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BIOCHEMISTRY – A SHORT COURSE 3RD EDITION
BIOCHEMISTRY – A SHORT COURSE 3RD EDITION
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,BiochemistryA Short Course
Third Edition
John L. Tymoczko
Jeremy M. Berg
Lubert Stryer
, Publisher: Kate Ahr Parker
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ISBN-10: 1-4641-2613-5
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Printed in the United States of America
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,To our teachers
and students
,About the Authors
John L. Tymoczko is Towsley Professor of Biology Biology from 2011 to 2013. He is a Fellow of the American
at Carleton College, where he has taught since 1976. He Association for the Advancement of Science and a member
currently teaches Biochemistry, Biochemistry Laboratory, of the Institute of Medicine of the National Academy of
Oncogenes and the Molecular Biology of Cancer, and Sciences. He is a recipient of the American Chemical
Exercise Biochemistry and co-teaches an introductory Society Award in Pure Chemistry (1994), the Eli Lilly
course, Energy Flow in Biological Systems. Professor Award for Fundamental Research in Biological Chemistry
Tymoczko received his B.A. from the University of Chicago (1995), the Harrison Howe Award (1997), and the Howard
in 1970 and his Ph.D. in Biochemistry from the University Schachman Public Service Award (2011), was named
of Chicago with Shutsung Liao at the Ben May Institute Maryland Outstanding Young Scientist of the Year (1995),
for Cancer Research. He then had a postdoctoral position and received public service awards from the Biophysical
with Hewson Swift of the Department of Biology at the Society, the American Society for Biochemistry and
University of Chicago. The focus of his research has been Molecular Biology, the American Chemical Society,
on steroid receptors, ribonucleoprotein particles, and and the American Society for Cell Biology. He also
proteolytic processing enzymes. received numerous teaching awards, including the
W. Barry Wood Teaching Award (selected by medical
Jeremy M. Berg received his B.S. and M.S degrees students), the Graduate Student Teaching Award, and the
in Chemistry from Stanford (where he did research Professor’s Teaching Award for the Preclinical Sciences.
with Keith Hodgson and Lubert Stryer) and his Ph.D. He is coauthor, with Stephen J. Lippard, of the textbook
in Chemistry from Harvard with Richard Holm. He Principles of Bioinorganic Chemistry.
then completed a postdoctoral fellowship with Carl
Pabo in Biophysics at Johns Hopkins University School Lubert Stryer is Winzer Professor of Cell Biology,
of Medicine. He was an Assistant Professor in the Emeritus, in the School of Medicine and Professor of
Department of Chemistry at Johns Hopkins from 1986 Neurobiology, Emeritus, at Stanford University, where
to 1990. He then moved to Johns Hopkins University he has been on the faculty since 1976. He received his
School of Medicine as Professor and Director of the M.D. from Harvard Medical School. Professor Stryer
Department of Biophysics and Biophysical Chemistry, has received many awards for his research on the
where he remained until 2003. From 2003 to 2011, he interplay of light and life, including the Eli Lilly Award
served as Director of the National Institute of General for Fundamental Research in Biological Chemistry, the
Medical Sciences at the National Institutes of Health. In Distinguished Inventors Award of the Intellectual Property
2011, he moved to the University of Pittsburgh, where he Owners’ Association, and election to the National Academy
is now Professor of Computational and Systems Biology of Sciences and the American Philosophical Society. He
and Pittsburgh Foundation Professor and Director of the was awarded the National Medal of Science in 2006. The
Institute for Personalized Medicine. He served as President publication of his first edition of Biochemistry in 1975
of the American Society for Biochemistry and Molecular transformed the teaching of biochemistry.
iv
,Preface
A
s humans, we are adept learning machines. Long before a baby learns
that she can change a sheet of paper by crumpling it, she is absorbing
vast amounts of information. This learning continues throughout life in
myriad ways: learning to ride a bike and to take social cues from friends; learning
to drive a car and balance a checkbook; learning to solve a quadratic equation
and to interpret a work of art.
