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Biochemistry A Short Course 3rd Edition Ebook PDF Version
Biochemistry A Short Course 3rd Edition Ebook PDF Version
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 in
the same 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 concentration6.4
electrons gradient
FABPEnzymes
for biosynthetic of an uncharged
Facilitate the Formation of theAntiporter
Transition ✓coenzyme
system2 Explain A 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 an
in enzyme,
the synthesis
and listofthe
membrane 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 eitherNa+ 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+ + +
NatheGlucose ΔG°′ = −31.4 kJ mol−1 (−7.5 kcal mol−1)
that is no longer
Na the substrate+but is not+ yet product. The Natransition
+ state is the
Na+ After a meal rich in Nalipids,Nathe blood
least-stable and most-seldom-occurring species appears
along themilky because
reaction pathwayof the high
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 difference in free energy between the transition state and the substrate is
•called
the Quick
tissue. The Quizzes + emulate
triacylglycerols are thenthatHS momentand
resynthesized in astored.
lectureIn thewhen 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
the+ free energy
6.3): it?”
K+
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.Na Chylomicrons
+
+ 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 =itGsoX −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
orbar. they
even eveninconsume
days) the absence theofmeals.
a catalyst. These moleculesreaction
for the
are kinetically
high-jump bar; more athletes will be able to clear
Snake venom, handsaliva,
the without
The essence needing
of catalysis to look updriving a basic structure
of the a highly + modified form
quiteofstable consists
face of of 50 to 60
C R9 C R9 in the a large thermodynamic 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
stability issame
of these
of the molecules (Digitalis
species.inConsider
the absence purpurea) is a catalysts
of specific highly poisonous
is essential for their
especially well illustrated rattlesnakes
by biological function because
a hostit ofenables
plant dueenzymes
to the to control
high 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
thethe
pump
structures not snakebite,
blood.
structure
available of the causing
Certain
substrate
to thioesters. atoloss
steroids of
promote cellular
byderived
athe
components.
from
formation
rather small set of the The (Tablereactions
transition
of carriers 15.2). The
by decreasing
existenceΔG‡,of
theafree energy set of
recurring
[roger hall/Shutterstock.]
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
steroids exert their effect by component of
Did YoutheKnow?
• inhibiting connective tissue
Na –K features
+ +
pump. are shorthyaluronidase
(p. 56), whereas 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 destroyInterestingly, 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 1:42 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
NAD2+ CO 2
For Students
• 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
working with data, developing critical thinking skills, connecting topics, and
applying knowledge to real scenarios.
• e-Book allows students to read the online version of the textbook, which
combines the contents of the printed book, electronic study tools, and a full
complement of student media specifically created to support the text.
• Hundreds of Self-Graded Practice Problems allow students to test their
understanding of concepts explained in the text, with immediate feedback.
• Metabolic Map helps students understand the principles and applications of
the core metabolic pathways. Students can work through guided tutorials with
embedded assessment questions, or explore the Metabolic Map on their own
using the dragging and zooming functionality of the map.
• Problem-Solving Videos, created by Scott Ensign of Utah State University,
provide 24/7 online problem-solving help to students. Through a two-part
approach, each 10-minute video covers a key textbook problem representing a
topic that students traditionally struggle to master. Dr. Ensign first describes a
proven problem-solving strategy and then applies the strategy to the problem
at hand in clear, concise steps. Students can easily pause, rewind, and review
any steps they wish until they firmly grasp not just the solution but also the
reasoning behind it. Working through the problems in this way is designed to
make students better and more confident at applying key strategies as they solve
other textbook and exam problems.
• Living Figures allow students to view textbook illustrations of protein
structures online in interactive 3-D using Jmol. Students can zoom and rotate 54
“live” structures to get a better understanding of their three-dimensional nature
and can experiment with different display styles (space-filling, ball-and-stick,
ribbon, backbone) by means of a user-friendly interface.
• Self-Assessment Tool allows students to test their understanding by taking
an online multiple-choice quiz provided for each chapter, as well as a general
chemistry review.
• Animated Techniques illustrate laboratory techniques described in the
text.
x Preface
For Instructors
All the features listed above for students plus:
• e-Book Instructors teaching from the e-Book can assign
either the entire textbook or a custom version that includes
only the chapters that correspond to their syllabi. They can
choose to add notes to any page of the e-Book and share
these notes with their students. These notes may include
text, animations, or photographs.
• Clicker Questions are aligned with key concepts and misconceptions in
each chapter so instructors can assess student understanding in real time during
lectures.
• Newly Updated Lecture PowerPoint Files have been developed to
minimize preparation time for new users of the book. These files offer suggested
lectures including key illustrations and summaries that instructors can adapt to
their teaching styles.
• Updated Textbook Images and Tables are offered as high-resolution JPEG
files. The JPEGs are also offered in separate PowerPoint files.
• Test Bank, by Harvey Nikkel of Grand Valley State University, Susan Knock
of Texas A&M University at Galveston, and Joseph Provost of Minnesota State
University Moorhead, offers more than 1500 questions in editable Word format.
Student Companion
(1-319-03295-8)
For each chapter of the textbook, the Student Companion includes:
• Chapter Learning Objectives and Summary
• Self-Assessment Problems, including multiple-choice, short-answer,
matching questions, and challenge problems, and their answers
• Expanded Solutions to the end-of-chapter problems in the textbook
Preface xi
CLINICAL INSIGHTS This icon signals the beginning of a Clinical Insight in the text.
Defects in organelle function may lead to disease (p. 14) The six-carbon sugar is cleaved into two three-carbon
Pathological conditions result if protein intake is fragments (p. 287)
inadequate (p. 44) Excessive fructose consumption can lead to pathological
Defects in collagen structure result in pathological conditions (p. 295)
conditions (p. 57) Many adults are intolerant of milk because they are deficient in
Protein misfolding and aggregation are associated with some lactase (p. 297)
neurological diseases (p. 63) Galactose is highly toxic if the transferase is missing (p. 298)
Variations in KM can have physiological consequences (p. 114) Aerobic glycolysis is a property of rapidly growing cells (p. 304)
Loss of allosteric control may result in pathological Cancer and exercise training affect glycolysis in a similar
conditions (p. 123) fashion (p. 305)
Penicillin irreversibly inactivates a key enzyme in bacterial Insulin fails to inhibit gluconeogenesis in type 2 diabetes (p. 323)
cell-wall synthesis (p. 138) Substrate cycles amplify metabolic signals (p. 323)
Functional magnetic resonance imaging reveals regions of the Defective regulation of pyruvate dehydrogenase results in lactic
brain processing sensory information (p. 152) acidosis (p. 338)
Hemoglobin’s oxygen affinity is adjusted to meet Enhanced pyruvate dehydrogenase kinase activity facilitates the
environmental needs (p. 154) development of cancer (p. 339)
Sickle-cell anemia is a disease caused by a mutation in The disruption of pyruvate metabolism is the cause of
hemoglobin (p. 157) beriberi (p. 339)
Thalassemia is caused by an imbalanced production of Defects in the citric acid cycle contribute to the development of
hemoglobin chains (p. 159) cancer (p. 354)
Glucose is a reducing sugar (p. 171) Loss of iron-sulfur cluster results in Friedreich’s ataxia (p. 371)
The hormone erythropoietin is a glycoprotein (p. 178) ATP synthase can be regulated (p. 395)
Proteoglycans are important components of cartilage (p. 179) Oxidative phosphorylation can be inhibited at many
Mucins are glycoprotein components of mucus (p. 180) stages (p. 398)
Lack of glycosylation can result in pathological conditions (p. 182) Mitochondrial diseases are being discovered in increasing
Lectins facilitate embryonic development (p. 183) numbers (p. 399)
Influenza virus binds to sialic acid residues (p. 183) Hers disease is due to a phosphorylase deficiency (p. 453)
Premature aging can result from the improper attachment of a Diabetes mellitus results from insulin insufficiency and
hydrophobic group to a protein (p. 199) glucagon excess (p. 466)
Lipid vesicles can be formed from phospholipids (p. 207) A biochemical understanding of glycogen-storage diseases is
The association of prostaglandin H2 synthase-1 with the possible (p. 467)
membrane accounts for the action of aspirin (p. 211) The pentose phosphate pathway is required for rapid cell
Multidrug resistance highlights a family of membrane pumps growth (p. 481)
with ATP-binding domains (p. 214) Glucose 6-phosphate dehydrogenase deficiency causes a drug-
Harlequin ichthyosis is a dramatic result of a mutation in an induced hemolytic anemia (p. 481)
ABC transporter protein (p. 214) Triacylglycerols are hydrolyzed by hormone-stimulated
Digitalis inhibits the Na+–K+ pump by blocking its lipases (p. 490)
dephosphorylation (p. 215) Pathological conditions result if fatty acids cannot enter the
Mutations in protein kinase A can cause Cushing’s mitochondria (p. 493)
syndrome (p. 230) Ketogenic diets may have therapeutic properties (p. 498)
Cholera and whooping cough are due to altered G-protein Diabetes can lead to a life-threatening excess of ketone-body
activity (p. 231) production (p. 499)
Some receptors contain tyrosine kinase domains within their Ketone bodies are a crucial fuel source during
covalent structures (p. 235) starvation (p. 500)
The conversion of proto-oncogenes into oncogenes disrupts Some fatty acids may contribute to the development of
the regulation of cell growth (p. 239) pathological conditions (p. 501)
Protein kinase inhibitors may be effective anticancer Fatty acid metabolism is altered in tumor cells (p. 513)
drugs (p. 240) A small fatty acid that causes big problems (p. 513)
Protein digestion begins in the stomach (p. 248) Aspirin exerts its effects by covalently modifying a key
Celiac disease results from the inability to properly digest enzyme (p. 515)
certain proteins (p. 251) Phosphatidylcholine is an abundant phospholipid (p. 526)
Exercise depends on various means of generating ATP (p. 265) Gangliosides serve as binding sites for pathogens (p. 527)
Lack of activated pantothenate results in neurological Disrupted lipid metabolism results in respiratory distress
problems (p. 271) syndrome and Tay–Sachs disease (p. 528)
xii Preface
The absence of the LDL receptor leads to familial The separation of DNA strands requires specific helicases and
hypercholesterolemia and atherosclerosis (p. 536) ATP hydrolysis (p. 630)
Cycling of the LDL receptor is regulated (p. 537) Bacterial topoisomerase is a therapeutic target (p. 632)
HDL seems to protect against atherosclerosis (p. 537) Telomeres are replicated by telomerase, a specialized
The clinical management of cholesterol levels can be polymerase that carries its own RNA template (p. 639)
understood at a biochemical level (p. 538) Some genetic diseases are caused by the expansion of repeats of
Bile salts facilitate lipid absorption (p. 539) three nucleotides (p. 644)
Vitamin D is necessary for bone development (p. 541) Many cancers are caused by the defective repair of
Androgens can be used to artificially enhance athletic DNA (p. 650)
performance (p. 542) Many potential carcinogens can be detected by their mutagenic
Blood levels of aminotransferase serve a diagnostic action on bacteria (p. 650)
function (p. 553) Some antibiotics inhibit transcription (p. 667)
Metabolism in context: inherited defects of the urea cycle cause Many bacterial cells release chemical signals that regulate gene
hyperammonemia (p. 558) expression in other cells (p. 670)
Inborn errors of metabolism can disrupt amino acid Inappropriate enhancer use may cause cancer (p. 680)
degradation (p. 565) Induced pluripotent stem cells can be generated by
Determining the basis of the neurological symptoms of introducing four transcription factors into differentiated
phenylketonuria is an active area of research (p. 566) cells (p. 680)
Tetrahydrofolate carries activated one-carbon units (p. 576) Steroid-hormone receptors are targets for drugs (p. 683)
High homocysteine levels correlate with vascular disease (p. 578) Mutations that affect pre-mRNA splicing cause disease
Salvage pathways recycle pyrimidine bases (p. 589) (p. 696)
Several valuable anticancer drugs block the synthesis of Most human pre-mRNAs can be spliced in alternative ways to
thymidylate (p. 595) yield different proteins (p. 697)
The synthesis of deoxyribonucleotides is controlled by the Mutations in eukaryotic initiation factor 2 cause a curious
regulation of ribonucleotide reductase (p. 597) pathological condition (p. 730)
The loss of adenosine deaminase activity results in severe Some antibiotics inhibit protein synthesis (p. 730)
combined immunodeficiency (p. 598) Diphtheria toxin blocks protein synthesis in eukaryotes by
Gout is induced by high serum levels of urate (p. 599) inhibiting translocation (p. 731)
Lesch–Nyhan syndrome is a dramatic consequence of Ricin fatally modifies 28S ribosomal RNA (p. 732)
mutations in a salvage-pathway enzyme (p. 600) Next-generation sequencing methods enable the rapid
Folic acid deficiency promotes birth defects such as spina determination of a complete genome sequence (p. 753)
bifida (p. 600) PCR is a powerful technique in medical diagnostics, forensics,
Damaging DNA can inhibit cancer-cell growth (p. 622) and studies of molecular evolution (p. 756)
BIOLOGICAL INSIGHTS This icon signals the beginning of a Biological Insight in the text.
