Lehninger, principles of biochemistry 5th ed d nelson, m cox (w h freeman, 2008) 1

HNI

PRINCIPLESOF BIOCHEMISTRY
FIFTH

EDITION

David L. Ne lson
Professorof Bio chemistry
Uniuersity of Wisconsin-Madison

Michael M. Cox
Professor of Bi,ochemistry
Uni,uersity of Wi,sconsin-Madi,son

l=
ANDCOMPANY
W.H.FREEMAN
N e wY o r k


4


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On the cover: RNA polymeraseII from yeast, bound to DNA and in the act of transcribing it into RNA.
Imagecreatedby H. Adam Steinbergusing PDB ID 1I6Has modi.fledby Seth Darst.

Library of CongressControl Number: 2007941224
ISBN-13:978-0-7167-7108-1

ISBN-I0: 0-7167-7r08-X
@2008by W. H. Freemanand Company
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To Our Teachers
PauLR. Burton
Albert Fi,ntuolt
Wi,LLi,am
P. Jencks
Eugene P. Kennedy
Homer Knoss
ArtLtur Kornberg
L RobertLeltman
EarL K, I{elson
Dauid E, Sh,eppard
Harold B. Wti,te


DaVid L. NelSOn,bornin Fairmont,
Minnesora,
received his BS in Chemistry and Biology from St. Olaf
College in 1964 and earned his PhD in Biochemistry at

Stanford Medical School under Arthur Kornberg. He
was a postdoctoral felLowat the Harvard Medical School
with Eugene P. Kennedy, who was one of Albert
Lehninger's first graduate students. Nelson joined the
faculty of the University of Wisconsin-Madison h 1971
and became a full professor of blochemrstry in 1982. He
is the Director of the Center for Biology Education at
the University of Wisconsin-Madison.
Nelson's research has focused on the signal transductions that regulate ciliary motion and exocytosis in
the protozoan Parameci,um. The enzymes of signal
transductions, including a variety ofprotein kinases, are
primary targets of study. His research group has used
enzyme purification, immunological techniques, electron microscopy, genetics, molecuiar biology, and electrophysiologyto study these processes
Dave Nelson has a distinguished record as a lecturer
and research superuisor. For 36 years he has taught an
intensive survey of brochemistry for advanced biochemistry undergraduates in the life sciences. He has also
taught a survey of biochemistry for nursing students,
and graduate courses on membrane structure and function and on molecular neurobiology. He has sponsored
numerous PhD, MS, and undergraduate honors theses,
and has received awards for his outstanding teaching,
including the Dreyfus Teacher-Scholar Award, the
Atwood Distinguished Professorship, and the Unterkofler
Excellence in Teaching Award from the University of
Wisconsin System.In 1991-1992he was a visiting professor of chemistry and biology at Spelman College. His
second love is history and in his dotage he has begun to
teach the history of biochemistry to r-mdergraduatesand
to collect antique scientific instruments.

MiChagl M. COXwasbornin Wlmington,
I)elaware.

In his first biochemistry
course,Lehninger's
Biochem'istry was a major influence in refocusing his fascination
with biology and inspiring him to pursue a career in biochemistry. After graduating from the University of
Delaware inl974, Cox went to Brandeis University to do
his doctoral work with MIIiam P Jencks, and then to
Stanford in 1979 for postdoctoral study with I. Robert
Lehman. He moved to the University of WisconsinMadison in 1983, and became a full professor of
biochemistry in 1992.
Cox's doctoral research was on general acid and
base catalysis as a model for enz;,,rne-catalyzedreacvl

David
[. Nelson
andMichael
M.Cox

tions. At Stanford,he beganwork on the enzymesinvolvedin geneticrecombination.The work focusedparticularly on the RecAprotein, designingpuriflcation and
assaymethodsthat are still in use, and illuminating the
processof DNAbranchmigration.Explorationof the en4,.rnesof genetic recombinationhas remained the central themeof his research.
Mike Cox has coordinateda large and active researchteam at Wisconsin,investigatingthe enzymology,
topology,and energeticsof genetic recombination.A
primary focus has been the mechanism of RecA
protein-mediatedDNA strand exchange,the role of ATP
in the RecA system,and the regulationof recombinational DNA repair. Part of the researchprogram now
focuseson organismsthat exhibit an especiallyrobust
capacityfor DNA repair, such asDei,nococcusrad'i,odurans, and the applicationsof those repair systemsto
biotechnology.For the past24 yearshe has taught (with
DaveNelson)the suwey of biochemistryto undergraduatesand haslectured in graduatecourseson DNA structure and topology,protein-DNAinteractions,and the
biochemistryof recombination.A more recent project

has been the organizationof a new courseon professionalresponsibilityfor fi.rst-yeargraduatestudents.He
has received awards for both his teaching and his
research,including the Dreyfus Teacher-ScholarAward
and the 1989EIi Lilly Award in BiologicalChemistry His
hobbiesinclude gardening,wine collecting,and assisting
in the designof laboratorybuildings.


I n this twenty-flrst century a typical scienceeducation
I often leavesthe philosophicalunderpinningsof scienceunstated,or relies on oversimplifieddefinitions.As
you contemplatea careerin science,it may be usefulto
consideronce againthe terms science, scientist, and
scientifie method.
Science is both a way of thinking about the natural
world and the sum of the information and theory that result from such thinking.The power and successof scienceflow directlyfrom its relianceon ideasthat can be
tested: information on natural phenomenathat can be
observed,measured,and reproducedand theoriesthat
havepredictivevalue.The progressof sciencerestson a
foundationalassumptionthat is often unstatedbut crucial to the enterprise:that the lawsgoverningforcesand
phenomenaexisting in the universe are not subject to
change.The NobellaureateJacquesMonodreferredto
this underlyingassumptionasthe "postulateof objectivity." The natural world can therefore be understoodby
applying a processof inquiry-the scientific method.
Sciencecould not succeedin a universe that played
tricks on us. Other than the postulateof objectivity,science makesno inviolate assumptionsabout the natural
world.A usefiilscientiflcideais onethat (1) hasbeenor
can be reproduciblysubstantiatedand (2) can be used
to accuratelypredict new phenomena.
Scientrflcideastake many forms.The terms that scientists use to describetheseforms havemeaningsquite
differentfrom thoseappliedby nonscientists.