Of course, much of learning is necessary for survival, and even the simplest
organisms learn to avoid danger and recognize food. However, humans are
especially gifted in that we also acquire skills and knowledge to make our lives
richer and more meaningful. Many students would agree that reading novels
and watching movies enhance the quality of our lives because we can expand our
horizons by vicariously being in situations we would never experience, reacting
sympathetically or unsympathetically to characters who remind us of ourselves
or are very different from anyone we have ever known. Strangely, at least to us
as science professors, science courses are rarely thought of as being enriching or
insightful into the human condition. Larry Gould, a former president of Carleton
College, was also a geologist and an Arctic explorer. As a scientist, teacher, and
administrator, he was very interested in science education especially as it related
to other disciplines. In his inaugural address when he became president he said,
“Science is a part of the same whole as philosophy and the other fields of learn-
ing. They are not mutually exclusive disciplines but they are independent and
overlapping.” Our goal was to write a book that encourages students to appreci-
ate biochemistry in this broader sense, as a way to enrich their understanding of
the world.
v
, vi Preface
New to this Edition
This third edition takes into account recent discoveries and advances that have
changed how we think about the fundamental concepts in biochemistry and
human health. To meet the needs of instructors and students alike, particular
attention has been paid to the topics outlined below.
Expanded Physiological Focus
A hallmark feature of Biochemistry: A Short Course is its physiological perspective
on biochemical processes and its integration of clinical examples to apply and
reinforce concepts. In the third edition, we build on this aspect of the book with:
• A NEW section: “Mutations in Genes Encoding Hemoglobin Subunits Can
Result in Disease” (Chapter 9)
• 17 new Clinical Insights, demonstrating the relevance of biochemistry to
human health and disease.
199
Summary
can insert into the hydrophobic interior of the membrane and localize the protein
to the membrane surface. Such localization is required for protein function. Three
Features highlighting the physiological aspect of biochemistry have been
such attachments are shown in Figure 11.10: (1) a palmitoyl group attached to a
cysteine residue by a thioester bond, (2) a farnesyl group attached to a cysteine expanded, and include the following:
residue at the carboxyl terminus, and (3) a glycolipid structure termed a glyco-
sylphosphatidylinositol (GPI) anchor attached to the carboxyl terminus.
CLInICAL InSIgHT CLINICAL INSIGHTS
In the Clinical Insights, students see how the concepts most
Premature Aging Can Result from the Improper Attachment
of a Hydrophobic group to a Protein
Farnesyl is a hydrophobic group that is often
attached to proteins, usually so that the protein is
able to associate with a membrane (Figure 11.10).
recently considered affect an aspect of a disease or its cure. By
Inappropriate farnesylation has been shown to result
in Hutchinson–Gilford progeria syndrome (HGPS), exploring biochemical concepts in the context of a disease, stu-
a rare disease of premature aging. Early postnatal
development is normal, but the children fail to
(B)
dents learn how these concepts are relevant to human life and
thrive, develop bone abnormalities, and have a small
beaked nose, a receding jaw, and a complete loss of
hair (Figure 11.11). Affected children usually die at
what happens when biochemistry goes awry.
an average age of 13 years of severe atherosclerosis, a
cause of death more commonly seen in the elderly.
BIOLOGICAL INSIGHTS
The cause of HGPS appears to be a mutation in
the gene for the nuclear protein lamin, a protein that
forms a scaffold for the nucleus and may take part in
the regulation of gene expression. The folded
polypeptide that will eventually become lamin is
(A) Biochemistry affects every aspect of our world, sometimes in
(C)
modified and processed many times before the
mature protein is produced. One key processing 15-year-old boy suffering from hGpS. (B) a strange and amazing ways. Like Clinical Insights, Biological
Figure 11.11 Hutchinson–gilford progeria syndrome (HgPS). (a) a
normal nucleus. (c) a nucleus from a
hGpS patient. [(a) ap photo/Gerald herbert; (B and c) Scaffidi, p., Gordon, L. and
event is the removal of a farnesyl group that had
been added to the nascent protein earlier in
processing. In HGPS patients, the farnesyl group is
Insights bolster students’ understanding of biochemical concepts
Misteli, T. (2005). The call nucleus and aging: Tantalizing clues and hopeful promises.