Hemoglobin adaptations allow oxygen transport in extreme A volcanic eruption can affect photosynthesis worldwide
environments (p. 155) (p. 432)
Glucosinolates protect plants and add flavor to our diets (p. 173) Why bread becomes stale: the role of starch (p. 434)
Blood groups are based on protein glycosylation patterns (p. 181) Glycogen depletion coincides with the onset of fatigue
Membranes of extremophiles are built from ether lipids with (p. 455)
branched chains (p. 197) A deficiency of glucose 6-phosphate dehydrogenase confers an
Venomous pit vipers use ion channels to generate a thermal evolutionary advantage in some circumstances (p. 483)
image (p. 216) Hibernation presents nitrogen disposal problems (p. 558)
Snake venoms digest from the inside out (p. 254) Urea is not the only means of disposing of excess
Fermentations provide usable energy in the absence of nitrogen (p. 559)
oxygen (p. 294) Enzymes of the purine-synthesis pathway are associated with
Mitochondria are the result of an endosymbiotic event (p. 365) one another in vivo (p. 592)
The dead zone: too much respiration (p. 377) Many bacterial cells release chemical signals that regulate gene
Regulated uncoupling leads to the generation of heat (p. 396) expression in other cells (p. 670)
Chloroplasts, like mitochondria, arose from an endosymbiotic RNA editing changes the proteins encoded by mRNA (p. 698)
event (p. 409) Next-generation sequencing methods enable the rapid
Chlorophyll in potatoes suggests the presence of a toxin (p. 413) determination of a complete genome sequence (p. 753)
Many herbicides inhibit the light reactions of PCR is a powerful technique in medical diagnostics, forensics,
photosynthesis (p. 421) and studies of molecular evolution (p. 756)
Preface xiii
Acknowledgments
Our thanks go to the instructors and professors who have reviewed the chapters
of this book. Their sharp eyes and keen insights strongly influenced us as we
wrote and shaped the various drafts of each chapter to create this completed work.
The German scientist, writer, and statesman Johann Wolfgang von Goethe once
remarked, “Thinking is easy, acting is difficult, and to put one’s thoughts into
action is the most difficult thing in the world.” While we may disagree with
Goethe’s assertion that thinking is easy, we emphatically agree with the rest of the
quotation. Thinking about biochemistry and then putting those thoughts into
a book that is clear, welcoming, stimulating, and challenging is, if not the most
difficult thing in the world, still very demanding. This task would be utterly im-
possible without our wonderful colleagues at W. H. Freeman. They are intelligent,
dedicated, caring people who have taught us much about how to present science
to students and, in the process, brought out the best in us. Although we have had
the pleasure of working with our collaborators at W. H. Freeman on a number of
projects, our appreciation of and gratefulness for their efforts and guidance are as
sincere now as they were when we were inexperienced authors. Our experiences
with this edition have been as delightful and rewarding as our past projects. We
have many people to thank for this experience, some of whom we have worked
with previously and some new to the effort. First, we would like to acknowledge
the encouragement, patience, excellent advice, and good humor of our Publisher,
Kate Ahr Parker. Kate can suggest difficult challenges with such grace and equa-
nimity that we readily accept the challenge. New to our book team is our Senior
Acquisitions Editor, Lauren Schultz. Her unfailing enthusiasm was a source of
support and energy for the author team. New to our book team for this edition is
Heidi Bamatter, our Developmental Editor. Heidi is another in a line of outstand-
ing development editors that we have had the pleasure to work with at Freeman.
Her insight, patience, and guidance made this effort successful and enjoyable.
Elizabeth Geller, Senior Project Editor, managed the flow of the project with ad-
mirable efficiency. Teresa Wilson, our Manuscript Editor, enhanced the literary
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design and layout that made the book welcoming and accessible. Christine Buese
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tions. Paul Rohloff, Production Manager, made sure the difficulties of schedul-
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sors to examine our book, all of our own excitement and enthusiasm for this
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W. H. Freeman a true pleasure.
Thanks also to our many colleagues at our own institutions as well as through-
out the country who patiently answered our questions and encouraged us on our
quest. Finally, we owe a debt of gratitude to our families. Without their support,
comfort, and understanding, this project could never have been undertaken, let
alone successfully completed.
Brief Contents
xv
Contents
PART I SECTION 2
The Molecular Design of Life Protein Composition and Structure 35
xvi
Contents xvii
4.5 The Amino Acid Sequence of a Protein 6.4 Enzymes Facilitate the Formation of
Determines Its Three-Dimensional Structure 60 the Transition State 103
Proteins Fold by the Progressive Stabilization of The Formation of an Enzyme–Substrate Complex Is
Intermediates Rather Than by Random Search 61 the First Step in Enzymatic Catalysis 103
Some Proteins Are Inherently Unstructured and Can The Active Sites of Enzymes Have Some Common Features 104
Exist in Multiple Conformations 62 The Binding Energy Between Enzyme and Substrate Is
Clinical Insight Protein Misfolding and Aggregation Important for Catalysis 105
Are Associated with Some Neurological Diseases 63 Transition-State Analogs Are Potent Inhibitors of Enzyme 106
Chapter 5 Techniques in Protein Biochemistry 69
Chapter 7 Kinetics and Regulation 111
5.1 The Proteome Is the Functional Representation
7.1 Kinetics Is the Study of Reaction Rates 112
of the Genome 70
7.2 The Michaelis–Menten Model Describes
5.2 The Purification of a Protein Is the First Step in
the Kinetics of Many Enzymes 113
Understanding Its Function 70
Clinical Insight Variations in KM Can Have
Proteins Can Be Purified on the Basis of Differences in
Physiological Consequences 114
Their Chemical Properties 71
KM and Vmax Values Can Be Determined by Several Means 115
Proteins Must Be Removed from the Cell to Be Purified 71
KM and Vmax Values Are Important Enzyme Characteristics 115
Proteins Can Be Purified According to Solubility, Size,
Charge, and Binding Affinity 72 kcat/KM Is a Measure of Catalytic Efficiency 116
Proteins Can Be Separated by Gel Electrophoresis and Most Biochemical Reactions Include Multiple Substrates 117
Displayed 74 7.3 Allosteric Enzymes Are Catalysts and Information
A Purification Scheme Can Be Quantitatively Evaluated 77 Sensors 118
5.3 Immunological Techniques Are Used to Purify Allosteric Enzymes Are Regulated by Products of
and Characterize Proteins 78 the Pathways Under Their Control 120
Centrifugation Is a Means of Separating Proteins 78 Allosterically Regulated Enzymes Do Not Conform to
Gradient Centrifugation Provides an Assay for the Michaelis–Menten Kinetics 121
Estradiol–Receptor Complex 79 Allosteric Enzymes Depend on Alterations in Quaternary
Antibodies to Specific Proteins Can Be Generated 80 Structure 121
Monoclonal Antibodies with Virtually Any Desired Regulator Molecules Modulate the R m T Equilibrium 122
Specificity Can Be Readily Prepared 81 The Sequential Model Also Can Account for
The Estrogen Receptor Can Be Purified by Allosteric Effects 123
Immunoprecipitation 83 Clinical Insight Loss of Allosteric Control May
Proteins Can Be Detected and Quantified with Result in Pathological Conditions 123
the Use of an Enzyme-Linked Immunosorbent Assay 84 7.4 Enzymes Can Be Studied One Molecule at a Time 123
Western Blotting Permits the Detection of Proteins
Separated by Gel Electrophoresis 84 Chapter 8 Mechanisms and Inhibitors 131
5.4 Determination of Primary Structure Facilitates 8.1 A Few Basic Catalytic Strategies Are Used by
an Understanding of Protein Function 86 Many Enzymes 131
Mass Spectrometry Can Be Used to Determine a 8.2 Enzyme Activity Can Be Modulated by
Protein’s Mass, Identity, and Sequence 88 Temperature, pH, and Inhibitory Molecules 132
Amino Acids Are Sources of Many Kinds of Insight 90 Temperature Enhances the Rate of Enzyme-Catalyzed
Reactions 132
SECTION 3
Most Enzymes Have an Optimal pH 133
Basic Concepts and Kinetics of Enzymes 95
Enzymes Can Be Inhibited by Specific Molecules 134
Chapter 6 Basic Concepts of Enzyme Action 97 Reversible Inhibitors Are Kinetically Distinguishable 135
6.1 Enzymes Are Powerful and Highly Specific Catalysts 97 Irreversible Inhibitors Can Be Used to Map
Proteolytic Enzymes Illustrate the Range of Enzyme the Active Site 137
Specificity 98 Clinical Insight Penicillin Irreversibly Inactivates a
There Are Six Major Classes of Enzymes 98 Key Enzyme in Bacterial Cell-Wall Synthesis 138
6.2 Many Enzymes Require Cofactors for Activity 99 8.3 Chymotrypsin Illustrates Basic Principles of