Ahypothesesis an idea or assumptionthat providesa reasonable
and testableexplanationfor one or more observations,
but it may lack extensiveexperimentalsubstantiation.A
sci,enti,fi,ctheorA is much more than a hunch. It is an
idea that has been substantiatedto some extent and
provides an explanationfor a body of experimentalobservations.A theory can be tested and built upon and is
thus a basisfor further advanceand innovation.When a
scientiflctheory has been repeatedlytested and validatedon manyfronts,it canbe acceptedas a fact.
In one importantsense,what constitutesscienceor
a scientiflc idea is defined by whether or not it is published in the scientiflc literature after peer review by
other working scientists.About 16,000peer-reviewed
scientific journals worldwide publish some 1.4 million
articles eachyear, a continuing rich harvest of information that is the birthright of every human being.
Scientists are indiredualswho rigorouslyapply the
scientific method to understand the natural world.
Merely having an advanceddegreein a scientiflc discipline doesnot makeone a scientist,nor doesthe lack of
such a degreeprevent one from making important scientific contributions.A scientistmust be willing to challenge any idea when new findings demandit. The ideas
that a scientistacceptsmust be basedon measurable,

reproducibleobservations,
and the scientistmust report
with completehonesty.
theseobservations
The scientific method is actually a collection of
paths,all of wtuch may lead to scientificdiscovery.In the
hypothesi,sand erperiment path,a scientistposesa hypothesis,then subjectsit to experimentaltest. Many of
the processesthat biochemistswork with everyday were
discoveredin this manner.The DNA structure elucidated
by JamesWatsonand FrancisCrick led to the hypothesis
that basepairjrg is the basisfor information transfer in

po\mucleotide sS,nthesis.
This hlpothesis helpedinspire
the discoveryof DNA and RNA pol5.'rnerases.
Watsonand Crick produced their DNA structure
through a process of model bui,ldi,ng and calculat'ion. No actual experimentswere involved, although
the model building and calculations used data collectedby other scientists.Many adventurousscientists
haveappliedthe processoferp\oration and obseruat'ion as a path to discovery.Historicalvoyagesof discovery (Charles Darwin's 1831 voyage on H.M.S.
Beagleamongthem) helpedto map the planet,catalog
its living occupants,and changethe way we view the
world. Modern scientists follow a similar path when
they explore the ocean depths or launch probes to
other planets.An analogof hypothesisand experiment
is hypothesi,sand deduct'ion. Crick reasoned that
there must be an adaptor molecule that facilitated
translationof the information in messengerRNA into
protein.This adaptorhypothesisled to the discoveryof
transfer RNA by MahlonHoaglandand Paul Zamecnik.
Not all paths to discoveryinvolve planrung.Serendipi,tg often plays a role. The discovery of penicilJin by
Alexander Fleming in 1928, and of RNA catalysts by
ThomasCechin the early 1980s,wereboth chancediscoveries,albeit by scientistswell preparedto exploit them.
Irnpi,rati,on canalsoleadto important advances.The polymerasechainreaction(PCR),now a centralpart of biotechnology, was developedby Kary Mullis afler a flash of
inspration dudng a road trip in northern Califomiain 1983.
Thesemany paths to scientiflc discoverycan seem
quite different, but they have some important things
in common. They are focused on the natural world.
They rely on reproducCbleobseruat'ion anilor erperiment. Nl of the ideas,insights, and experimentalfacts
that arise from these endeavorscan be tested and
reproducedby scientistsan5,wherein the world. All can
be usedby other scientiststo build new hypothesesand
make new discoveries.All lead to information that is

properlyincludedin the realm of science.Understanding our universerequires hard work. At the sametime,
no human endeavoris more exciting and potentially rewarding than trying, and occasionallysucceeding,to understandsomepart of the natural world.
vtl


first edition of Pnnctples oJBi,ochenuistry, v'ritten
Albert Lehningertwenty-flveyearsago,hasservedas
the starting point and the model for our four subsequent
editions.Overthat quarter-centurythe world of biochemistry haschangedenormously.
yearsago,not a
TWenty-flve
singlegenomehadbeensequenced,
not a singlemembrane
proternhad beensolvedby crystallography,
and not a sinjust beendishnockout
mouse
existed.
RibozJrmes
had
$e
covered, PCR technology introduced, and archaea
recognizedasmembersof a kingdomseparatefrom bacteria Now,newgenomicsequences
areannouncedweekly,
new protern structures even more frequently, and researchershave engineeredthousandsof djfferent lcrockout mice, with enormouspromise for advancesin basic
biochemistryphysiology,and medicine.This ffih edition
containsthe photographsof 31 Nobellaureateswho have
receivedtheirprizesfor Chemistryor for Physiologror Medicine sincethat first edition of Prhrciples of Binchemistry.
One major challengeof each edition has been to reflect the torrent of new information without making the
book overwhelmingfor students having their first encounterwith biochemistry.This hasrequiredmuch careful sifting aimed at emphasizingprinciples while still
conveyingthe excitementof current researchand its

promisefor the future. The cover of this new edition exempli-fles
this excitementand promise:in the x-ray structure of RNA polymerase,we seeDNA, RNA, and protein
in their informationalroles,in atomrcdimensions,caught
in the central act of in-formationtransfer.

We are at the threshold of a new molecularphysiology in which processessuch as membrane excitation,
secretion,hormoneaction,vision, gustation,olfaction,
respiration,musclecontraction,and cell movementswill
be explicablein molecularterms and will becomeaccessible to genetic dissectionand pharmacologicalmanipulation. Knowledgeof the molecular structures of the
highly organizedmembrane complexes of oxidative
phosphorylation and photophosphorylation,for example, will certainly bring deepenedinsight into those
processes,
so centralto life. (Thesedevelopments
make
us wish we were young again,just beginningour careers
in biochemicalresearchand teaching. Our book is not
the only thing that has acquired a touch of silver over
the years!)
In the past two decades,we have striven alwaysto
maintain the qualitiesthat made the original Lehninger
text a classic-clear wdting, careftrlexplanationsof difflcult concepts,and communicatingto studentsthe ways
in which biochemistryis understoodand practicedtoday.
Wehavewritten togetherfor twenty yearsand taught together for almosttwenty-flve.Our thousandsof students
at the Universityof Wisconsin-Madison
over thoseyears
havebeen an endlesssourceof ideasabout how to present biochemistrymore clearly;they haveenlightenedand
rnspired us. We hope that this twenty-flfth aruLiversary
edition will erLlightenand inspire current studentsof biochemistryeverywhere,and perhapsleadsomeof them to
Iovebiochemistryaswe do.

Major
Recent
Advances
in Biochemistry
Every chapter has been thoroughly revised and updated to include the most important advancesin biochemistryincluding:
r

Conceptsof proteomes and proteomics,
introducedearlierin the book (Chapter1)

r

New discussionof amyloid diseasesin the
context of protein folding (Chapter 4)

r

New section on pharmaceuticals developedfrom
an understandingof enzymemechanism,using
penicillinand HIV proteaseinlLibitorsas examples
(Chapter6)

r

New discussionof sugar analogs as drugs that
target viral neuraminidase(Chapter 7)

r

New material on green fluorescent protein

(Chapter9)

r

New sectionon lipidomics (Chapter10)

r

w descriptionsof volatile lipids used as signals
vi

by plants, and of bird feather pigmentsderived
from coloredlipids in plant foods (Chapter10)
Expandedand updated sectionon lipid rafrts and
caveolae to rncludenew material on membrane
curvature and the proteins that influenceit, and
introducng amphitropic proteins and anmrlar
Iipids (Chapter11)
New sectionon the emergingrole of ribulose
5-phosphate as a central regulator of $ycolysis
(Chapter 15)
andgluconeogenesis
New Box 16-1, MoonlightingErzymes:Proteins
with More Than One Job
New sectionon the role of transcriptionfactors
(PPARs) in regulationof lipid catabolism
(Chapter17)
Revisedand updated sectionon fatty acid
synthase, including new structural information
on FASI (Chapter21)