PLoS Biol 3 (11): e395. courtesy of paola Scaffidi.]
not removed, owing to a mutation in the lamin. The incorrectly processed lamin
results in a deformed nucleus (Figure 11.11) and aberrant nuclear function that as they learn how simple changes in biochemical processes can
have dramatic effects.
results in HGPS. Much research remains to determine precisely how the failure
to remove the farnesyl group leads to such dramatic consequences.
SUMMARy For a complete list of clinical and biological insights see
20.3 The respiratory Chain Consists of Proton Pumps and a Physical Link to the Citric Acid Cycle 377
pages xi–xii.
11.1 Fatty Acids Are a Main Source of Fuel
Lipids are defined as water-insoluble molecules that are soluble in organic
BIOLOgICAL InsIghT
solvents. Fatty acids are an important lipid in biochemistry. Fatty acids are
hydrocarbon chains of various lengths and degrees of unsaturation that ter-
minate with a carboxylic acid group. The fatty acid chains in membranes
Theusually
Dead Zone: Too Much Respiration
Some
contain between 14 and 24 carbon atoms; they may be saturated or
unsaturated. Short chain length and unsaturation enhance the fluidity of
marine organisms perform so much cellular respiration, and therefore
NUTRITIONAL EXAMPLES
fatty acids and their derivatives by lowering the melting temperature.
consume
11.2 so much
Triacylglycerols molecular
Are the Storage oxygen,
Form of Fatty Acids that the oxygen concentration in the Examples of the underlying relationship between nutrition and
water
Fatty is decreased
acids to a levelmolecules
are stored as triacylglycerol that isintoo low
adipose cells.to sustain other organisms. One
Triacylg-
such
lycerols are composed of three fatty acids esterified to a glycerol backbone.
hypoxicare
Triacylglycerols (low
storedlevels of oxygen)
in an anhydrous form. zone is in the northern Gulf of Mexico, biochemistry abound.
off There
11.3 the Arecoast
Threeof Louisiana
Common where Lipids
Types of Membrane
theTheMississippi
major classes River flows
of membrane into
lipids are phospholipids, glycolipids,
and cholesterol. Phosphoglycerides, a type of phospholipid, consist of a Increased Coverage of the Fundamentals
the Gulf (Figure 20.16). The
Mississippi is extremely nutrient The third edition features a greater emphasis on the fundamen-
rich due to agricultural runoff; so
plant microorganisms, called
Tymoczko_c11_189-202hr1_pv2.1.0.indd 199 1/23/15 11:57 AM
tals of biochemistry, specifically where metabolism is concerned
phytoplankton, proliferate so (Chapters 14 and 15). In an effort to explain metabolism more
robustly that they exceed the
amount that can be consumed by fully, we’ve expanded on the following areas within Chapters 14
other members of the food chain.
When the phytoplankton die, they
and 15:
sink to the bottom and are •DiDDigestive
You Know? enzymes
consumed by aerobic bacteria. Figure 20.16 The gulf of Mexico dead
In anaerobic respiration in some
The aerobic bacteria thrive to zone. The size of the dead zone in the Gulf of
Mexico off Louisiana varies annually but may
•organisms,
Protein digestion
chemicals other than oxygen
such a degree that other bottom- are used as the final electron acceptor in
dwelling organisms, such as extend from the Louisiana and Alabama coasts
to the westernmost coast of Texas. reds and
•an electron-transport
Celiac disease chain. Because
shrimp and crabs, cannot obtain none of these electron acceptors are as
•electropositive
Energy
oranges represent high concentrations of
enough O2 to survive. The term phytoplankton and river sediment. [NASA/
2 as O , not as much energy
“dead zone” refers to the inability is released and, consequently, not as
Goddard Space Flight Center/Scientific
of this area to support fisheries. Visualization Studio.] • Phosphates in biochemical processes
much ATP is generated.
Toxic Derivatives of Molecular Oxygen such As superoxide Radical Are
scavenged by Protective Enzymes
Molecular oxygen is an ideal terminal electron acceptor because its high
affinity for electrons provides a large thermodynamic driving force. However,
the reduction of O2 can result in dangerous side reactions. The transfer of four
electrons leads to safe products (two molecules of H2O), but partial reduction
generates hazardous compounds. In particular, the transfer of a single electron
, Preface vii
Teaching and Learning Tools
In addition to providing an engaging contextual framework for the biochemis-
try throughout the book, we have created several opportunities for students to
check their understanding, reinforce connections across the book, and practice
what they have learned. These opportunities present themselves both in features
throughout the text and in the many resources offered in LaunchPad.