6.3 Gibbs Free Energy Is a Useful Thermodynamic Catalysis and Inhibition 140
Function for Understanding Enzymes 100 Serine 195 Is Required for Chymotrypsin Activity 140
The Free-Energy Change Provides Information About Chymotrypsin Action Proceeds in Two Steps Linked by a
the Spontaneity but Not the Rate of a Reaction 100 Covalently Bound Intermediate 141
The Standard Free-Energy Change of a Reaction Is The Catalytic Role of Histidine 57 Was Demonstrated by
Related to the Equilibrium Constant 101 Affinity Labeling 142
Enzymes Alter the Reaction Rate but Not the Reaction Serine Is Part of a Catalytic Triad That Includes
Equilibrium 102 Histidine and Aspartic Acid 142
xviii Contents
Chapter 9 Hemoglobin, an Allosteric Protein 149 Biological Insight Blood Groups Are Based on
9.1 Hemoglobin Displays Cooperative Behavior 150 Protein Glycosylation Patterns 181
9.2 Myoglobin and Hemoglobin Bind Oxygen in Clinical Insight Lack of Glycosylation Can Result
in Pathological Conditions 182
Heme Groups 150
Clinical Insight Functional Magnetic Resonance 10.4 Lectins Are Specific Carbohydrate-Binding
Imaging Reveals Regions of the Brain Processing Proteins 182
Sensory Information 152 Lectins Promote Interactions Between Cells 183
9.3 Hemoglobin Binds Oxygen Cooperatively 152 Clinical Insight Lectins Facilitate Embryonic
Development 183
9.4 An Allosteric Regulator Determines the
Oxygen Affinity of Hemoglobin 154 Clinical Insight Influenza Virus Binds to
Sialic Acid Residues 183
Clinical Insight Hemoglobin’s Oxygen Affinity Is
Adjusted to Meet Environmental Needs 154
Chapter 11 Lipids 189
Biological Insight Hemoglobin Adaptations Allow
Oxygen Transport in Extreme Environments 155 11.1 Fatty Acids Are a Main Source of Fuel 190
9.5 Hydrogen Ions and Carbon Dioxide Promote the Fatty Acids Vary in Chain Length and Degree of
Unsaturation 191
Release of Oxygen 155
The Degree and Type of Unsaturation Are Important
9.6 Mutations in Genes Encoding Hemoglobin
to Health 192
Subunits Can Result in Disease 156
11.2 Triacylglycerols Are the Storage Form of
Clinical Insight Sickle-Cell Anemia Is a Disease
Caused by a Mutation in Hemoglobin 157
Fatty Acids 193
NEW Clinical Insight Thalassemia is Caused by an 11.3 There Are Three Common Types of
Imbalanced Production of Hemoglobin Chains 159 Membrane Lipids 194
Phospholipids Are the Major Class of
SECTION 4 Membrane Lipids 194
Carbohydrates and Lipids 165 Membrane Lipids Can Include Carbohydrates 196
Chapter 10 Carbohydrates 167 Steroids Are Lipids That Have a Variety of Roles 196
Biological Insight Membranes of Extremophiles
10.1 Monosaccharides Are the Simplest Carbohydrates 168
Are Built from Ether Lipids with Branched Chains 197
Many Common Sugars Exist in Cyclic Forms 169
Membrane Lipids Contain a Hydrophilic and
NEW Pyranose and Furanose Rings Can Assume a Hydrophobic Moiety 197
Different Conformations 171
Some Proteins Are Modified by the Covalent
NEW Clinical Insight Glucose Is a Reducing Sugar 171 Attachment of Hydrophobic Groups 198
Monosaccharides Are Joined to Alcohols and Clinical Insight Premature Aging Can Result from
Amines Through Glycosidic Bonds 172 the Improper Attachment of a Hydrophobic Group
Biological Insight Glucosinolates Protect Plants to a Protein 199
and Add Flavor to Our Diets 173
10.2 Monosaccharides Are Linked to Form Complex SECTION 5
Carbohydrates 173
Cell Membranes, Channels, Pumps, and
Specific Enzymes Are Responsible for Oligosaccharide
Assembly 173
Receptors 203
Sucrose, Lactose, and Maltose Are the Common
Disaccharides 174
Chapter 12 Membrane Structure and
Glycogen and Starch Are Storage Forms of Glucose 175 Function 205
Cellulose, a Structural Component of Plants, Is 12.1 Phospholipids and Glycolipids Form
Made of Chains of Glucose 175 Bimolecular Sheets 206
10.3 Carbohydrates Are Attached to Proteins to Clinical Insight Lipid Vesicles Can Be Formed
Form Glycoproteins 177 from Phospholipids 207
Carbohydrates May Be Linked to Asparagine, Serine, or Lipid Bilayers Are Highly Impermeable to Ions and
Threonine Residues of Proteins 177 Most Polar Molecules 207
Clinical Insight The Hormone Erythropoietin Is a 12.2 Membrane Fluidity Is Controlled by Fatty Acid
Glycoprotein 178 Composition and Cholesterol Content 208
Proteoglycans, Composed of Polysaccharides and 12.3 Proteins Carry Out Most Membrane Processes 209
Protein, Have Important Structural Roles 178 Proteins Associate with the Lipid Bilayer in
Clinical Insight Proteoglycans Are Important a Variety of Ways 209
Components of Cartilage 179 Clinical Insight The Association of Prostaglandin H2
Clinical Insight Mucins Are Glycoprotein Synthase-l with the Membrane Accounts for
Components of Mucus 180 the Action of Aspirin 211
Contents xix
12.4 Lipids and Many Membrane Proteins Diffuse The Activated Insulin-Receptor Kinase Initiates a Kinase
Laterally in the Membrane 211 Cascade 237
12.5 A Major Role of Membrane Proteins Is to Insulin Signaling Is Terminated by the Action of
Function As Transporters 212 Phosphatases 238
The Na+–K+ ATPase Is an Important Pump in 13.5 Calcium Ion Is a Ubiquitous Cytoplasmic
Many Cells 213 Messenger 238
Clinical Insight Multidrug Resistance Highlights 13.6 Defects in Signaling Pathways Can Lead to
a Family of Membrane Pumps with ATP-Binding Diseases 239
Domains 214 Clinical Insight The Conversion of
Clinical Insight Harlequin Ichthyosis Is a Dramatic Proto-oncogenes into Oncogenes Disrupts
Result of a Mutation in an ABC Transporter Protein 214 the Regulation of Cell Growth 239
Secondary Transporters Use One Concentration Clinical Insight Protein Kinase Inhibitors May
Gradient to Power the Formation of Another 214 Be Effective Anticancer Drugs 240
Clinical Insight Digitalis Inhibits the Na+-K+ Pump
by Blocking Its Dephosphorylation 215 PART II
Specific Channels Can Rapidly Transport Ions Across Transducing and Storing Energy
Membranes 216
Biological Insight Venomous Pit Vipers Use Ion SECTION 6
Channels to Generate a Thermal Image 216 Basic Concepts and Design of Metabolism 245
The Structure of the Potassium Ion Channel Reveals
the Basis of Ion Specificity 216
Chapter 14 Digestion: Turning a Meal into
The Structure of the Potassium Ion Channel Explains
Cellular Biochemicals 247
Its Rapid Rate of Transport 218 14.1 Digestion Prepares Large Biomolecules for
Use in Metabolism 247
Chapter 13 Signal-Transduction Pathways 225 Most Digestive Enzymes Are Secreted as Inactive
13.1 Signal Transduction Depends on Molecular Precursors 248
Circuits 225 14.2 Proteases Digest Proteins into Amino Acids and
13.2 Receptor Proteins Transmit Information into Peptides 248
the Cell 227 NEW Clinical Insight Protein Digestion Begins in the
Seven-Transmembrane-Helix Receptors Change Stomach 248
Conformation in Response to Ligand Binding and NEW Protein Digestion Continues in the Intestine 249
Activate G Proteins 227 NEW Clinical Insight Celiac Disease Results from
Ligand Binding to 7TM Receptors Leads to the the Inability to Properly Digest Certain Proteins 251
Activation of G Proteins 228 14.3 Dietary Carbohydrates Are Digested by
Activated G Proteins Transmit Signals by Binding to Alpha-Amylase 251
Other Proteins 229 14.4 The Digestion of Lipids Is Complicated by
Cyclic AMP Stimulates the Phosphorylation of Their Hydrophobicity 252
Many Target Proteins by Activating Protein Kinase A 229 Biological Insight Snake Venoms Digest from
NEW Clinical Insight Mutations in Protein Kinase A the Inside Out 254
Can Cause Cushing’s Syndrome 230
G Proteins Spontaneously Reset Themselves Chapter 15 Metabolism: Basic Concepts and
Through GTP Hydrolysis 230 Design 257
Clinical Insight Cholera and Whooping Cough Are 15.1 Energy Is Required to Meet Three
Due to Altered G-Protein Activity 231 NEW Fundamental Needs 258
The Hydrolysis of Phosphatidylinositol Bisphosphate by 15.2 Metabolism Is Composed of Many
Phospholipase C Generates Two Second Messengers 232 Interconnecting Reactions 258
13.3 Some Receptors Dimerize in Response to Ligand Metabolism Consists of Energy-Yielding Reactions and
Binding and Recruit Tyrosine Kinases 233 Energy-Requiring Reactions 259
Receptor Dimerization May Result in Tyrosine Kinase A Thermodynamically Unfavorable Reaction Can
Recruitment 233 Be Driven by a Favorable Reaction 260
Clinical Insight Some Receptors Contain Tyrosine 15.3 ATP Is the Universal Currency of Free Energy 260
Kinase Domains Within Their Covalent Structures 235
ATP Hydrolysis Is Exergonic 261
Ras Belongs to Another Class of Signaling G Proteins 236
ATP Hydrolysis Drives Metabolism by Shifting
13.4 Metabolism in Context: Insulin Signaling the Equilibrium of Coupled Reactions 261
Regulates Metabolism 236 The High Phosphoryl-Transfer Potential of
The Insulin Receptor Is a Dimer That Closes Around ATP Results from Structural Differences Between
a Bound Insulin Molecule 236 ATP and Its Hydrolysis Products 263
xx Contents
Phosphoryl-Transfer Potential Is an Important Form of Clinical Insight Galactose Is Highly Toxic If the
Cellular Energy Transformation 264 Transferase Is Missing 298
Clinical Insight Exercise Depends on Various 16.4 The Glycolytic Pathway Is Tightly Controlled 299