Preface tx

Updatedcoverageof
the nitrogen cycle,
including new Box
22-1, UnusualLife
Stylesof the Obscure
but Abundant,
discussinganammox
bacteria (Chapter22New Box 24-2,
Epigenetics,Nucleosome
Structure,and Histone
Variantsdescribingthe
role of histone
modification and
FIGURE
21-3 Thestructure
typeI systems.
offattyacidsynthase
nucleosome deposition
in the transmissionof
New information on the roles of RNA
epigeneticinformation in heredity
in protein biosynthesis
New information on the initiation of replication
(Chapter 27)
and the dymamicsat the replicationfork,
New sectionon riboswitches

introducing AAA+ ATPases and their functions
(Chapter28)
in replication and other aspectsof DNA
metabolism(Chapter25)
New Box 28-1, Of Fins,Whgs, Beaks,and Things,
New sectionon the expandedunderstandingof
the roles of RNA in cells (Chapter 26)

describingthe cormectionsbetweenevolution
and development

Biochemical
Methods
An appreciation of biochemistry often
requires an understanding of how biochemical information is obtained. Some
of the new methodsor updatesdescribed
in this editionare:
r

Circulardicluoism (Chapter4)

r

Measurementof glycated
hemoglobinas an indicator of
averagebloodglucoseconcentration,
over days,in personswith diabetes
(Chapter7)

r

Useof MALDI-MSin determinationof
oligosaccharide
structure (Chapter7)

r

ForensicDNA analysis,a majorupdate
coveringmodernSTRanalysis(Chapter 9)

r

More on microarrays(Chapter9)

r

Use of tags for protein analysisand
purification (Chapter9)

r

r

PET combinedwith
CT scansto pinpoint cancer
(Chapter14)

Glutathione
(GSH)

G€ne for tusion prctein

flcuflt9-12 The useof taggedproteinsin protein purification. The use of a CST tag is illustrated(a) Clu(CST)is a smallenzyme(depicted
tathione-s-transferase
(a Slutahereby the purpleicon)that bindsglutathione
at
materesidue
to whicha Cys-Clydipeptideis attached
the carboxylcarbonof theClu sidechain,hencetheabbreviationCSH) (b) The CST tag is fusedto the catr
boxyl terminus of the target protein by Senetic
engineeringThe taggedprotein is expressedin host
cells,and is presentin the crudeextractwhen the cells
are lysed The extract is subjectedto chromatography
on a column containinga mediumwith immobilized
SlutathioneThe CsT{aggedproteinbinds to the 8lutathione,retardinBits migrationthroughthe column,
while the other proteinswash through rapidly The
elutedfrom the column
taggedproteinis subsequently
or
elevatedsaltconcentration
with a solutioncontaining
free glutathione

I

v

Express tu8ion
Foteh h a cell

Add gotein

EIub

fusion plobin

IIGURE
9-12

Chromatinimmunoprecipitationand ChlP-chip
experiments(Chapter24)

r

Developmentof bacterial strainswith altered ge
netic codes,for site-specific insertion of novel
amino acids into proteins (Chapter 27)


x

Preface

Medically
Relevant
Examples
This icon is used throughoutthe book to denote
materialof specialmedicalinterest.As teachers,
our goal is for students to learn biochemistryand to
understand its relevance to a healthier life and a

healthier planet. We have included many new examples that relatebiochemistryto medicineand to health
issuesin general.Someof the medicalapplicationsnew
to this edition are:
r
r

r

r
r

The role of polyunsaturatedfatty acidsand trans
fatty acidsin cardiovascular
disease(Chapter10)
G protein-coupledreceptors(GCPRs)and the
range of diseasesfor which drugs targeted to
GPCRsare beingusedor developed(Chapter12)
G proterns,the regulationof GTPaseactivity,
and the medicalconsequences
of defectiveG protein
function(Chapter12),includingnew Box 12-2,
G Proteins:Binary Switchesin Health and Disease
Box 12-5,Developmentof ProteinKinaseInhibitors
for CancerTleatment
Box 14-1,HtghRateof Glycolysisin Tlmors Suggests
Targetsfor Chemotherapyand FacrlitatesDiagnosis

r

Box 15-3, GeneticMutationsThat Leadto Rare

Formsof Diabetes

r

Mutationsin citric acid cycle enzyrnesthat lead to
cancer(Chapter16)

r

Perniciousanemiaand associatedproblemsin strict
vegetarians(Chapter 18)

r

Updatedinformationon cyclooxygenase
hhibitors
(pain relieversVioxx, Celebrex,Bextra)
(Chapter21)

r

HMG-CoAreductase(Chapter21) and Box 21-3,
The Lipid Hypothesisand the Developmentof
Statins

r

Box 24-1, CuringDiseaseby Inhibiting
Topoisomerases,
describingthe use of

topoisomeraseinhibitors in the treatment
of bacterial rnfectionsand cancer,including
material on ciprofloxacin (the antibiotic effective
for anthrax)

Special
Theme:
Understanding
Metabolism
through
0besity
andDiabetes
Obesity and its medical consequences-cardiovascular diseaseand diabetes-are fast becomingepidemic
in the industrializedworld, and we include new material on the biochemicalconnectionsbetween obesity
and health throughout this edition. Our focus on diabetes provides an integrating theme throughout the
chapterson metabolismand its control, and this will,
we hope, inspire some students to find solutions for
this disease.Some of the sectionsand boxes that
highlight the interplay of metabolism, obesity, and
diabetesare:

@
Fatty acid oxidatioD
Stawation response

Fat synthesie
and storage

and storage
Adipokineproduction

Fatty acid oxidati
Themogenesis

r

Untreated DiabetesProducesLife-ThreatenineAci
dosis(Chapter2)

r

Box 7-1 , Blood GlucoseMeasurementsin the
Diagnosisand T?eatmentof Diabetes,introducing
hemoglobinglycation and AGEsand
their role in the pathologyof advanceddiabetes
Box 11-2,DefectiveGlucoseand WaterT?ansport
in TWoFormsof Diabetes

FIGURE
23-42
r

AdiposeTissueGeneratesGlycerol3-phosphate
(Chapter21)
by Glyceroneogenesis

r

GlucoseUptakeIs Deficientin T}pe 1 DiabetesMel
Iitus (Chapter14)

r

DiabetesMellitus Arises from Defectsin Insulin
Productionor Action (Chapter23)

r

KetoneBodiesAre Overproducedin Diabetesand
during Starvation (Chapter 17)

r

r

SomeMutationsin MitochondrialGenomesCause
Disease(Chapter19)
DiabetesCan Resultfrom Defectsin the Mitochon
dria ofPancreaticB Cells(Chapter19)

Section23.4,Obesityand the Regulationof Body
Mass,discussesthe role of adiponectinand insulin
sensitivity and tlpe 2 diabetes

r

Section23.5,Obesity,the MetabolicS;'ndrome,and
T\pe 2 Diabetes,includesa discussionof managing
type 2 diabeteswith exercise,diet, and medication

r

r


Advances
in Teaching
Biochemistry

1l-3
WORKED
EXAMPII

f

Revisingtlus textbookis neverjust an updatingexercise.At Ieastasmuch time
is spent reexamininghow the core topics of biochemrstryare presented.We
haverevisedeachchapterwith an eyeto helpingstudentslearn and masterthe
fundamentalsof biochemistry.Studentsencounteringbiochemistryfor the first
trmeoften havedifflcultywith two key aspectsof the course:approachingquantitative problemsand drawingon what they learnedin orgarucchemistryto help
them understandbiochemistry.Those samestudents must also learn a complex language,with conventionsthat are often unstated.Wehavemadesome
major changesin the book to help studentscope with all these challenges:
new problem-solvingtools, a focus on organic chemistry foundations, and
highlightedkey conventions.