ACTIVE LEARNING RESOURCES
In this new edition, we’ve responded to instructor requests to provide
resources that aid in creating an active classroom environment. All of the new
media resources for Biochemistry: A Short Course will be available in our new
system. For more information on LaunchPad see page ix. To
help students adapt to an interactive course, we’ve added the following resources:
NEW Case Studies are a series of online biochemistry case studies that
are assignable and assessable. Authored by Justin Hines, Assistant Professor of
Chemistry at Lafayette College, each case study gives students practice in work-
ing with data, developing critical thinking skills, connecting topics, and applying
knowledge to real scenarios. We also provide instructional guidance with each
case study (with suggestions on how to use the case in the classroom) and aligned
assessment questions for quizzes and exams.
NEW Clicker Questions are aligned with key concepts and misconceptions
in each chapter so instructors can assess student understanding in real time dur-
ing lectures.
END-OF-CHAPTER PROBLEMS
Each chapter includes a robust set of practice problems. We have revised and
added to the total number of questions in the third edition.
• Data Interpretation Problems train students to analyze data and reach
scientific conclusions.
• Chapter Integration Problems draw connections between concepts across
chapters.
• Challenge Problems require calculations, understanding of chemical
structures, and other concepts that are challenging for most students.
Brief solutions to all the end-of-chapter problems are provided in the
“Answers to Problems” section in the back of the textbook. We are also pleased
to offer expanded solutions in the accompanying Student Companion, by Frank
Deis, Nancy Counts Gerber, Richard Gumport, and Roger Koeppe. (For more
details on this supplement see page x.)
MARGIN FEATURES
We use the margin features in the textbook in several ways to help engage stu-
dents, emphasize the relevance of biochemistry to their lives, and make it more
accessible. We have given these features a new look to make them clearer and
more easily identifiable.
, 270 15 Metabolism: Basic concepts and Design
Reactive site is reduced to a methylene group in several steps. This sequence of reactions
requires an input6.4ofenzymes Facilitate the Formation of the transition State 103
four electrons:
consequently cannotHalter the H equilibrium of a chemical reaction. Consider an + Enzyme
H2 H2
viii Preface enzyme-catalyzed reaction, the conversion O
12.5 A Major of substrate,
role ofRS,Membrane
into
C product,
R9 P.
Proteins
+ 4H + 4e
C presence + Is to C R9
– Function as Transporters
R C + H2O 215
Figure 6.2 graphs H the rate of product formation with time in the
H2
254 cotransporters.
14 Digestion: Turning a Meal These proteins
into Cellular andcan
Biochemicals be classified
absence N+ as
of enzyme. Noteeither
thatNH anti-
the
2 amount of product A
formed Ois the same A B
O
porters or symporters. Antiporters whether or notOthethe
couple enzyme His present, but, in the present example, the amount
downhill flow CELL
Product
PLearning
•Oof– product Objectives are used in many different
take hours ways in the classroom. To help
LUMEN INTESTINAL The electron donor in most reductive biosyntheses is NADPH, the reduced form
formed in seconds whenNH the enzyme is present might
of one species to the uphillor Oflow of another in the opposite 2 of nicotinamide adenine dinucleotide phosphate (NADP+). NADPH differs from
direction across the membrane; reinforce
centuries
O
HOkeyOH
to
symporters
Why
formconcepts
if
does the rateHuse
the enzyme
N
the flow
of product
while
were
of the
formation
absent student
(Table
NADH in thatisthe
6.1). reading
2′-hydroxyl
level off with time? The reaction
thegroup
chapter we havemoiety
of its adenosine indicated
is esterified with
No enzyme
Triacylglycerols them O P
one species to drive the flow of Oa different
has – with
reached
O
a and ✓ number
speciesN in the same
equilibrium. Substrate S N and
is still integrated
phosphate
SER
being (Figure
converted them
into 15.16).
producton P, a
NADPH chapter level
carries electronsasinwell as
the same in
waythe
as NADH.
but P is being convertedO rate suchHowever,
into S Nat aPhospholipids, NADPH
that the amount of isP used almost exclusivelySeconds
remains for reductive biosyntheses, whereas
direction
H 2O
across the membrane section (Figureintroductions.