Means of Generating ATP 265 Glycolysis in Muscle Is Regulated by Feedback
Phosphates Play a Prominent Role in Inhibition to Meet the Need for ATP 299
Biochemical Processes 266 The Regulation of Glycolysis in the Liver
15.4 The Oxidation of Carbon Fuels Is an Corresponds to the Biochemical Versatility of
Important Source of Cellular Energy 266 the Liver 300
Carbon Oxidation Is Paired with a Reduction 266 A Family of Transporters Enables Glucose to Enter and
Compounds with High Phosphoryl-Transfer Potential Leave Animal Cells 303
Can Couple Carbon Oxidation to ATP Synthesis 267 NEW Clinical Insight Aerobic Glycolysis Is a
Property of Rapidly Growing Cells 304
15.5 Metabolic Pathways Contain Many Recurring
Motifs 268 Clinical Insight Cancer and Exercise Training Affect
Glycolysis in a Similar Fashion 305
Activated Carriers Exemplify the Modular Design and
Economy of Metabolism 268 16.5 Metabolism in Context: Glycolysis Helps
Clinical Insight Lack of Activated Pantothenate
Pancreatic Beta Cells Sense Glucose 305
Results in Neurological Problems 271 Chapter 17 Gluconeogenesis 313
Many Activated Carriers Are Derived from Vitamins 271 17.1 Glucose Can Be Synthesized from
15.6 Metabolic Processes Are Regulated in Noncarbohydrate Precursors 314
Three Principal Ways 273 Gluconeogenesis Is Not a Complete Reversal of
The Amounts of Enzymes Are Controlled 274 Glycolysis 314
Catalytic Activity Is Regulated 274 The Conversion of Pyruvate into Phosphoenolpyruvate
The Accessibility of Substrates Is Regulated 275 Begins with the Formation of Oxaloacetate 316
Oxaloacetate Is Shuttled into the Cytoplasm and
SECTION 7 Converted into Phosphoenolpyruvate 317
Glycolysis and Gluconeogenesis 281 The Conversion of Fructose 1,6-bisphosphate into
Fructose 6-phosphate and Orthophosphate Is an
Chapter 16 Glycolysis 283 Irreversible Step 318
16.1 Glycolysis Is an Energy-Conversion Pathway 284 The Generation of Free Glucose Is an Important
Hexokinase Traps Glucose in the Cell and Control Point 319
Begins Glycolysis 284 Six High-Transfer-Potential Phosphoryl Groups Are
Fructose 1,6-bisphosphate Is Generated from Glucose Spent in Synthesizing Glucose from Pyruvate 319
6-phosphate 286 17.2 Gluconeogenesis and Glycolysis Are
Clinical Insight The Six-Carbon Sugar Is Cleaved Reciprocally Regulated 320
into Two Three-Carbon Fragments 287 Energy Charge Determines Whether Glycolysis or
The Oxidation of an Aldehyde Powers the Formation Gluconeogenesis Will Be More Active 320
of a Compound Having High Phosphoryl-Transfer The Balance Between Glycolysis and Gluconeogenesis
Potential 288 in the Liver Is Sensitive to Blood-Glucose
ATP Is Formed by Phosphoryl Transfer from Concentration 321
1,3-Bisphosphoglycerate 289 Clinical Insight Insulin Fails to Inhibit
Additional ATP Is Generated with the Formation Gluconeogenesis in Type 2 Diabetes 323
of Pyruvate 290 Clinical Insight Substrate Cycles Amplify
Two ATP Molecules Are Formed in the Conversion Metabolic Signals 323
of Glucose into Pyruvate 291 17.3 Metabolism in Context: Precursors Formed by
16.2 NAD+ Is Regenerated from the Metabolism of Muscle Are Used by Other Organs 324
Pyruvate 291
SECTION 8
Fermentations Are a Means of Oxidizing NADH 292
The Citric Acid Cycle 329
Biological Insight Fermentations Provide Usable
Energy in the Absence of Oxygen 294 Chapter 18 Preparation for the Cycle 331
16.3 Fructose and Galactose Are Converted into 18.1 Pyruvate Dehydrogenase Forms Acetyl
Glycolytic Intermediates 294 Coenzyme A from Pyruvate 332
NEW Fructose Is Converted into Glycolytic Intermediates The Synthesis of Acetyl Coenzyme A from
by Fructokinase 295 Pyruvate Requires Three Enzymes and
NEW Clinical Insight Excessive Fructose Five Coenzymes 333
Consumption Can Lead to Pathological Conditions 295 Flexible Linkages Allow Lipoamide to Move Between
NEW Galactose Is Converted into Glucose 6-phosphate 296 Different Active Sites 335
Clinical Insight Many Adults Are Intolerant of Milk 18.2 The Pyruvate Dehydrogenase Complex Is
Because They Are Deficient in Lactase 297 Regulated by Two Mechanisms 337
Contents xxi
Clinical Insight Defective Regulation of Pyruvate The Electron-Transport Chain Is a Series of
Dehydrogenase Results in Lactic Acidosis 338 Coupled Oxidation–Reduction Reactions 368
Clinical Insight Enhanced Pyruvate NEW Clinical Insight Loss of Iron-Sulfur Cluster
Dehydrogenase Kinase Activity Facilitates the Results in Friedreich’s Ataxia 371
Development of Cancer 339
20.3 The Respiratory Chain Consists of Proton
Clinical Insight The Disruption of Pyruvate Pumps and a Physical Link to the Citric
Metabolism Is the Cause of Beriberi 339
Acid Cycle 371
The High-Potential Electrons of NADH Enter
Chapter 19 Harvesting Electrons from the Respiratory Chain at NADH-Q Oxidoreductase 371
the Cycle 343 Ubiquinol Is the Entry Point for Electrons from
19.1 The Citric Acid Cycle Consists of Two Stages 344 FADH2 of Flavoproteins 373
19.2 Stage One Oxidizes Two Carbon Atoms to Electrons Flow from Ubiquinol to Cytochrome c
Gather Energy-Rich Electrons 344 Through Q-Cytochrome c Oxidoreductase 373
Citrate Synthase Forms Citrate from Oxaloacetate and The Q Cycle Funnels Electrons from a Two-Electron
Acetyl Coenzyme A 344 Carrier to a One-Electron Carrier and Pumps Protons 374
The Mechanism of Citrate Synthase Prevents Cytochrome c Oxidase Catalyzes the Reduction of
Undesirable Reactions 345 Molecular Oxygen to Water 375
Citrate Is Isomerized into Isocitrate 346 Biological Insight The Dead Zone: Too Much
Isocitrate Is Oxidized and Decarboxylated to Respiration 377
Alpha-Ketoglutarate 346 Toxic Derivatives of Molecular Oxygen Such As Superoxide
Succinyl Coenzyme A Is Formed by the Oxidative Radical Are Scavenged by Protective Enzymes 377
Decarboxylation of Alpha-Ketoglutarate 347
19.3 Stage Two Regenerates Oxaloacetate and
Chapter 21 The Proton-Motive Force 383
Harvests Energy-Rich Electrons 347
21.1 A Proton Gradient Powers the Synthesis of ATP 384
A Compound with High Phosphoryl-Transfer
Potential Is Generated from Succinyl Coenzyme A 347 ATP Synthase Is Composed of a Proton-Conducting
Unit and a Catalytic Unit 385
Succinyl Coenzyme A Synthetase Transforms
Types of Biochemical Energy 348 Proton Flow Through ATP Synthase Leads to the
Oxaloacetate Is Regenerated by the Oxidation of Release of Tightly Bound ATP 386
Succinate 349 Rotational Catalysis Is the World’s Smallest
The Citric Acid Cycle Produces High-Transfer-Potential Molecular Motor 387
Electrons, an ATP, and Carbon Dioxide 349 Proton Flow Around the c Ring Powers ATP
19.4 The Citric Acid Cycle Is Regulated 352 Synthesis 388
The Citric Acid Cycle Is Controlled at Several Points 352 21.2 Shuttles Allow Movement Across
The Citric Acid Cycle Is a Source of Biosynthetic Mitochondrial Membranes 390
Precursors 353 Electrons from Cytoplasmic NADH Enter
The Citric Acid Cycle Must Be Capable of Being Rapidly Mitochondria by Shuttles 390
Replenished 353 The Entry of ADP into Mitochondria Is Coupled to
Clinical Insight Defects in the Citric Acid Cycle the Exit of ATP 392
Contribute to the Development of Cancer 354 Mitochondrial Transporters Allow Metabolite Exchange
19.5 The Glyoxylate Cycle Enables Plants and Between the Cytoplasm and Mitochondria 393
Bacteria to Convert Fats into Carbohydrates 355 21.3 Cellular Respiration Is Regulated by
the Need for ATP 393
SECTION 9 The Complete Oxidation of Glucose Yields About
Oxidative Phosphorylation 361 30 Molecules of ATP 393
The Rate of Oxidative Phosphorylation Is Determined
Chapter 20 The Electron-Transport Chain 363 by the Need for ATP 395
20.1 Oxidative Phosphorylation in Eukaryotes
NEW Clinical Insight ATP Synthase Can Be
Takes Place in Mitochondria 364
Regulated 395
Mitochondria Are Bounded by a Double Membrane 364
Biological Insight Mitochondria Are the Biological Insight Regulated Uncoupling Leads to
Result of an Endosymbiotic Event 365 the Generation of Heat 396
20.2 Oxidative Phosphorylation Depends on Electron Clinical Insight Oxidative Phosphorylation Can Be
Transfer 366 Inhibited at Many Stages 398
The Electron-Transfer Potential of an Electron Is Clinical Insight Mitochondrial Diseases Are Being
Measured as Redox Potential 366 Discovered in Increasing Numbers 399
Electron Flow Through the Electron-Transport Power Transmission by Proton Gradients Is a
Chain Creates a Proton Gradient 367 Central Motif of Bioenergetics 400
xxii Contents
SECTION 10 Thioredoxin Plays a Key Role in Regulating
The Light Reactions of Photosynthesis and the Calvin Cycle 435
the Calvin Cycle 405 Rubisco Also Catalyzes a Wasteful Oxygenase Reaction 436
The C4 Pathway of Tropical Plants Accelerates
Chapter 22 The Light Reactions 407 Photosynthesis by Concentrating Carbon Dioxide 436
22.1 Photosynthesis Takes Place in Chloroplasts 408 Crassulacean Acid Metabolism Permits Growth in Arid
Biological Insight Chloroplasts, Like Mitochondria, Ecosystems 438
Arose from an Endosymbiotic Event 409
SECTION 11
22.2 Photosynthesis Transforms Light Energy into
Glycogen Metabolism and the Pentose
Chemical Energy 409
Phosphate Pathway 443
Chlorophyll Is the Primary Receptor in Most