EnergeticsofPumping
bYSYnPort

lglumseli,
--=

mtio that can be
.':
lglucosejour
plasma
membrme Na*-glucose symachieved by the
porter of an epithelial cell, when [Na-]6 is 12 mM,
-50 mV
[Nat]."1 is 145 ro, the membrme potential is
'C
(inside negative), and the temperature is 37
Cahulal,e lhe maimm

Soltrtion: Using Equation 11-4 (p 396), we can calcuNa+
late the energy inherent in an electrochemical
gradient-that
is, the cost of moving one Na- ion up
gradientl
this

AG.
' _ R?lnry+ + zr a,r,
tNal,"

We then substitute standardvaluesfor-&, ?, and J, and
the given valuesfor [Na-] (expressedas molar concentrations), +l for Z (because Na+ has a positive
charge), md 0 050 V for a,y' Note that the membrane
potential is -50 mV (inside negative),so the chmge in
potential when m ion moves from inside to outside is
50 mV.

N e wPr o b l e m-5 o lTvionogl s

1 45 x 10-'
1.2xto 2
+ 1(96,500
JV.mol)(0 050V)

AGt : (8 315J/mol K)(3to rcm

r New in-text Worked Examples help studentsimprove their
quantitativeproblem-solvingskills, taking them through someof the
most difficult equations.

= 112 kJ/mol
This AGr is the potential energyper mole of Na- in the
Na* $adient that is available to pmp glucose Given
that two Na- ions passdom their electrochemicalgradient md into the cell for each glucose canied in by
slmport, the energyavailableto pmp 1 mol of Llucose
is2 x II2 kJ/mol = 22 4 kJ/mol We can now calculate
the concentrationratio of Elucosethat cm be achieved
by this pmp (from Equation l1-3, p 396):

r More than 100 new end-of-chapter problems give students
further opportunity to practice what they have learned.
r New Data Analysis Problems (one at the end of eachchapter), con
tributed by BrianWhite of the Universityof Massachusetts-Boston,
en
couragestudentsto slmthesizewhat they have learnedand apply their
knowledgeto the interpretationof datafrom the literature.

_ __. [glucose]r
lG, = ft?ln:iLgrucoselour

Remnuing, then substitutingthe valuesof AGt,,&,and
?, gives
22.4kJ/mol
. [g]ucosel* AG, =
- o ot
'n
n,r
E:rs .llorot' tlir"o""l.,,

F o c uosn0 r g an(h
i c e mi stry
F o u n d a ti o ns
r

r

lglucosel,.
lglucose]""t

New Section 13.2, Chemical logic and common biochemical
reactions, discussesthe common biochemical reaction types that
underlie all metabolic reactions.

11-3
WORKED
EXAMPLE

Chemical logic is reinforcedin the discussions
of
centralmetabolicpathways.

cHooPoi
tNS'

r

r

-

Mechanism figures feature step-by-step
descriptionsto help studentsunderstandthe
reactionprocess.

,

Fodatim
of etrzFe.
subFate @nplex fre
C)€ ha! e
dive.sik
pf, (5 5 in€bad
duced
of 8) when NAD+ iE bu4
ed is in the Eore readive,
ffiolab fom

CF

cvs
6l
v

"NAnl
-\

cH"oPo"'-o
1-_'
Hcor/'o. ' P

./
c:o

In this edition, many of the conventionsthat are so
necessaryfor understandingeach biochemicaltopic
and the biochemicalliterature are broken out of the
14-7
text and highlighted. These Key Conventions
FIGURE
include clear statementsof many assumptionsand
conventionsthat studentsare often expectedto assimilatewithout
being told (for example,peptide sequencesare uritten from aminoto carboxyl-terminalend, Ieft to right; nucleotide sequencesare
writtenfrom5' to 3' end left 1nrioht)

CF

\

OH
P.ND+

cu"OPO?
t-

I
S
I
cv"

^L
\tl

NsH
-

I a ovalmt thioheninetal
lbkry. foms bHeen ih€
subshatemd the -SPUP of he cys residu€
L

Y9OH
u!c4

fre @alent thiqbr
thkago betuem the
suhEaE

sd €nzFe
ph6phdobEis
udese
(sthck by 4) releasiry
fre se@nd pdud,
l,g-bbphdphqly@me

Ns,

HCOH

n,t"b

\ e

Glycerddehyd€
3-phosphah

In the presentationof reaction mechanisms,
we consistentlyuse a set of conventions
introducedand explainedin detail with the
first enzymemechanismencountered
(chymotrypsin,pp. 208-209).Someof
the new problems focus on chemical
mechanismsand reinforcemechanisticthemes.

Key(onventions

NS*

Gtyceraldehyde
3-phosphaE

ah
I The €nzr€aubst
intemediatetuoddiledby
tuNs*boudbse

CH,OPO:
HCOH
C:O
S

prcduct leaves fte
fr€ N0H
active sik ud is replaced by
another nolecule of NS+.

cvg

KtY (0NVENTI0N:
When an amino acid sequenceof a
peptide, polypeptide,or protern is displayed,the aminoterminal end is placed on the left, the caxboxyl-terminal
end on the right The sequenceis read left to dght, begiming with the amino-terminal end I


Media
and5upplements
A fulI packageof media resourcesand supplementsprovides instructors and students with innovative tools to
support a variety of teaching and learning approaches.

All these resourcesare fully integrated with the style
and goalsof the fifth edition textbook.

eBook
This online version of the textbook
combinesthe contentsof the printed
book, electronicstudy tools, and a
full complement of student media
specifically created to support the
text. The eBookalsoprovidesusefirl
materialfor instructors.
r

eBook study tools include instant navigationto arry
sectionor pageof the book,boolanarks,higlrlightirg,
note-taking,instant searchfor any term, pop-up keyterm definitions,and a spokenglossary.

r

The text-speci-flcstudent media, fully integrated
throughout the eBook,include animatedenzyme
mechanisms,animatedbiochemicaltechniques,
problem-solvingvideos,molecularstructure
tutorials in Jmol, Protein Data Bank IDs in Jmol, living graphs,and online quizzes(each describedun
der "Additional Student Media"below).

r

Instructor features include the ability to add
notes or files to any page and to sharethese

noteswith students.Notesmay include text, Web
links, animations,or photos.Instructors can also
assignthe entire text or a customversion of the
eBook.