12.18).
constant. Enzymes accelerate the attainment
They H are also
ofNADH
cholesterol, tied
is used
equilibria but do
to the
primarily end-of-chapter
not shift for
problems
theirthe generation of ATP.Time
to assist
Hours
The extra phosphoryl group
Glucose is moved into students some
positions.animal
The cells
inequilibriumby the
developing sodium-
positionproblem-solving
is and ononly
proteins
a function NADPH skills
of the isfree-energy and
a tag that instructors
enables
differ- enzymes toindistinguish
assessing students’
between high-potential
Lipases HO
reactantsOPO products. by electrons to be used in anabolismFigure 6.2 Enzymes
2–
glucose linked transporter (SGLT), ence between a symporter and3powered and those accelerate
to be used the reaction
in catabolism.
understanding of some of the key concepts
TAG in each chapter.
rate. the
TAGsame equilibrium point is reached but
the simultaneous entry of Figure
Na+. 15.16
This The free-energy
structure of input of 3. An Activated Carrier of Two-Carbon much moreFragments. Coenzyme
quickly in the presence A (also called
of an enzyme.
Na flowing down its concentration gradient
+ Fatty acids nicotinamide
+
is+sufficient to
adenine dinucleotide CoA-SH), anotherB central molecule in metabolism, is a carrier of acyl groups
Chylomicrons To lymph
phosphate (NADP ). NaDp provides (Figure 15.17). A key constituent of
generate a +66-fold concentration
6.4
electrons gradient
FABPEnzymes
for biosynthetic of an uncharged
Facilitate the Formation of theAntiporter
Transition ✓coenzyme
2 Explain A
system
isrelation
the the vitamin
Symporter betweenpantothenate.
the
FATPpurposes. NoticeTriacylglycerols
Acyl groups are important constituents both in
transition catabolism,
state as insite
and the active theofoxidation
molecule such as glucose (Figure 12.19).
State
that the reactive site isRecall
the samethat the so-
in NaDp +
of fatty12.18
acids, and in anabolism, as in the synthesis
an enzyme, and of membrane
list the lipids. The
characteristics
Monoacylglycerols and NaD+. Figure Antiporters and symporters. Secondary transporters
dium ion gradient was initially generated
The free-energy by thebetween
difference Na+–K +
terminal
reactantscan
and sulfhydryl
products
transport group
accounts
two for inthe
substrates inCoA isof
opposite
active
the sites.site. Acyl groups are linked to
reactive
directions (antiporters) or two
ATPase, demonstrating thatequilibrium
the action of aofreaction,
the secondary
but enzymesac-accelerate howsulfhydryl
the
substratesquickly this
in the equilibrium
group
same of CoAis by
direction thioester bonds. The resulting derivative is
(symporters).
attained. How can we explain the rate enhancement inan terms ofCoA.
thermodynam-
tive transporter depends on the 14.10
Figure primary active
Chylomicron transporter. acids andacyl
formation. Free fattycalled An acyl group
monoacylglycerols often linked to CoA is the acetyl unit; this
are absorbed
ics? To do so, we have to consider not the end points of the reaction but the
called acetyl
derivative
by intestinal epithelial cells. Triacylglycerols are resynthesized andis packaged withCoA.
otherThe ΔG°′
lipids and for the hydrolysis of acetyl CoA has a
chemical pathway between the end points. large negative value:
proteins to form chylomicrons, which are then released into the lymph system.