Photosynthetic Systems 410 Chapter 24 Glycogen Degradation 445
Light-Harvesting Complexes Enhance the Efficiency
24.1 Glycogen Breakdown Requires Several Enzymes 446
of Photosynthesis 411
Phosphorylase Cleaves Glycogen to Release Glucose
Biological Insight Chlorophyll in Potatoes
1-phosphate 446
Suggests the Presence of a Toxin 413
A Debranching Enzyme Also Is Needed for
22.3 Two Photosystems Generate a Proton the Breakdown of Glycogen 447
Gradient and NADPH 413
Phosphoglucomutase Converts Glucose 1-phosphate
Photosystem I Uses Light Energy to Generate Reduced into Glucose 6-phosphate 448
Ferredoxin, a Powerful Reductant 414
Liver Contains Glucose 6-phosphatase,
Photosystem II Transfers Electrons to a Hydrolytic Enzyme Absent from Muscle 448
Photosystem I and Generates a Proton Gradient 415
24.2 Phosphorylase Is Regulated by Allosteric
Cytochrome b6 f Links Photosystem II to
Interactions and Reversible Phosphorylation 449
Photosystem I 416
Liver Phosphorylase Produces Glucose for Use by
The Oxidation of Water Achieves Oxidation–Reduction Other Tissues 449
Balance and Contributes Protons to the Proton
Muscle Phosphorylase Is Regulated by
Gradient 416
the Intracellular Energy Charge 450
22.4 A Proton Gradient Drives ATP Synthesis 418
Biochemical Characteristics of Muscle Fiber Types Differ 451
The ATP Synthase of Chloroplasts Closely Resembles
NEW Phosphorylation Promotes the Conversion of
That of Mitochondria 418
Phosphorylase b to Phosphorylase a 451
NEW The Activity of Chloroplast ATP Synthase Is
Phosphorylase Kinase Is Activated by
Regulated 419
Phosphorylation and Calcium Ions 452
Cyclic Electron Flow Through Photosystem I Leads
Clinical Insight Hers Disease Is Due to a
to the Production of ATP Instead of NADPH 419
Phosphorylase Deficiency 453
The Absorption of Eight Photons Yields One O2 ,
Two NADPH, and Three ATP Molecules 420
24.3 Epinephrine and Glucagon Signal
the Need for Glycogen Breakdown 453
The Components of Photosynthesis Are
Highly Organized 421 G Proteins Transmit the Signal for the Initiation
of Glycogen Breakdown 453
Biological Insight Many Herbicides Inhibit the
Light Reactions of Photosynthesis 421 Glycogen Breakdown Must Be Rapidly Turned
Off When Necessary 455
Chapter 23 The Calvin Cycle 427 Biological Insight Glycogen Depletion Coincides
with the Onset of Fatigue 455
23.1 The Calvin Cycle Synthesizes Hexoses from
Carbon Dioxide and Water 428 Chapter 25 Glycogen Synthesis 459
Carbon Dioxide Reacts with Ribulose
25.1 Glycogen Is Synthesized and Degraded by
1,5-bisphosphate to Form Two Molecules of
3-Phosphoglycerate 429
Different Pathways 459
UDP-Glucose Is an Activated Form of Glucose 460
Hexose Phosphates Are Made from
Phosphoglycerate, and Ribulose 1,5-bisphosphate Glycogen Synthase Catalyzes the Transfer of
Is Regenerated 430 Glucose from UDP-Glucose to a Growing Chain 460
Three Molecules of ATP and Two Molecules of A Branching Enzyme Forms Alpha-1,6 Linkages 461
NADPH Are Used to Bring Carbon Dioxide to Glycogen Synthase Is the Key Regulatory Enzyme
the Level of a Hexose 430 in Glycogen Synthesis 461
Biological Insight A Volcanic Eruption Can Affect Glycogen Is an Efficient Storage Form of Glucose 462
Photosynthesis Worldwide 432 25.2 Metabolism in Context: Glycogen Breakdown
Starch and Sucrose Are the Major Carbohydrate and Synthesis Are Reciprocally Regulated 462
Stores in Plants 433 Protein Phosphatase 1 Reverses the Regulatory
Biological Insight Why Bread Becomes Stale: Effects of Kinases on Glycogen Metabolism 462
The Role of Starch 434 Insulin Stimulates Glycogen Synthesis by Inactivating
23.2 The Calvin Cycle Is Regulated by the Environment 434 Glycogen Synthase Kinase 464
Contents xxiii
Glycogen Metabolism in the Liver Regulates NEW Clinical Insight Ketogenic Diets May Have
the Blood-Glucose Concentration 465 Therapeutic Properties 498
Clinical Insight Diabetes Mellitus Results from Animals Cannot Convert Fatty Acids into Glucose 498
Insulin Insufficiency and Glucagon Excess 466 27.4 Metabolism in Context: Fatty Acid Metabolism
Clinical Insight A Biochemical Understanding of Is a Source of Insight into Various
Glycogen-Storage Diseases Is Possible 467 Physiological States 499
Clinical Insight Diabetes Can Lead to a
Chapter 26 The Pentose Phosphate
Life-Threatening Excess of Ketone-Body Production 499
Pathway 473
Clinical Insight Ketone Bodies Are a Crucial
26.1 The Pentose Phosphate Pathway Yields Fuel Source During Starvation 500
NADPH and Five-Carbon Sugars 474
NEW Clinical Insight Some Fatty Acids May Contribute
Two Molecules of NADPH Are Generated in to the Development of Pathological Conditions 501
the Conversion of Glucose 6-phosphate into
Ribulose 5-phosphate 474
The Pentose Phosphate Pathway and Glycolysis Chapter 28 Fatty Acid Synthesis 507
Are Linked by Transketolase and Transaldolase 474 28.1 Fatty Acid Synthesis Takes Place in Three Stages 507
26.2 Metabolism in Context: Glycolysis and Citrate Carries Acetyl Groups from Mitochondria
the Pentose Phosphate Pathway Are to the Cytoplasm 508
Coordinately Controlled 478 Several Sources Supply NADPH for Fatty Acid Synthesis 508
The Rate of the Pentose Phosphate Pathway Is The Formation of Malonyl CoA Is the Committed
Controlled by the Level of NADP+ 478 Step in Fatty Acid Synthesis 509
The Fate of Glucose 6-phosphate Depends on Fatty Acid Synthesis Consists of a Series of
the Need for NADPH, Ribose 5-phosphate, and ATP 478 Condensation, Reduction, Dehydration, and
NEW Clinical Insight The Pentose Phosphate Reduction Reactions 510
Pathway Is Required For Rapid Cell Growth 481 The Synthesis of Palmitate Requires 8 Molecules of
26.3 Glucose 6-phosphate Dehydrogenase Acetyl CoA, 14 Molecules of NADPH, and
7 Molecules of ATP 512
Lessens Oxidative Stress 481
Fatty Acids Are Synthesized by a Multifunctional
Clinical Insight Glucose 6-phosphate
Enzyme Complex in Animals 512
Dehydrogenase Deficiency Causes a Drug-Induced
Hemolytic Anemia 481 Clinical Insight Fatty Acid Metabolism Is Altered in
Tumor Cells 513
Biological Insight A Deficiency of Glucose
6-phosphate Dehydrogenase Confers an Clinical Insight A Small Fatty Acid That Causes
Evolutionary Advantage in Some Circumstances 483 Big Problems 513
28.2 Additional Enzymes Elongate and Desaturate
SECTION 12 Fatty Acids 514
Fatty Acid and Lipid Metabolism 487 Membrane-Bound Enzymes Generate Unsaturated
Fatty Acids 514
Chapter 27 Fatty Acid Degradation 489
Eicosanoid Hormones Are Derived from
27.1 Fatty Acids Are Processed in Three Stages 489 Polyunsaturated Fatty Acids 514
Clinical Insight Triacylglycerols Are Hydrolyzed Clinical Insight Aspirin Exerts Its Effects by
by Hormone-Stimulated Lipases 490 Covalently Modifying a Key Enzyme 515
NEW Free Fatty Acids and Glycerol Are Released into 28.3 Acetyl CoA Carboxylase Is a Key Regulator of
the Blood 491 Fatty Acid Metabolism 516
Fatty Acids Are Linked to Coenzyme A Before Acetyl CoA Carboxylase Is Regulated by Conditions
They Are Oxidized 491 in the Cell 516
Clinical Insight Pathological Conditions Result if Acetyl CoA Carboxylase Is Regulated by a Variety of
Fatty Acids Cannot Enter the Mitochondria 493 Hormones 516
Acetyl CoA, NADH, and FADH2 Are Generated by
28.4 Metabolism in Context: Ethanol Alters Energy
Fatty Acid Oxidation 493
Metabolism in the Liver 517
The Complete Oxidation of Palmitate Yields
106 Molecules of ATP 495
27.2 The Degradation of Unsaturated and Chapter 29 Lipid Synthesis: Storage Lipids,
Odd-Chain Fatty Acids Requires Additional Steps 495 Phospholipids, and Cholesterol 523
An Isomerase and a Reductase Are Required for the 29.1 Phosphatidate Is a Precursor of Storage
Oxidation of Unsaturated Fatty Acids 495 Lipids and Many Membrane Lipids 523
Odd-Chain Fatty Acids Yield Propionyl CoA in the Triacylglycerol Is Synthesized from Phosphatidate in
Final Thiolysis Step 497 Two Steps 524
27.3 Ketone Bodies Are Another Fuel Source Phospholipid Synthesis Requires Activated Precursors 524
Derived from Fats 497 NEW Clinical Insight Phosphatidylcholine Is an
Ketone-Body Synthesis Takes Place in the Liver 497 Abundant Phospholipid 526
xxiv Contents
Sphingolipids Are Synthesized from Ceramide 526 30.2 Ammonium Ion Is Converted into Urea in Most
Clinical Insight Gangliosides Serve as Binding Terrestrial Vertebrates 555
Sites for Pathogens 527 NEW Carbamoyl Phosphate Synthetase Is the Key
Clinical Insight Disrupted Lipid Metabolism Regulatory Enzyme for Urea Synthesis 556
Results in Respiratory Distress Syndrome and NEW Carbamoyl Phosphate Reacts with Ornithine to Begin the
Tay–Sachs Disease 528 Urea Cycle 556
Phosphatidic Acid Phosphatase Is a Key The Urea Cycle Is Linked to Gluconeogenesis 557
Regulatory Enzyme in Lipid Metabolism 529 Clinical Insight Metabolism in Context:
29.2 Cholesterol Is Synthesized from Acetyl Inherited Defects of the Urea Cycle Cause
Coenzyme A in Three Stages 529 Hyperammonemia 558
The Synthesis of Mevalonate Initiates the Synthesis of Biological Insight Hibernation Presents Nitrogen
Cholesterol 530 Disposal Problems 558
Squalene (C30) Is Synthesized from Six Molecules of Biological Insight Urea Is Not the Only Means of