1-4292-1911-4),fully optimized for maximum visibility in the lecture hall.
r

r A list of Protein Data Bank IDs for the structures
in the text is provided,arrangedby fuure number. A
new feature in this edition is an index to all structures in the Jmol interactiveWebbrowserapplet.
r

Living Graphs illustrate key equationsfrom the
textbook, showingthe graphic results of changing
parameters.

r

A comprehensiveTest Bank in PDF and editable
Word formats includes 150multiple-choiceand
short-answerproblemsper chapter,rated by level
of difflcr-rltv.

Additional
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also in the eBook, and many are availableon the book
Web site (www.whfreeman.com/lehningerSe).
The
student mediainclude:
New Problem-Solving
Videos, createdby
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online problem-solvinghelp
to students.Througha
two-part approach,each
10-minutevideo coversa
key textbookproblemrepresenting a topic that students traditionally struggle to
master.Dr. Ensignfirst describesa provenproblemsolvingstrategyand then appliesthe strategyto the
problemat hand in clear,concisesteps.Studentscan
easilypause,rewind, and reviewany stepsasthey
wish until they firmly graspnot just the solutionbut
alsothe reasoningbehind it. Workingthrough the
problemsin this way is designedto makestudents
better and more confidentat applyingkey strategies
as they solveother textbook and examproblems.
r

Additional
Instructor
Media
Instructors are provided with a comprehensive set
of teachingtools, each developedto support the text,
lecture presentations,and individual teachingstyles.All
instructor media are available for download on the

book Web site (www.whfreeman.com/lehningerbe)
and on the Instructor Resource CDIDVD (ISBN
I-4292-1912-2).
Thesemediatoolsinclude:
r

r

Fully optimized JPEG flles of every flgure, photo,
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The 150most popularimagesin the textbookare
availablein an Overhead Thanspaxency Set (ISBN

Animated Enzyme Mechanisms and Animated
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fi.lesand preloadedinto PowerPoint,in both PC and
Macintoshformats,for lecturepresentation.(See
list of animationtopics on the inside front cover.)

r

Studentversionsof the Animated Enzyme
Mechanisms and Animated Biochemical
Techniques help studentsunderstandkey

mechanismsand techniquesat their own pace.
For a completelist of animationtopics, seethe
inside front cover.


Preface
[.t"]

Protein
Terthrv

Struclurc

Discussion Questions: provided for
eachsection;designedfor individual
review,study groups,or classroom
discussion

Archltecture
of Largc Globula(

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Acknowledgements

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A Self-Tbst: "Do you know the terms?";
crosswordpuzzles;multiple-choice,
fact-driven questions;and questions
that ask studentsto apply their new
knowledgein new directions-plus
answers!

6Mh*{hddM

. A.d.drtuh€lrx
,
q!tu
h S

r

Moleeular Structure Thtorials, using the JmolWeb browser applet, allow students to explore in
more depth the molecular structures included in
the textbook, including:
Protein Architecture
Bacteriorhodopsin
Lac Repressor
Nucleotides
MHC Molecules
Tfimeric G Protehs
Oxygen-BindingProteins
RestrictionEndonucleases
HammerheadRibozyme

r

Online Quizzes include approximately 20 challengrng multiple-choice questions for each chapter,
with automatic grading and text references and
feedback on all answers.

TheAbsolute,
Ultimate
Guide
toLehninger

Principles
of
Biochemistry,
FifthEdition,
StudyGuide
ondSolutions
(University
Manual,
byMarcy
Osgood
of NewMexico
(University
School
of Medicine)
andKaren
Ocorr
of
-"1
California,
5an Diego);
1- 4292-1241
The Absolute, Ult'imnte Guide combinesan irmovative
study guide with a reliable solutions manual (providing
extended solutions to end-of-chapterproblems) in one
convenientvolume. ThorougNy class-tested,the Study
Guideincludesfor each chapter:
r

Major Coneepts: a roadmapthrough the chapter

r

What to Review: questionsthat recap key points
from previous chapters

This book is a team effort, and producing it
would be impossiblewithout the outstanding
people at W. H. Freeman and Companywho
supported us at every step along the way.
Randi Rossignol(Senior Editor) and l(ate Alu
(Executive Editor) arranged reviews, made
many helpful suggestions,encouragedus, kept us on
taxget, and tried valiant$ (if not always successfully)to
keep us on schedr:le.Our outstanding Project Editor, Liz
Geller,somehowkept the book movingthrough production
in spite of our misseddeadlinesand last-minute changes,
and did so with her usual grace and skill. We thank
Vicki Tomaselli for developing the design, and Marsha
Cohenfor the beautiful layout. We againhad the good fortune to work with Linda Strange,a superbcopy editorwho
has edited all flve editions of Prirrci,plns of Binchenaistrg
(as well as the two editions of its predecessor,Lehninger's
Bi,ochenaistry). Her contributions are invaluable and
enhancethe text wherever she touches it. We were also
again fortunate to have the contributions and insights of
MorganRyan,who worked with us on the third and fourtlt
editions.We thark photo researcherDena Dgtlio Betz for
her help locatingimages,and Nick TVmoczkoand Whitney
Clench for keeping the paper and files flowing among all
participants in the project. Our gratitude also goes to
DebbieClare,AssociateDirector of Marketing,for her creativity and good humor in coordinating the sales and

marketingeffort.
In Madison,Brook Soltvedt is (and has been for all
the editionswe haveworked on) our first-line editor and
critic. Sheis the first to seemanuscriptchapters,aids in
manuscript and art development,ensuresinternal consistencyin content and nomenclature,and keepsus on
task with more-or-lessgentle prodding. As she did for
the fourth edition, ShelleyLusetti, now of New Mexico
State University,read every word of the text in proofs,
caughtmunerousmistakes,and mademany suggestions
that improved the book.
The new art in this edition, including the new molecuIar graphics,was done by Adam Steinberg,here in Madison, who often made valuable suggestionsthat led to
better and clearer illustrations. This edition also contains
many molecular graphics produced for the third and
fourth editions by Jean-YvesSgro, another Madison


colleague. We feel very fortunate to have such gifted partners as Brook, Shelley, Adam, and Jean-Yveson our team.
We are also deeply indebted to Brian White of the University of Massachusetts-Boston, who wrote the new
data analysis problems at the end of each chapter.
Many colleagues played a special role through their
interest in the project and their timely input. Prominent
among these are Laurens Arderson of the University
of Wisconsin-Madison; Jeffrey D. Esko of the University of
California, San Diego; Jack Kirsch and his students at
the University of California, Berkeley; and Dana Aswad,
Shiou-Chuan (Sheryl) Tsai, Michael G. Cumsky, and
their colleagues (listed below) at the University of
California, Irvine. Many others helped us shape this ffih
edition with their comments, suggestions, and criticisms.
To all of them, we are deeply grateful:

RichardM. Amasino,Uniu ersitg oJ Wi,sconsi,n-M
adison
LouiseE. Anderson,Uni,uersi,tyof lllinoi,s at Cltdcago
Cheryl Bailey,Uni,uersi,tgof Nebraskq Li,ncoln
Kenneth Balazovich,Uni,uersi,tgoJMi,chi,gon
ThomasO. Baldwin, Uni,uersitg of Ari,zona
VaheBandarian, Uniu ersitg oJAdzona
EugeneBarber,Uni,uersi,tgof Rochester
SebastianY Bednarek,Uni,uersi,tgoJ Wisconsi,n-Mudi,son
RamachandraBhal, Lincoln Uniuersity
JamesBlankenship,CorneII Uni,uersi,ty
SandraJ. Bonetti, Colorado State [Jniuersitg, Pueblo
BarbaraBowman,Uni,uersi,tyoJ CaliJorni,a,Berkeley
Scott D. Briggs,Purdue Uniuersi,ty
Jeff Brodsky,Uni,uersi,tgof Pi,ttsburgh
Ben Caldwell,Mi,ssouri WesterruState Uniuersi,ty
David Camerini,Uniuers'itg oJ CaliJorni,a,Irui,ne
GuillaumeChanfreau,Uni,uersity oJ Cali,Jorni,a,Los Angeles
MelanieCocco,Uni,uersitg oJCali,Jontia,Irui,ne
Jeffrey Cohlberg,CaliJorni,a Stute [Jniuersi,tg,Lotzg Beach
Kim D. Collins,Uniuersi,tg of Marytand
CharlesT. Dameron,Duquesne Uni,uersi,ty
Richard S. Eisenstein,Uni,uersi,tgoJ Wisconsi,n-Mad,i,son
GeraldW. Feigenson,CorneLLUni,uersi,ty
Robert H. Fillingame,Uni,uersi,tgoJ Wisconsin-Madisota
Brian Fox, Uni,uersi,ty oJ Wisconsin-Madi,son
GeraldD. Frenkel,Rutgers {Jni,uersi,tg
Perry Frey, Uni,uersi,tgoJ Wi,sconsin-Madi,son
David E. Graham,Uni,uersi,tgoJ Teras-Austin
William J. Grimes,Uni,uersi,tyof Ari,zona

Mart}'n Gurn, Teras A&M Uni,uersitg
Olivia Hanson,Uni,uersi,tyoJ Central Oklahoma
Amy Hark, Muh,IenbergCoILege
ShaunV. Hernandez,Uni,uersi,tgoJ Wi,sconsi,n-Madison
Peter Hinkle, Conwll Uniuersi,tg
P. ShingHo, Oregon State Uni,uersi,tA
CharlesG. Hoogstraten,Mi,chigan State Uni,uersi,tA
Gerwald Jogl,Brown Uniuersitg
Sir HansKornberg,Boston Uni,uersity
Bob Landick, Uni,uersi,tgoJ Wi,sconsin-Mad,ison
Patrick D. Larkin, Teras A&M Uni,uersi,ty,Corptn Christi,
Ryan P. LiegeI, Uniuersitg oJ Wi,sconsin-Madi,son
Maria Lhder, Cali,forni,aState Uni,uersi,tg,Fullerton
Andy C. LiWang,Teras A&A,[Uni,uersitg
Johr Makemson,Florida Internati,onal [lni,uersi,tg
JohnC. Matthews,UiriDersifuof MississzWt,Schno|oJPha,rmang
BenjaminJ. McFarland,SeattlePacifi,c Uni,uersi,ty
Anant Menon, Wei,LL
CorneII Medi,cal CoILege
SabeehaMerchant,Uni,uersi,tgoJCali,fotnia, Los Angeles

Scott C. Mohr,Boston Uni,uersi,tg
Kimberly Mowry,Brown Uniuersi,ty
LeishaMullins, Teras A&M Uni,uersi,tg
SewiteNegash,Cali,Jorni,aState Uni,uersi,ty,Long Beach
Allen W Nicholson,Temple Uni,uersi,ty
Hiroshi Nikaido, Uni,uersitgof CaliJorni,a,Berkeley
JamesNtambi, Uni,uersi,tgoJ Wisconsi,n-Madi,son
Timothy F. Osborne,Uni,uersi,tgof Cali,Jornia,Iyai,ne
Jos6R. P6rez-Castifleira,Uni,uersi,tgoJSeui,lle,Spai,n

Terry Platt, Uni,uersi,tgof Rochester
WendyPogozelski,State Uni,uersitg oJNew York at Geneseo
-Modi,son
JonathanPopper,Uni,uersi,tgoJ Wi,sconsi,n
ThomasPoulos,Uniuersi,tgoJ CaliJorn'i,a,Irui,ne
Jack Preiss,Mi,chi,ga.llSta,teUniuersi,W
Arma Radominska-Pandya,
Uni,uersi,tgoJArkansas
Ron Raines,Uni,uersi,tgoJ Wi,scon
si,n-Madi,son
Tom A. Rapoport,Harvard Medi,ca|School
JasonJ. Reddick,Uni,uersi,tgoJNorth Caroli,na, Greensboro
Mary Roberts,Boston College
Ingrid K. Rttf, Uni,uersi,tyoJCali,forni,a,Irui,ne
AboozarSoleimani,Tehran Uni,uersi,tg,Iran
Mark Spaller,Wayne Sta,teUni,uersi,tA
StephenSpiro,Uniuersitg oJ Teras at DaILo,s
NarasimhaSreerama,Colorado State Uni,uersi,ty
Jon D. Stewart, Uni,uersi,tyof Florida
Koni Stone,CaliJotni.a State Uni,uersitA,Stanislo,us
Jon R. Stultzfus,Mi,chigan State Uni,uersi,tg
JeremyThorner, Uni,uersi,tgof Cali,forni,a,Berkeleg
Dean R. ToIan,Boston Uni,uersi,ty
SandraL. Tirrchi,Mi,Ilersui,IleUni,uersi,tg
ManuelVarela,Eastern New Meni,coUni,uersi,tg
Bob Warburton,SheTsherdUni,uersi,ty
Ttacy Ware,Salem State CoLIege
SusanWeintraub,Unintersi,tgoJ Teras, Health Sci,enceCsttter
MichaelYaffe,MassachusettsInsti,tute of Technologg
We lack the space here to acknowledge all the other

individuals whose special efforts went into this book.
We offer instead our sincere thanks-and the finished
book that they helped guide to completion. We, of
course, assume full responsibility for errors of fact or
emphasis.
We want especially to thank our students at the
University of Wisconsin-Madison for their nunerous comments and suggestions.If something in the book does not
work, they are never shy about letting us lcrow it. We are
gratefirl to the students and staff of our research groups and
of the Center for Biologz Education, who helped us balance
the competing demands on our time; to our colleagues in
the Department of Biochemistry at the University of
Wiscorsin-Madison, who helped us with advice and criticism;
and to the marry students and teachers who have written to
suggest ways of improving the book. We hope our readers
will continue to provide input for future editions.
Finally, we express our deepest appreciation to our
wives, Brook and Beth, and our families, who showed
extraordinary patience with, and support for, our book
writing.