A chemicalK reaction
+ of substrate+S to form product P goes through a transition
+ + K Na+
state that has+a Na
X‡Na higher free
Na+energy than+ does either
Na+ SCoA
Acetyl or P. +
The double dagger +
+ H2O m acetate + CoA + H
+ Na Na
Na
3 Na+ denotes the transitionNastate.
+ TheNatransition
+ Namolecular
state is a fleeting structure
Na+ + Na + ΔG°′ = −31.4 kJ mol−1 (−7.5 kcal mol−1)
that is no longer
Na the substrate+but is not+ yet theGlucose
product. The Natransition
+ state is the
Na+ After a meal rich in Nalipids,Nathe blood appears milky because of the high
least-stable and most-seldom-occurring species along the reaction pathway
content
becauseofit chylomicrons.
is the one with theThese
highestparticles
free energy.bind to membrane-bound
Reactive group K+ lipoprotein NH2
N
lipases, primarily at adipose tissue and muscle, where the triacylglycerols –are O –
O
S m X‡ → P OH
once again degraded into free fatty acids and monoacylglycerol H
N
H forHtransport into
N P P N
N
•The
the difference
Quick
tissue. in free energy between
The Quizzes + emulate
triacylglycerols the transition
are thenthatHS moment state and
resynthesized thestored.
in
and asubstrate
lectureInisthe
when O a professor
muscle O O asks,
O
N
? QUICk QUIz explain why a person
who has a trypsinogen deficiency will andΔGother
“Do ‡
you
(Figure get
K+ ofNa
called the+ free energy
6.3): it?”
+
activation
K tissues, they can be
These
or simply the activation energy, symbolized
K oxidized to provide energy,
+
questions allow as willObe
students
O
to
by
H 3Cdiscussed
check
CH3
O
in
their
O
understanding of
suffer from more digestion difficulties than
Na+–K+ ATPase Chapter 27.NaChylomicrons
+ K + also ‡function in SGLT
the transport+ of fat-soluble vitamins 2–O PO
3 OH
will a person lacking most other zymogens. the
and material
Figure 15.17
cholesterol.
A (CoA-SH).
as they coenzyme
The structureKof
+
read
ΔG =itGso X −they
‡
can immediately
GS-Mercapto-
ethylamine unitNa+
K Pantothenate unitgauge whether they need to
K Glucose
review
Note that athediscussion or can
energy of activation, advance
or ΔG ‡
, does nottoenter
Glucose K+the next topic.
into the final ΔG Answers are given at the
calculation for the reaction,
Na+because the energy that
The had to beof
hydrolysis Ka+thioester
added to reach
is the
thermodynamically more favorable than that of an
ATP + H2O 2 K+
end
ADP +ofPi each
transition state ischapter.
released whenGlucose
the transition state ester,
oxygen becomessuchthe
as product. The acids, because the electrons of the C=O bond
those in fatty
activation energy immediately suggests how enzymes form lessaccelerate the reaction
stable resonance rate
structures with the C−S bond than with the C−O
BIOLOgICAL
without altering ΔG ofInSIgHT
the
Figure 12.19 Secondary transport. The ion gradient set reaction:
up by theenzymes
Na+–K +function to lower the activation
bond.ATPase can be
Consequently, Transition state, X ‡
acetyl CoA has a high acetyl-group-transfer potential be-
energy.
Snake
used to move materials into the cell,
In
O Venoms
through
other words,
the actionDigest enzymes
of aOfrom
facilitate
the Inside
secondary
the •
formation
transporterOutsuch
cause
Margin
of
transfer
the Structures
transition state. provide
of the acetyl group is exergonic.
as the ‡
a quick reminder
Acetyl CoA carries an activated
The combination of substrate and enzyme creates a reaction pathway whose ∆G (uncatalyzed)
Na+–glucose linked transporter, aMost
symporter.
Canimals
transition-state CoAingest
energyfood isClowerand,CoA in response
than
of toagroup,
acetyl
what it would
molecule
this just as ATP
beingestion,
or carries
group
without theproduce
an that
enzyme enzymes
students
activated phosphoryl maygroup. have
∆G‡ (catalyzed)
isseen Additional features ofhaveactivated
thethecarriers are responsible for two key aspects of
R
that digest
(Figure
S
6.3).the food.
