint. Enzymes are proteins that act as catalysts, which are compounds that increase the rate of chemical
reactions (Fig. 8.1). Enzyme catalysts bind reactants (substrates), convert them to products, and release
the products. Although enzymes may be modified during their participation in this reaction sequence, they
return to their original form at the end. In addition to increasing the speed of reactions, enzymes provide a
means for regulating the rate of metabolic pathways in the body. This chapter describes the properties of
enzymes that allow them to function as catalysts. The next chapter explains the mechanisms of enzyme
regulation.Enzyme-Binding Sites. An enzyme binds the substrates of the reaction and converts them to products.
The substrates are bound to specific substrate-binding sites on the enzyme through interactions with the
amino acid residues of the enzyme. The spatial geometry required for all the interactions between the
substrate and the enzyme makes each enzyme selective for its substrates and ensures that only specific
products are formed.
Active Catalytic Sites. The substrate-binding sites overlap in the active catalytic site of the enzyme, the
region of the enzyme where the reaction occurs. Within the catalytic site, functional groups provided by
coenzymes, tightly bound metals, and, of course, amino acid residues of the enzyme, participate in
catalysis.
Activation Energy and the Transition State. The functional groups in the catalytic site of the enzyme
activate the substrate and decrease the energy needed to form the high-energy intermediate stage of the
reaction known as the transition-state complex. Some of the catalytic strategies employed by enzymes,
such as general acid–base catalysis, formation of covalent intermediates, and stabilization of the
transition state, are illustrated by chymotrypsin.
pH and Temperature Profiles. Enzymes have a functional pH range determined by the pKa of the
functional groups in the active site and the interactions required for three-dimensional structure. Increasesof temperature, which do not lead to protein denaturation, increase the reaction rate.
Mechanism-Based Inhibitors. The effectiveness of many drugs and toxins depends on their ability to
inhibit an enzyme. The strongest inhibitors are covalent inhibitors, compounds that form covalent bonds
with a reactive group in the enzyme active site, or transition-state analogs that mimic the transition-state
complex.
Enzyme Names. Most enzyme names end in “-ase.” Enzymes usually have both a common name and a
systematic classification that includes a name and an Enzyme Commission (EC) number. THE WAITING ROOM
A year after recovering from salicylate poisoning (see Chapter 4), Dennis V. was playing in his
grandfather’s basement. Dennis drank an unknown amount of the insecticide malathion, which is
sometimes used for killing fruit flies and other insects (Fig. 8.2). Sometime later, when he was not feeling
well, Dennis told his grandfather what he had done. Mr. V. retrieved the bottle and rushed Dennis to the
emergency department of the local hospital. On the way, Dennis vomited repeatedly and complained of
abdominal cramps. At the hospital, he began salivating and had an uncontrollable defecation.
In the emergency department, physicians passed a nasogastric tube for stomach lavage, started
intravenous fluids, and recorded vital signs. Dennis’s pulse rate was 48 beats/minute (slow), and his
blood pressure was 78/48 mm Hg (low). The physicians noted involuntary twitching of the muscles in hisextremities.
Lotta T. was diagnosed with acute gouty arthritis involving her right great toe (see Chapter 5). The
presence of insoluble urate crystals within the joint space confirmed the diagnosis. Several weeks
after her acute gout attack subsided, Ms. T. was started on allopurinol therapy in an oral dose of 150 mg
twice per day. Allopurinol therapy is effective because the drug inhibits the activity of a specific enzyme.
Al M., a 44-year-old man who has been an alcoholic for the past 5 years, has a markedly
diminished appetite for food. One weekend, he became unusually irritable and confused after
drinking two 750-mL bottles of scotch and eating very little. His landlady convinced him to visit his
doctor. Physical examination indicated a heart rate of 104 beats/minute. His blood pressure was slightly
low, and he was in early congestive heart failure. He was poorly oriented to time, place, and person.
I. The Enzyme-Catalyzed Reaction
Enzymes, in general, provide speed, specificity, and regulatory control to reactions in the body. Enzymes
are usually proteins that act as catalysts, compounds that increase the rate of chemical reactions. Enzymecatalyzed reactions have three basic steps:
1.Binding of substrate (a reactant): E + S ↔ ES
2.Conversion of bound substrate to bound product: ES ↔ EP
3.Release of product: EP ↔ E + P
An enzyme binds the substrates of the reaction it catalyzes and brings them together at the right
orientation to react. The enzyme then participates in the making and breaking of bonds required for
product formation, releases the products, and returns to its original state once the reaction is completed.
Enzymes do not invent new reactions; they simply make reactions occur faster. The catalytic power of
an enzyme (the rate of the catalyzed reaction divided by the rate of the uncatalyzed reaction) is usually in
the range of 106 to 1014. Without the catalytic power of enzymes, reactions such as those involved in nerve
conduction, heart contraction, and digestion of food would occur too slowly for life to exist.
Each enzyme usually catalyzes a specific biochemical reaction. The ability of an enzyme to select just
one substrate and distinguish this substrate from a group of very similar compounds is referred to as
specificity (Fig. 8.3). The enzyme converts this substrate to just one product. The specificity as well as
the speed of enzyme-catalyzed reactions result from the unique sequence of specific amino acids that form
the three-dimensional structure of the enzyme.Most, if not all, of the tissues and organs in the body are adversely affected by chronic
ingestion of excessive amounts of alcohol, including the liver, pancreas, heart, reproductive
organs, central nervous system, and the fetus. Some of the effects of alcohol ingestion, such as the
psychotropic effects on the brain or inhibition of vitamin transport, are direct effects caused by
ethanol itself. However, many of the acute and chronic pathophysiologic effects of alcohol relate
to the pathways of ethanol metabolism (see Chapter 33). A. The Active Site
To catalyze a chemical reaction, the enzyme forms an enzyme–substrate complex in its active catalytic site
(Fig. 8.4). The active site is usually a cleft or crevice in the enzyme formed by one or more regions of the
polypeptide chain. Within the active site, cofactors and functional groups from the polypeptide chain
participate in transforming the bound substrate molecules into products.Initially, the substrate molecules bind to their substrate-binding sites, also called the substraterecognition sites (see Fig. 8.4B). The three-dimensional arrangement of binding sites in a crevice of the
enzyme allows the reacting portions of the substrates to approach each other from the appropriate angles.
The proximity of the bound substrate molecules and their precise orientation toward