DavidL. Nelson
MichaelM. Cox
Madison,Wisconsin
January2008


Preface

vilt

1 The
Foundations
ofBiochemistry

I STRUCTURE
AND
CATAIYSIS
2 Water
3 Amino
Acids.
Peptides,
andProteins
4 The
Three-Dimensional
Strufiure
ofProteins
5 Protein
Funrtion
6 Enzymes
7 Carbohydrates
andGlyrobiology
8 Nucleotides
andNucleic
Acids
9 DNA-Based
Information
Technoloqies
10Lipids
11Biological

Membranes
andTransport
12Biosignaling

a

41
+.1

71
113
153
183
235
271
103
343
371
417

II BIOENERGETICS
AND
METABOLISM 485
13 Bioenergetics
andBiochemical
Reaction
Types
489
14 Glycolysis,
Gluconeogenesis,

andthePentose
Phosphate
Pathway
527
'15
Principles
ofMetabolic
Regulation
569
16The
Citric
Aridtyde
515
(atabolism
17Fatty
Acid
olt
18Amino
Acid
0xidation
andtheProduction
ofUrea
673
19 Oxidative
Phosphorylation
andPhotophosphorylation
v07
20ftrbohydrate
Biosynthesis
inPlants

andBacteria
773
2l Lipid
Biosynthesis
805
22Biosynthesis
ofAmino
Acids,
Nucleotides,
and
Related
Mohcules
851
23Hormonal
Regulation
andlntegration
of
Mammalian
Metabolism
90i

III INFORMATION
PATHWAYS

945

24Genes
andChromosomes
25DNA
Metabolism

26RNA
Metabolism
27Protein
Mrtabolism
28Regulation
ofGene
Expression

947
975
1021
1065
't1
15

AppendixA CommonAbbreviationsin theBiochemical
Research LiteratureA- 1
AppendixBAbbreviatedSolutionsto ProblemsAS-l
GlossaryG-|
CreditsC-l
lndexl-l

1 TheFoundations
ofBiochemistry
Foundations
1.1(ellular
Cells Are the Structural and Functional
Units of All Living Organisms
Cellular DimensionsAre Limited by Diffusion
There Are Three Distinct Domains of Life

E sch,erichia coli ls the Most-Studied Bacterium
Eukaryotic Cells Have a Variety of Membranous
Organelles,Which Can Be Isolated for Study
The Cytoplasm Is Organizedby the Cytoskeleton
and Is HigNy Dynamic
Cells Build SupramolecularStructures
In Vitro Studies May Overlook Important
Interactions among Molecules

1.2(hemicalFoundations
BiomoleculesAre Compoundsof Carbon with
a Variety of FunctionalGroups
Cells Contain a Universal Set of Small Molecules

Mass,and
Molecular
Box1-l MolecularWeight
Units
Their
Conect
MacromoleculesAre the Major
Constituentsof Cells
Three-DimensionalStructure Is Described
by Configuration and Conformation

J
J

4
5

.7

8
I
10

l1
11
13

14
t4
15

0pticalActiuatyilnVino,Vefitus1 7
Box1-2louisPasteurand
lnteractionsbetweenBiomolecules
Are Stereospeciic

1.3PhpicalFoundations
Living OrganismsExist in a Dynamic
Steady State, Never at Equilibrium with
Their Surroundings
OrganismsTtansform Energr and Matter
from Their Surroundings

18

19
20

20

21
Boxl-3Entropy:TheAdvantagesofBeingDisotganized
The Flow of Electrons Provides Energ5r
for Organisms
Creating and Maintaining Order Requires Work
andEnerry
Energ5lCoupling Links Reactions in Biologr
K"rand AG" Are Measuresof a Reaction's
Tendencyto ProceedSpontaneously
EnzymesPromote Sequencesof Chemical Reactions
Metabolism Is Regr:latedto Achieve Balance
andEconomy

Foundations
1.4Genetic
Genetic Continuity Is Vested in Single
DNA Molecnles
The Structure of DNA Allows for Its Replication
and Repair with Near-Perfect Fidelity
The Linear Sequencein DNA Encodes Proteins with
Ttree-Dimensional Structures

22
22
22
24
25
26

27
27
28
29
xv


1.5Evolutionary
Foundations
Changesin the HereditaryInstructions
Allow Evolution
Biomolecu-les
First Arose by ChemicalEvolution
RNA or RelatedPrecursorsMay HaveBeen the
First Genesand Catalysts
BiologicalEvolution BeganMore Than
Three and a Half Billion YearsAgo
The First Cell ProbablyUsedInorganicFuels
Eukaryotic CellsEvolvedfrom Simpler
Precursorsin SeveralStages
MolecularAnatomy RevealsEvolutionary
Relationships
Functional GenomicsShowsthe Allocationsof
Genesto SpecificCellularProcesses
GenomicComparisonsHaveIncreasir4;
Importance in Human Biology and Medicine

29

2.4Water
asaReactant

65

tq

2.5TheFitness
oftheAqueous
Environment
forLiving
0rganisms

65

3 Amino
Acids,
Peptides,
andProteins

7'.|

3.1Amino
Acids

72

30
31
32

32

33
35
35

I STRUCTURE
AND
CATALYSIS

41

2 Water

43

2.1Weak
Interactions
inAqueous
Systems

43

HydrogenBondingGivesWater lts
UnusualProperties
WaterForms HydrogenBondswith Polar Solutes
WaterInteracts Electrostaticallywith
ChargedSolutes
Entropy Increasesas Crystalline
SubstancesDissolve

NonpolarGasesAre Poorly Solublein Water
NonpolarCompoundsForce Energetically
Unfavorable Changesin the Structure of Water
van der WaalsInteractions Are WeakInteratomic
Attractions
WeakInteractionsAre Crucialto Macromolecular
Structure and Function
SolutesAffect the Colligative Properties of
AqueousSolutions

51

2.2lonization
ofWater,
Weak
Acids,
andWeak
Bases

54

Pure WaterIs Slightly Ionized
The Ionizationof WaterIs Expressedby an
Equilibrium Constant
The pH ScaleDesignatesthe H+ and OHConcentrations
WeakAcids and BasesHave Characteristic
Acid DissociationConstants
Titration Curves Revealthe pK. of Weak Acids

54

2.3Buffering
pHChanges
against
in
Biological
Systems
Buffers Are Mixtures of WeakAcids and Their
ConjugateBases
The Henderson-Hasselbalch
EquationRelates
pH, pK., and Buffer Concentration
WeakAcids or BasesBuffer Cellsand
TissuesagainstpH Changes
UntreatedDiabetesProduces
Life-ThreateningAcidosis

Box2-1Medicine:0n
Being
0netOwnRabbit
(Don't
TryThisatHome!)