Because
H3C
Many
the
S
venomous
activation energysnakes, lower, onearlier
morethe otherin
molecules the
hand, book
do or in another course.
statemetabolism. First, NADH,
will be NADPH, and FADH 2 react slowly with O2 in the absence
Acyl CoA Acetyl CoA Substrate
energy required to reachdigestive
the transition and more product formed
Free energy
opposite. They inject enzymes into
ofThis their
allows
a catalyst. prospective
Likewise, students
ATP meals to
andofacetyltounderstand
begin
CoA are hydrolyzed theslowly
topic at∆G of many
(in times
faster. Decreasing the activation barrier is analogous to lowering the height a
CLInICAL InSIGHT the digestion
O process from O –
the inside out, hours before
theorbar.
they
evenThedays)
eveninconsume
the absence theofmeals.
a catalyst. These moleculesreaction
for the
are kinetically
high-jump bar; more athletes will be able to clear
Snake venom, hand without essence needing
of catalysis to look up a basic structure
of the a highly + modified form
quiteofstable
saliva, consists
face of of 50 to 60
C R9 C R9 in the a large thermodynamic driving force for reaction with O2
+is stabilization
+ O transition O state.Dephosphorylation
Digitalis Inhibits the nadifferent –K
R Pump protein by andBlocking
R
peptideIts components orregard
organic
that differ
to theamongchemistryspeciesFigure principle
of 12.20
snake elsewhere.
Foxglove.
ATP and Foxglove
(in electron carriers) and H2O (for ProductThe kinetic
acetyl CoA).
The interplay between active and transport
possibly
O andamong
even secondary
O individual
–
activesnakes
The Formation of an Enzyme–Substrate Complex Is the First Step
transport
stabilityof the issame
of these molecules (Digitalis
species.inConsider
the absence purpurea)
of specificis a catalysts
highly poisonous
is essential for their
especially well illustrated rattlesnakes
by biological function because
a hostit ofenables
plant dueenzymes
to the tohighcontrol the flow ofoffree
concentration
Reaction progress energy and
potent
in theC action of the14.11).
R9(Figure cardiotonic
+ Rattlesnakesteroids. venomHeart contains enzymes
C R9
Enzymatic Catalysis
R S R S reducing power. cardiotonic steroids.
Figure Digitalis,decrease
6.3 Enzymes one of the the most
that
failure can result if the muscles Much digest
in
Oxygenof
the
the
the are tissues
heart
catalytic areof
power the
not victim.
able to Phospholipases
contract
of enzymes comes from with
theirmost digest
binding cell membranes
to and then at
esters stabilized by resonance Second, interchanges of activated
widely used groups
activation
drugs, isin metabolism
energy.
obtained
enzymesfrom are accomplished
foxglove.
accelerate
the
sufficient strength to effectively site
altering of
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blood.
structure
available of the causing
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steroids of
promote cellular
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athe
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rather small set of the The (Tablereactions
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plants, such as digitalis and phospholipases
ouabain, arealso
state. Thus, the first stepdisrupt
known theismembranes
in catalysis the formationof
as cardiotonic steroids
activated
of red blood
because
carriers cells,
an enzyme–substrate
in all destroying
organisms
(ES)
is onethem
of activation.
of the unifying motifs of biochemistry.
of their ability to strengthen (a process called hemolysis).
heart contractions. Collagenase
Interestingly, digests the protein collagen, a major
cardiotonic
component
• Did of
You
steroids exert their effect by inhibiting the Na –K pump. connective
Know? + tissue (p.
features
+ 56), whereas
are shorthyaluronidase
asides digests
hyaluronidate, a glycosaminoglycan (p. 178) component of connective DiD You tissue.Know?
Digitalis is a mixture ofto the
cardiotonic
The biochemical
combined
steroids
action of both topic
derived being discussed.
from
collagenase
the dried leaf of
and hyaluronidase is to destroy Interestingly, digitalis was used effectively
292 16 Glycolysis Tymoczko_c06_095-110hr_pv2.0.1.indd
the foxglove plant Digitalis purpurea
103
(Figure 12.20). The compound increases
12/30/14 1:39 PM
They
tissue
derived
atput
the sitea personal
of the bite,face on
enabling science,
the venom or,to spread more readily long before the discovery of the Na+–K+
nuTriTion FACTS the force of contraction heartfrom
ofthroughout muscle the vitamin
Tymoczko_c15_257-280hr1_pv2.0.2.indd niacin, a dietary
and270is consequently requirement
a choice drug for human beings. Con- 1/23/15 1
in the treatment of congestive
in the
sequently, heart
vein
NAD the+of
failure.