Isopentenyl Pyrophosphate (C5) 530 Disposing of Excess Nitrogen 559
Squalene Cyclizes to Form Cholesterol 532 30.3 Carbon Atoms of Degraded Amino Acids
29.3 The Regulation of Cholesterol Synthesis Emerge as Major Metabolic Intermediates 559
Takes Place at Several Levels 532 Pyruvate Is a Point of Entry into Metabolism 560
29.4 Lipoproteins Transport Cholesterol and Oxaloacetate Is Another Point of Entry into
Triacylglycerols Throughout the Organism 534 Metabolism 561
Low-Density Lipoproteins Play a Central Role in Alpha-Ketoglutarate Is Yet Another Point of Entry into
Cholesterol Metabolism 535 Metabolism 561
Clinical Insight The Absence of the LDL Receptor Succinyl Coenzyme A Is a Point of Entry for
Leads to Familial Hypercholesterolemia and Several Nonpolar Amino Acids 562
Atherosclerosis 536 The Branched-Chain Amino Acids Yield Acetyl
NEW Clinical Insight Cycling of the LDL Receptor Coenzyme A, Acetoacetate, or Succinyl Coenzyme A 562
Is Regulated 537 Oxygenases Are Required for the Degradation of
Clinical Insight HDL Seems to Protect Against Aromatic Amino Acids 563
Atherosclerosis 537 Methionine Is Degraded into Succinyl Coenzyme A 565
NEW Clinical Insight The Clinical Management of Clinical Insight Inborn Errors of Metabolism
Cholesterol Levels Can Be Understood at a Can Disrupt Amino Acid Degradation 565
Biochemical Level 538 NEW Clinical Insight Determining the Basis of the
29.5 Cholesterol Is the Precursor of Steroid Neurological Symptoms of Phenylketonuria
Hormones 539 Is an Active Area of Research 566
NEW Clinical Insight Bile Salts Facilitate Lipid
Absorption 539 Chapter 31 Amino Acid Synthesis 571
Steroid Hormones Are Crucial Signal Molecules 539 31.1 The Nitrogenase Complex Fixes Nitrogen 572
Vitamin D Is Derived from Cholesterol by The Molybdenum–Iron Cofactor of Nitrogenase
the Energy of Sunlight 540 Binds and Reduces Atmospheric Nitrogen 573
Clinical Insight Vitamin D Is Necessary for Bone Ammonium Ion Is Incorporated into an Amino
Development 541 Acid Through Glutamate and Glutamine 573
Clinical Insight Androgens Can Be Used to 31.2 Amino Acids Are Made from Intermediates
Artificially Enhance Athletic Performance 542 of Major Pathways 574
Oxygen Atoms Are Added to Steroids by Human Beings Can Synthesize Some Amino Acids
Cytochrome P450 Monooxygenases 542 but Must Obtain Others from the Diet 574
Metabolism in Context: Ethanol Also Is Processed by Some Amino Acids Can Be Made by Simple
the Cytochrome P450 System 543 Transamination Reactions 575
SECTION 13 Serine, Cysteine, and Glycine Are Formed from
The Metabolism of Nitrogen-Containing 3-Phosphoglycerate 576
Molecules 549 Clinical Insight Tetrahydrofolate Carries
Activated One-Carbon Units 576
Chapter 30 Amino Acid Degradation and S-Adenosylmethionine Is the Major Donor of
the Urea Cycle 551 Methyl Groups 578
30.1 Nitrogen Removal Is the First Step in Clinical Insight High Homocysteine Levels
the Degradation of Amino Acids 552 Correlate with Vascular Disease 578
Alpha-Amino Groups Are Converted into Ammonium 31.3 Feedback Inhibition Regulates Amino Acid
Ions by the Oxidative Deamination of Glutamate 552 Biosynthesis 579
NEW Clinical Insight Blood Levels of The Committed Step Is the Common Site
Amonitransferases Serve a Diagnostic Function 553 of Regulation 579
NEW Serine and Threonine Can Be Directly Deaminated 553 Branched Pathways Require Sophisticated
Peripheral Tissues Transport Nitrogen to the Liver 554 Regulation 579
Contents xxv
Chapter 32 Nucleotide Metabolism 585 33.2 Nucleic Acid Strands Can Form a Double-Helical
32.1 An Overview of Nucleotide Biosynthesis and Structure 611
Nomenclature 586 The Double Helix Is Stabilized by Hydrogen
Bonds and the Hydrophobic Effect 611
32.2 The Pyrimidine Ring Is Assembled and
The Double Helix Facilitates the Accurate
Then Attached to a Ribose Sugar 587
Transmission of Hereditary Information 613
CTP Is Formed by the Amination of UTP 589
Meselson and Stahl Demonstrated That Replication Is
Kinases Convert Nucleoside Monophosphates into Semiconservative 614
Nucleoside Triphosphates 589
The Strands of the Double Helix Can Be Reversibly
NEW Clinical Insight Salvage Pathways Recycle Separated 615
Pyrimidine Bases 589
33.3 DNA Double Helices Can Adopt Multiple Forms 615
32.3 The Purine Ring Is Assembled on Ribose
Z-DNA Is a Left-Handed Double Helix in Which
Phosphate 590 Backbone Phosphoryl Groups Zigzag 616
AMP and GMP Are Formed from IMP 590 The Major and Minor Grooves Are Lined by
Clinical Insight Enzymes of the Purine-Synthesis Sequence-Specific Hydrogen-Bonding Groups 616
Pathway Are Associated with One Another in Vivo 592 Double-Stranded DNA Can Wrap Around Itself to Form
Bases Can Be Recycled by Salvage Pathways 593 Supercoiled Structures 617
32.4 Ribonucleotides Are Reduced to 33.4 Eukaryotic DNA Is Associated with Specific
Deoxyribonucleotides 593 Proteins 619
Thymidylate Is Formed by the Methylation of Nucleosomes Are Complexes of DNA and Histones 619
Deoxyuridylate 594 Eukaryotic DNA Is Wrapped Around Histones to Form
Clinical Insight Several Valuable Anticancer Drugs Nucleosomes 620
Block the Synthesis of Thymidylate 595 Clinical Insight Damaging DNA Can Inhibit
32.5 Nucleotide Biosynthesis Is Regulated by Cancer-Cell Growth 622
Feedback Inhibition 596 33.5 RNA Can Adopt Elaborate Structures 622
Pyrimidine Biosynthesis Is Regulated by Aspartate
Transcarbamoylase 596 Chapter 34 DNA Replication 627
The Synthesis of Purine Nucleotides Is Controlled by 34.1 DNA Is Replicated by Polymerases 628
Feedback Inhibition at Several Sites 596 DNA Polymerase Catalyzes Phosphodiester-Linkage
NEW Clinical Insight The Synthesis of Formation 628
Deoxyribonucleotides Is Controlled by the The Specificity of Replication Is Dictated by the
Regulation of Ribonucleotide Reductase 597 Complementarity of Bases 630
32.6 Disruptions in Nucleotide Metabolism Can Clinical Insight The Separation of DNA Strands
Cause Pathological Conditions 598 Requires Specific Helicases and ATP Hydrolysis 630
Clinical Insight The Loss of Adenosine Deaminase Topoisomerases Prepare the Double Helix for
Activity Results in Severe Combined Unwinding 632
Immunodeficiency 598 Clinical Insight Bacterial Topoisomerase Is a
Clinical Insight Gout Is Induced by High Serum Therapeutic Target 632
Levels of Urate 599 Many Polymerases Proofread the Newly Added
Clinical Insight Lesch–Nyhan Syndrome Is a Bases and Excise Errors 633
Dramatic Consequence of Mutations in a 34.2 DNA Replication Is Highly Coordinated 633
Salvage-Pathway Enzyme 600
DNA Replication in E. coli Begins at a Unique Site 634
Clinical Insight Folic Acid Deficiency Promotes
An RNA Primer Synthesized by Primase Enables DNA
Birth Defects Such As Spina Bifida 600
Synthesis to Begin 634
One Strand of DNA Is Made Continuously and
PART III the Other Strand Is Synthesized in Fragments 635
Synthesizing the Molecules of Life DNA Replication Requires Highly Processive
Polymerases 635
Section 14 The Leading and Lagging Strands Are Synthesized in a
Coordinated Fashion 636
Nucleic Acid Structure and DNA Replication 605
DNA Synthesis Is More Complex in Eukaryotes
Than in Bacteria 638
Chapter 33 The Structure of Informational
Telomeres Are Unique Structures at the Ends of
Macromolecules: DNA and RNA 607 Linear Chromosomes 638
33.1 A Nucleic Acid Consists of Bases Linked to Clinical Insight Telomeres Are Replicated by
a Sugar–Phosphate Backbone 608 Telomerase, a Specialized Polymerase That
DNA and RNA Differ in the Sugar Component and Carries Its Own RNA Template 639
One of the Bases 608
Nucleotides Are the Monomeric Units of Nucleic Acids 609 Chapter 35 DNA Repair and Recombination 643
DNA Molecules Are Very Long and Have Directionality 610 35.1 Errors Can Arise in DNA Replication 644
xxvi Contents
Clinical Insight Some Genetic Diseases Are Caused
Chapter 37 Gene Expression in Eukaryotes 675
by the Expansion of Repeats of Three Nucleotides 644 37.1 Eukaryotic Cells Have Three Types of RNA
Bases Can Be Damaged by Oxidizing Agents, Polymerases 676
Alkylating Agents, and Light 645 37.2 RNA Polymerase II Requires Complex
35.2 DNA Damage Can Be Detected and Repaired 647 Regulation 678
The Presence of Thymine Instead of Uracil in The Transcription Factor IID Protein Complex Initiates
DNA Permits the Repair of Deaminated Cytosine 649 the Assembly of the Active Transcription Complex 679
Clinical Insight Many Cancers Are Caused by Enhancer Sequences Can Stimulate Transcription at
the Defective Repair of DNA 650 Start Sites Thousands of Bases Away 679
Clinical Insight Many Potential Carcinogens Clinical Insight Inappropriate Enhancer Use
Can Be Detected by Their Mutagenic Action May Cause Cancer 680
on Bacteria 650 Multiple Transcription Factors Interact with Eukaryotic
35.3 DNA Recombination Plays Important Roles in Promoters and Enhancers 680
Replication and Repair 651 Clinical Insight Induced Pluripotent Stem Cells
Double Strand Breaks Can Be Repaired by Can Be Generated by Introducing Four Transcription
Recombination 652 Factors into Differentiated Cells 680
DNA Recombination Is Important in a Variety of 37.3 Gene Expression Is Regulated by Hormones 681