Biological
victim.
must be regenerated
Inhibition
Insights,
of thefor
Na + provide
glycolysis
–K +
pump
ATPase. In 1785, William Withering, a
to proceed. Thus, the final
Various proteolytic enzymes in the venom degrade basement membranes
British physician, heard tales of an elderly
by digitalis means that Na glimpses
process
+
(a thin
in the of
is notsheetpumpedof
how
pathway
outiswe
fibrous
the
of use
the
proteins,
biochemistry
regeneration
cell, of NAD
diminishing
including
+
collagen,
in
thethrough
that
the metabolism
underlies the
of
epithelial
woman, known as “the old woman of
pyruvate.
Na+ gradient. The reduced everyday
Na+and
cells) gradient life.in turn
components of affects
the the sodium–calcium
extracellular matrix, leading to severe Shropshire,”
tissue who cured people of “dropsy”
Figure 14.11 A rattlesnake poised to
exchanger. This exchanger,
strike. rattlesnakes inject digestive enzymes an
damage. example
Some of secondary
venoms contain active transport,
proteolytic enzymesrelies on
that stimulate (which today would be recognized as
the
Fermentations Are a Means of Oxidizing NADH
into their prospective Na
meals.influx
+
to simultaneously
[Biosphoto/ powerofthe
formation bloodexpulsion of Ca
clots as well from thethat
as+enzymes cell. Theblood clots. congestive
digest The net heart failure) with an extract of
Daniel Heuclin.] diminished Na gradienteffect
+ The sequence
results of in
these of reactions
enzymes
slower from
acting of
extrusion glucose
in Ca to
concert
2+ pyruvate
bymay
the be tois deplete
sodium– similar all
in most organisms
foxglove.
clotting factorsWithering conducted the first
and most types of cells. In contrast, the fate of pyruvate2+is variable. Three reac-
scientific study of the effects of foxglove
calcium exchanger. The subsequent increase in the intracellular level of Ca
tions of pyruvate are of primary importance: conversion into ethanol,onlactate, or heart failure and
congestive
enhances the ability of cardiac muscle and
carbon dioxide to contract.
water (Figure 16.4). The first two reactions aredocumented fermenta- its effectiveness.
tions that take place in the absence of oxygen. Fermentations are ATP-generating
processes in which organic compounds act as both donors and acceptors of elec-
Tymoczko_c14_245-256hr1_pv2.0.2.indd 254
trons. In the presence of oxygen, the most common situation in multicellular 1/23/15 12:27 PM
NiacinAlsocalledvitaminB3,niacinis organisms and for many unicellular ones, pyruvate is metabolized to carbon
acomponentofcoenzymesnAD+ • Nutrition Facts highlight essential vitamins in the margin next to where
dioxide and water through the citric acid cycle and the electron-transport chain
andnADP+(pp.268-270),whichare they are
(Sections discussed
8 and as part of an
9). In these circumstances, enzyme
oxygen acceptsmechanism or metabolic pathway.
electrons and protons
usedinelectron-transferreactions.
Tymoczko_c12_203-224hr1_pv2.0.3.indd 215
Therearemanysourcesofniacin,
toIn these
form water.boxes,
We now students
take a closer will discover
look at these threehow wefates
possible obtain vitamins from our 1/23/15
of pyruvate. 12:25 PM
includingchickenbreast.niacin diets and what happens if we do not have enough of them. These important
deficiencyresultsinthepotentially
fataldiseasepellagra,acondition molecules and their structures
Pyruvate are listed in table form in the appendix of the
characterizedbydermatitis,dementia, book as well, to help students easily
NADH find where each vitamin is discussed in
anddiarrhea.[BrandxPictures]
the book. CO
NAD+
2 CO 2
Acetaldehyde Lactate Acetyl CoA
Figure 16.4 Diverse fates of pyruvate.
ethanolandlactatecanbeformedby NADH
reactionsthatincludenADh.Alternatively,a
two-carbonunitfrompyruvatecanbe NAD+
coupledtocoenzymeA(seeChapter18)to Ethanol Further
, Preface ix
Media and Supplements
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• Case Studies are a series of online biochemistry case studies that are
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• Self-Assessment Tool allows students to test their understanding by taking
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chemistry review.
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text.
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