Biological Processes 652 Nuclear Hormone Receptors Have Similar Domain
Structures 681
Nuclear Hormone Receptors Recruit Coactivators and
Corepressors 682
SECTION 15 Clinical Insight Steroid-Hormone Receptors
RNA Synthesis, Processing, and Regulation 657 Are Targets for Drugs 683
Chapter 36 RNA Synthesis and Regulation 37.4 Histone Acetylation Results in Chromatin
in Bacteria 659 Remodeling 684
Metabolism in Context: Acetyl CoA Plays a Key Role in
36.1 Cellular RNA Is Synthesized by RNA Polymerases 659
the Regulation of Transcription 684
Genes Are the Transcriptional Units 660
Histone Deacetylases Contribute to Transcriptional
RNA Polymerase Is Composed of Multiple Subunits 661 Repression 686
36.2 RNA Synthesis Comprises Three Stages 661
Transcription Is Initiated at Promoter Sites on the DNA Chapter 38 RNA Processing in Eukaryotes 691
Template 661 38.1 Mature Ribosomal RNA Is Generated by
Sigma Subunits of RNA Polymerase Recognize the Cleavage of a Precursor Molecule 692
Promoter Sites 662 38.2 Transfer RNA Is Extensively Processed 692
RNA Strands Grow in the 5’-to-3’ Direction 663 38.3 Messenger RNA Is Modified and Spliced 693
Elongation Takes Place at Transcription Bubbles Sequences at the Ends of Introns Specify Splice Sites
That Move Along the DNA Template 664 in mRNA Precursors 694
An RNA Hairpin Followed by Several Uracil Residues Small Nuclear RNAs in Spliceosomes Catalyze
Terminates the Transcription of Some Genes 664 the Splicing of mRNA Precursors 695
The Rho Protein Helps Terminate the Transcription of Clinical Insight Mutations That Affect Pre-mRNA
Some Genes 665 Splicing Cause Disease 696
Precursors of Transfer and Ribosomal RNA Are Clinical Insight Most Human Pre-mRNAs Can
Cleaved and Chemically Modified After Transcription 666 Be Spliced in Alternative Ways to Yield Different
Clinical Insight Some Antibiotics Inhibit Proteins 697
Transcription 667 The Transcription and Processing of mRNA
36.3 The lac Operon Illustrates the Control of Are Coupled 698
Bacterial Gene Expression 668 Biological Insight RNA Editing Changes
An Operon Consists of Regulatory Elements and the Proteins Encoded by mRNA 698
Protein-Encoding Genes 668 38.4 RNA Can Function as a Catalyst 699
Ligand Binding Can Induce Structural Changes in
Regulatory Proteins 669 SECTION 16
Transcription Can Be Stimulated by Proteins Protein Synthesis and Recombinant DNA
That Contact RNA Polymerase 669 Techniques 705
Clinical and Biological Insight Many Bacterial Cells
Release Chemical Signals That Regulate Gene Chapter 39 The Genetic Code 707
Expression in Other Cells 670 39.1 The Genetic Code Links Nucleic Acid and
Some Messenger RNAs Directly Sense Metabolite Protein Information 708
Concentrations 670 The Genetic Code Is Nearly Universal 708
Contents xxvii
Transfer RNA Molecules Have a Common Design 709 Protein Synthesis Begins on Ribosomes That Are
Some Transfer RNA Molecules Recognize More Free in the Cytoplasm 733
Than One Codon Because of Wobble Signal Sequences Mark Proteins for Translocation
in Base-Pairing 711 Across the Endoplasmic Reticulum Membrane 733
The Synthesis of Long Proteins Requires a Low Error 40.6 Protein Synthesis Is Regulated by a Number of
Frequency 712 Mechanisms 735
39.2 Amino Acids Are Activated by Attachment to Messenger RNA Use Is Subject to Regulation 735
Transfer RNA 712 The Stability of Messenger RNA Also Can Be
Amino Acids Are First Activated by Adenylation 713 Regulated 736
Aminoacyl-tRNA Synthetases Have Highly Small RNAs Can Regulate mRNA Stability and Use 736
Discriminating Amino Acid Activation Sites 714
Proofreading by Aminoacyl-tRNA Synthetases Chapter 41 Recombinant DNA Techniques 743
Increases the Fidelity of Protein Synthesis 714
41.1 Nucleic Acids Can Be Synthesized from
Synthetases Recognize the Anticodon Loops and Protein-Sequence Data 744
Acceptor Stems of Transfer RNA Molecules 714
Protein Sequence Is a Guide to Nucleic Acid
39.3 A Ribosome Is a Ribonucleoprotein Particle Information 744
Made of Two Subunits 715 DNA Probes Can Be Synthesized by Automated
Ribosomal RNAs Play a Central Role in Protein Methods 744
Synthesis 715
41.2 Recombinant DNA Technology Has
Messenger RNA Is Translated in the 5’-to-3’ Revolutionized All Aspects of Biology 745
Direction 716
Restriction Enzymes Split DNA into Specific
Fragments 745
Chapter 40 The Mechanism of
Restriction Fragments Can Be Separated by Gel
Protein Synthesis 721 Electrophoresis and Visualized 746
40.1 Protein Synthesis Decodes the Information in Restriction Enzymes and DNA Ligase Are Key Tools for
Messenger RNA 722 Forming Recombinant DNA Molecules 747
Ribosomes Have Three tRNA-Binding Sites That 41.3 Eukaryotic Genes Can Be Manipulated with
Bridge the 30S and 50S Subunits 722 Considerable Precision 748
The Start Signal Is AUG Preceded by Complementary DNA Prepared from mRNA Can Be
Several Bases That Pair with 16S Ribosomal RNA 722 Expressed in Host Cells 748
Bacterial Protein Synthesis Is Initiated by Estrogen-Receptor cDNA Can Be Identified by
Formylmethionyl Transfer RNA 723 Screening a cDNA Library 749
Formylmethionyl-tRNAf Is Placed in the P Site of Complementary DNA Libraries Can Be Screened for
the Ribosome in the Formation of the 70S Initiation Synthesized Protein 750
Complex 724
Specific Genes Can Be Cloned from Digests of
Elongation Factors Deliver Aminoacyl-tRNA to Genomic DNA 750
the Ribosome 724
DNA Can Be Sequenced by the Controlled
40.2 Peptidyl Transferase Catalyzes Peptide-Bond Termination of Replication 751
Synthesis 725
Clinical and Biological Insight Next-Generation
The Formation of a Peptide Bond Is Followed by the Sequencing Methods Enable the Rapid
GTP-Driven Translocation of tRNAs and mRNA 725 Determination of a Complete Genome Sequence 753
Protein Synthesis Is Terminated by Release Factors Selected DNA Sequences Can Be Greatly Amplified by
That Read Stop Codons 728 the Polymerase Chain Reaction 754
40.3 Bacteria and Eukaryotes Differ in the Initiation Clinical and Biological Insight PCR Is a Powerful
of Protein Synthesis 728 Technique in Medical Diagnostics, Forensics, and
Clinical Insight Mutations in Initiation Factor 2 Studies of Molecular Evolution 756
Cause a Curious Pathological Condition 730 Gene-Expression Levels Can Be Comprehensively
40.4 A Variety of Biomolecules Can Inhibit Protein Examined 756
Synthesis 730
Clinical Insight Some Antibiotics Inhibit Protein Appendices A1
Synthesis 730
Glossary B1
Clinical Insight Diphtheria Toxin Blocks Protein
Synthesis in Eukaryotes by Inhibiting Translocation 731 Answers to Problems C1
Clinical Insight Ricin Fatally Modifies
28S Ribosomal RNA 732 Index D1
40.5 Ribosomes Bound to the Endoplasmic Reticulum Selected Readings
Manufacture Secretory and Membrane Proteins 733 (online at www.whfreeman.com/tymoczko3e) E1
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SECTION 1
Biochemistry Helps Us to
Understand Our World
1
In this section, we will learn some of the key concepts that structure the
study of biochemistry. We begin with an introduction to the molecules of
biochemistry, followed by an overview of the fundamental unit of biochemistry
and life itself—the cell. Finally, we examine the weak reversible bonds that
enable the formation of biological structures and permit the interplay between
molecules that makes life possible.
2
chapter 1
Biochemistry and the
Unity of Life
A
key goal of biochemistry, one that has been met with striking success, is to
understand what it means to be alive at the molecular level. Another goal
is to extend this understanding to the organismic level—that is, to under-
stand the effects of molecular manipulations on the life that an organism leads. For
instance, understanding how the hormone insulin works at the molecular level
illuminates how the organism controls the levels of common fuels—glucose and
fats—in its blood. Often, such understanding facilitates an understanding of dis-
ease states, such as diabetes, which results when insulin signaling goes awry. In
turn, this knowledge can be a source of insight into how the disease can be treated.
Biochemistry has been an active area of research for more than a century.
Much knowledge has been gained about how a variety of organisms manipulate
energy and information. However, one of the most exciting outcomes of bio-
chemical research has been the realization that all organisms have much in com-
mon biochemically. Organisms are remarkably uniform at the molecular level.
This observation is frequently referred to as the unity of biochemistry, but, in real-
ity, it illustrates the unity of life. French biochemist Jacques Monod encapsulated
this idea in 1954 with the phrase “Anything found to be true of [the bacterium]
E. coli must also be true of elephants.” This uniformity reveals that all organisms on
Earth have arisen from a common ancestor. A core of essential biochemical
processes, common to all organisms, appeared early in the evolution of life. The
3
4 1 Biochemistry and the Unity of Life
diversity of life in the modern world has been generated by evolutionary pro-
cesses acting on these core processes through millions or even billions of years.
We begin our study of biochemistry by looking at commonalities. We will
examine the molecules and molecular constituents that are used by all life forms
and will then consider the rules that govern how biochemical information is ac-
cessed and how it is passed from one generation to the next. Finally, we will take
an overview of the fundamental unit of life—the cell. This is just the beginning.
All of the molecules and structures that we see in this chapter we will meet again
and again as we explore the chemical basis of life.
1.2 There Are Four Major Classes of Biomolecules ✓ 1 Describe the key classes of
biomolecules and differentiate
Living systems contain a dizzying array of biomolecules. However, these biomol- between them.
ecules can be divided into just four classes: proteins, nucleic acids, lipids, and
carbohydrates.
1 2 3
Figure 1.1 Protein folding. The three-dimensional structure of a protein is dictated by the
sequence of amino acids that constitute the protein.
6 1 Biochemistry and the Unity of Life
NH2 angers. Perhaps the most prominent role of proteins is that
d
2– O –
O
–
O
N of catalysts—agents that enhance the rate of a chemical reac-
N
tion without being permanently affected themselves. Protein
H2
O
P P P C N catalysts are called enzymes. Every process that takes place in
O O O O
O O O N living systems depends on enzymes.
I see increasing reason to believe that the view formed some time
back as to the origin of the Makonde bush is the correct one. I have
no doubt that it is not a natural product, but the result of human
occupation. Those parts of the high country where man—as a very
slight amount of practice enables the eye to perceive at once—has not
yet penetrated with axe and hoe, are still occupied by a splendid
timber forest quite able to sustain a comparison with our mixed
forests in Germany. But wherever man has once built his hut or tilled
his field, this horrible bush springs up. Every phase of this process
may be seen in the course of a couple of hours’ walk along the main
road. From the bush to right or left, one hears the sound of the axe—
not from one spot only, but from several directions at once. A few
steps further on, we can see what is taking place. The brush has been
cut down and piled up in heaps to the height of a yard or more,
between which the trunks of the large trees stand up like the last
pillars of a magnificent ruined building. These, too, present a
melancholy spectacle: the destructive Makonde have ringed them—
cut a broad strip of bark all round to ensure their dying off—and also
piled up pyramids of brush round them. Father and son, mother and
son-in-law, are chopping away perseveringly in the background—too
busy, almost, to look round at the white stranger, who usually excites
so much interest. If you pass by the same place a week later, the piles
of brushwood have disappeared and a thick layer of ashes has taken
the place of the green forest. The large trees stretch their
smouldering trunks and branches in dumb accusation to heaven—if
they have not already fallen and been more or less reduced to ashes,
perhaps only showing as a white stripe on the dark ground.
This work of destruction is carried out by the Makonde alike on the
virgin forest and on the bush which has sprung up on sites already
cultivated and deserted. In the second case they are saved the trouble
of burning the large trees, these being entirely absent in the
secondary bush.
After burning this piece of forest ground and loosening it with the
hoe, the native sows his corn and plants his vegetables. All over the
country, he goes in for bed-culture, which requires, and, in fact,
receives, the most careful attention. Weeds are nowhere tolerated in
the south of German East Africa. The crops may fail on the plains,
where droughts are frequent, but never on the plateau with its
abundant rains and heavy dews. Its fortunate inhabitants even have
the satisfaction of seeing the proud Wayao and Wamakua working
for them as labourers, driven by hunger to serve where they were
accustomed to rule.
But the light, sandy soil is soon exhausted, and would yield no
harvest the second year if cultivated twice running. This fact has
been familiar to the native for ages; consequently he provides in
time, and, while his crop is growing, prepares the next plot with axe
and firebrand. Next year he plants this with his various crops and
lets the first piece lie fallow. For a short time it remains waste and
desolate; then nature steps in to repair the destruction wrought by
man; a thousand new growths spring out of the exhausted soil, and
even the old stumps put forth fresh shoots. Next year the new growth
is up to one’s knees, and in a few years more it is that terrible,
impenetrable bush, which maintains its position till the black
occupier of the land has made the round of all the available sites and
come back to his starting point.
The Makonde are, body and soul, so to speak, one with this bush.
According to my Yao informants, indeed, their name means nothing
else but “bush people.” Their own tradition says that they have been
settled up here for a very long time, but to my surprise they laid great
stress on an original immigration. Their old homes were in the
south-east, near Mikindani and the mouth of the Rovuma, whence
their peaceful forefathers were driven by the continual raids of the
Sakalavas from Madagascar and the warlike Shirazis[47] of the coast,
to take refuge on the almost inaccessible plateau. I have studied
African ethnology for twenty years, but the fact that changes of
population in this apparently quiet and peaceable corner of the earth
could have been occasioned by outside enterprises taking place on
the high seas, was completely new to me. It is, no doubt, however,
correct.
The charming tribal legend of the Makonde—besides informing us
of other interesting matters—explains why they have to live in the
thickest of the bush and a long way from the edge of the plateau,
instead of making their permanent homes beside the purling brooks
and springs of the low country.
“The place where the tribe originated is Mahuta, on the southern
side of the plateau towards the Rovuma, where of old time there was
nothing but thick bush. Out of this bush came a man who never
washed himself or shaved his head, and who ate and drank but little.
He went out and made a human figure from the wood of a tree
growing in the open country, which he took home to his abode in the
bush and there set it upright. In the night this image came to life and
was a woman. The man and woman went down together to the
Rovuma to wash themselves. Here the woman gave birth to a still-
born child. They left that place and passed over the high land into the
valley of the Mbemkuru, where the woman had another child, which
was also born dead. Then they returned to the high bush country of
Mahuta, where the third child was born, which lived and grew up. In
course of time, the couple had many more children, and called
themselves Wamatanda. These were the ancestral stock of the
Makonde, also called Wamakonde,[48] i.e., aborigines. Their
forefather, the man from the bush, gave his children the command to
bury their dead upright, in memory of the mother of their race who
was cut out of wood and awoke to life when standing upright. He also
warned them against settling in the valleys and near large streams,
for sickness and death dwelt there. They were to make it a rule to
have their huts at least an hour’s walk from the nearest watering-
place; then their children would thrive and escape illness.”
The explanation of the name Makonde given by my informants is
somewhat different from that contained in the above legend, which I
extract from a little book (small, but packed with information), by
Pater Adams, entitled Lindi und sein Hinterland. Otherwise, my
results agree exactly with the statements of the legend. Washing?
Hapana—there is no such thing. Why should they do so? As it is, the
supply of water scarcely suffices for cooking and drinking; other
people do not wash, so why should the Makonde distinguish himself
by such needless eccentricity? As for shaving the head, the short,
woolly crop scarcely needs it,[49] so the second ancestral precept is
likewise easy enough to follow. Beyond this, however, there is
nothing ridiculous in the ancestor’s advice. I have obtained from
various local artists a fairly large number of figures carved in wood,
ranging from fifteen to twenty-three inches in height, and
representing women belonging to the great group of the Mavia,
Makonde, and Matambwe tribes. The carving is remarkably well
done and renders the female type with great accuracy, especially the
keloid ornamentation, to be described later on. As to the object and
meaning of their works the sculptors either could or (more probably)
would tell me nothing, and I was forced to content myself with the
scanty information vouchsafed by one man, who said that the figures
were merely intended to represent the nembo—the artificial
deformations of pelele, ear-discs, and keloids. The legend recorded
by Pater Adams places these figures in a new light. They must surely
be more than mere dolls; and we may even venture to assume that
they are—though the majority of present-day Makonde are probably
unaware of the fact—representations of the tribal ancestress.
The references in the legend to the descent from Mahuta to the
Rovuma, and to a journey across the highlands into the Mbekuru
valley, undoubtedly indicate the previous history of the tribe, the
travels of the ancestral pair typifying the migrations of their
descendants. The descent to the neighbouring Rovuma valley, with
its extraordinary fertility and great abundance of game, is intelligible
at a glance—but the crossing of the Lukuledi depression, the ascent
to the Rondo Plateau and the descent to the Mbemkuru, also lie
within the bounds of probability, for all these districts have exactly
the same character as the extreme south. Now, however, comes a
point of especial interest for our bacteriological age. The primitive
Makonde did not enjoy their lives in the marshy river-valleys.
Disease raged among them, and many died. It was only after they
had returned to their original home near Mahuta, that the health
conditions of these people improved. We are very apt to think of the
African as a stupid person whose ignorance of nature is only equalled
by his fear of it, and who looks on all mishaps as caused by evil
spirits and malignant natural powers. It is much more correct to
assume in this case that the people very early learnt to distinguish
districts infested with malaria from those where it is absent.
This knowledge is crystallized in the
ancestral warning against settling in the
valleys and near the great waters, the
dwelling-places of disease and death. At the
same time, for security against the hostile
Mavia south of the Rovuma, it was enacted
that every settlement must be not less than a
certain distance from the southern edge of the
plateau. Such in fact is their mode of life at the
present day. It is not such a bad one, and
certainly they are both safer and more
comfortable than the Makua, the recent
intruders from the south, who have made USUAL METHOD OF
good their footing on the western edge of the CLOSING HUT-DOOR
plateau, extending over a fairly wide belt of
country. Neither Makua nor Makonde show in their dwellings
anything of the size and comeliness of the Yao houses in the plain,
especially at Masasi, Chingulungulu and Zuza’s. Jumbe Chauro, a
Makonde hamlet not far from Newala, on the road to Mahuta, is the
most important settlement of the tribe I have yet seen, and has fairly
spacious huts. But how slovenly is their construction compared with
the palatial residences of the elephant-hunters living in the plain.
The roofs are still more untidy than in the general run of huts during
the dry season, the walls show here and there the scanty beginnings
or the lamentable remains of the mud plastering, and the interior is a
veritable dog-kennel; dirt, dust and disorder everywhere. A few huts
only show any attempt at division into rooms, and this consists
merely of very roughly-made bamboo partitions. In one point alone
have I noticed any indication of progress—in the method of fastening
the door. Houses all over the south are secured in a simple but
ingenious manner. The door consists of a set of stout pieces of wood
or bamboo, tied with bark-string to two cross-pieces, and moving in
two grooves round one of the door-posts, so as to open inwards. If
the owner wishes to leave home, he takes two logs as thick as a man’s
upper arm and about a yard long. One of these is placed obliquely
against the middle of the door from the inside, so as to form an angle
of from 60° to 75° with the ground. He then places the second piece
horizontally across the first, pressing it downward with all his might.
It is kept in place by two strong posts planted in the ground a few
inches inside the door. This fastening is absolutely safe, but of course
cannot be applied to both doors at once, otherwise how could the
owner leave or enter his house? I have not yet succeeded in finding
out how the back door is fastened.