43
45

47
47

Amino Acids ShareCommonStructural Features

The Amino Acid Residuesin ProteinsAre
L Stereoisomers
Amino Acids Can Be Classifiedby R Group

Box3-1 Methods:
Absorption
ofLightbyMolecules:
Ihelambert-Beel
Law
UncommonAmino Acids Also Have
Irnportant Functions
Amino Acids CanAct as Acids and Bases
Amino Acids HaveCharacteristicTitration Curves
Titration CurvesPredict the Electric
Chargeof Amino Acids
Amino Acids Differ in Their Acid-BaseProperties

3.2Peptides
andProteins
PeptidesAre Chainsof Amino Acids
PeptidesCan Be Distinguishedby Their
IonizationBehavior
BiologicallyActive Peptidesand Polypeptides
Occur in a VastRangeof Sizesand
Compositions
SomeProteins ContainChemicalGroups
Other Than Amino Acids

72
,74

74

76
77
78
70

80
81

82
82
82
83
84

49

3.3Working
withProteins
50

Proteins Can Be Separatedand Purified
Proteins CanBe Separatedand Characterizedby
Electrophoresis
UnseparatedProteins Can Be Quantified

3.4TheStructure
ofProteins:

Primary
Structure

OI

58

59

The Function of a Protein Dependson Its
Amino Acid Sequence
The Amino Acid Sequencesof Millions of
ProteinsHaveBeen Determined
Short PolypeptidesAre Sequencedwith
AutomatedProcedures
LargeProteinsMust Be Sequencedin Smaller
Segments
Amino Acid SequencesCanAlso Be Deducedby
Other Methods

Box3-2Methods;
Investigating
Proteins
with
Mass
Spectrometry
61

64

SmallPeptidesand Proteins Can Be Chemically
Synthesized
Amino Acid SequencesProvideImportant
Biochemical Information
Protein SequencesCanElucidatethe History of
Life on Earth

Box3-3
Consensus
Sequencesand
Sequence
logos

85
85
88
91

92
93
93
94
95
98

98
100
I02
102

103


Contents xvii

'll3
4 TheThree-Dimensional
Strueture
ofProteins
4.10verview
ofProtein
Structure
A Protein'sCon-formationIs StabilizedLargelyby
WeakInteractions
The Peptide Bond Is Rigid and Planar

4.2Protein
5econdary
Structure
The a Helix Is a CommonProtein Secondary
Structure

Box4-1Methods:Knowing
theRightHand
fromtheleft

113
rt4
115

117
\t7
118

Amino Acid SequenceAffects Stability of the
a Helix
The B ConformationOrganizesPolypeptide
Chainsinto Sheets
B Tirrns Are Commonin Proteins
CommonSecondaryStructuresHave
CharacteristicDihedral Angles
CommonSecondaryStructuresCan Be
Assessedby Circular Dichroism

1.21.

4.3Protein
Tertiary
andQuaternary
Structures

123

Fibrous ProteinsAre Adapted for a
Structural Function

119

r20

r2r
r22

\23

Box4-2 Permanent
Waving
lsBiochemical
Engineering 125
Box4-3
Medicine:Why
Sailors,
Explorers,
andCollege
Students
Should
EatTheir
Fresh
Fruits
andVegetables126
Box4-4TheProtein
DataBank
129
Structural Diversity ReflectsFunctionalDiversity
in GlobularProteins
r29
MyoglobinProvidedEarly Cluesabout the Complexity
of Globr-rlar
Protein Structure
t29

GlobularProteinsHavea Variety of
Tertiary Structures
131

Box4-5
Methods;
Methods
forDetermining
the
Three-Dimensi0nal
Stlucture
ofaProtein
Protein Motifs Are the Basisfor Protein
Structural Classiflcation
Protein QuaternaryStructuresRangefrom Simple
Dimers to Large Complexes

4.4Protein
Denaturation
andFolding
Lossof Protein Structure Resultsin
Lossof Function
Amino Acid SequenceDetermines
Tertiary Structure
PolypeptidesFold Rapidlyby a StepwiseProcess
SomeProteinsUndergoAssistedFolding
Defectsin Protein Folding May Be the Molecular
Basisfor a WideRangeof Human Genetic
Disorders

5,1Reversible
Binding
ofaProtein
toaLigand:
0xygen-Binding
Proteins
OxygenCan Bind to a HemeProstheticGroup
MyoglobinHas a SingleBinding Site for Oxygen
Protein-LigandInteractionsCan Be Described
Quantitatively

Box5-1Medicine:Cahon
Monoxide:A
Stealthy
Killer
TWoModelsSuggestMechanismsfor
CooperativeBinding
HemoglobinAlso TfansportsH+ and CO2
OxygenBinding to HemoglobinIs Regulatedby
2,3-Bisphospho$ycerate
Sickle-CellAnemiaIs a MolecularDisease
of Hemo$obin

5.2(omplementary
lnteradions
between
Proteins
andLigands:The
lmmune
System

andlmmunoglobulins

158
158
159
160
160
162
163
165
165
167
168

174

The Immune ResponseFeaturesa Specialized
Array of Cellsand Proteins
170
Artibodies HaveTWoIdentical Antigen-BindingSites 171
Antibodies Bind Tightly and Specifically to Antigen 173
The Antibody-AntigenInteraction Is the Basisfor a
Variety of Important Analytical Procedures
I73

Modulated
Energy:
5.3Protein
lnteractions
by(hemical

Actin,
Myosin,
andMolecular
Motors
175
The Major Proteinsof MuscleAre Myosinand Actin
Additional ProteinsOrganizethe Thin and Thick
Filamentsinto OrderedStructures
MyosinThick FilamentsSlide along
Actin Thin Filaments

t75
176
\78

132
136
138

140
t40
t41
t42
t43

r45
Box4-6Medicine:
Death
byMisfolding:The
PrionDiseases 147

5 Protein
Funetion

Protein Structure Affects How LigandsBind
HemoglobinTfansportsOxygenin Blood
Hemoglobin Subunits Are Structurally Similar to
Myoglobin
Hemo$obin Undergoesa Structural Changeon
Binding Oxygen
HemoglobinBinds OxygenCooperatively
CooperativeLigand Binding Can Be Described
Quantitatively

153

6 Enzymes

183

6.1Anlntroduction
toEnzymes

183

Most EnzymesAre Proteins
Enz5rmes
Are Classifiedby the Reactions
They Catalyze

Work
6.2HowEnzymes
En4'rnes A-ffectReactionRates,Not Equilibria
ReactionRatesand Equilibria HavePrecise
Thermod)'namicDefinitions
A Few PrinciplesExplain the CatalyticPower and
Speciflcityof EnzJmres
WeakInteractionsbetweenEnzymeand
SubstrateAre Optimizedin the Tfansition State
Binding Energr Contributesto Reaction
Speciflcityand Catalysis
Speciic CatalyticGroupsContributeto Catalysis

184

r84
186
186
188
188
189
191
1.92

to Understanding
Kinetics
asanApproach
6.3Enzyme
194
Mechanism

154
r54

SubstrateConcentrationA-ffectsthe Rate of
194
Reactions
Enz)ryne-Catalyzed
The RelationshipbetweenSubstrateConcentration
and ReactionRate Can Be Expressed
195
Quantitatively


f

..J

Ivrrl

Contents

Box6-1Transformations
oftheMichaelis-Menten
Equation:
TheDouble-Reciprocal
Plot
197
Kinetic ParametersAre Usedto CompareEnzyme
Activities
Many EnzymesCata\ze Reactionswith TWoor

More Substrates
Pre-SteadyState Kinetics Can Provide
Evidencefor SpecificReactionSteps
Erzy'rnesAre Subjectto Reversibleor
IrreversibleInhibition

Tests
Box6-2Kinetic
forDetermining
lnhibition
Mechanisms
EnzSrmeActivity Depends on pH

6.4Examples
ofEnzymatic
Reactions
The ChymotrypsinMechanismInvolvesAcylation
and Deacyla[ionof a Ser Residue

Box6-3Evidence
forEnzyme-Transition
State
Complementadty
HexokinaseUndergoesInduced Fit on
SubstrateBinding
The EnolaseReactionMechanismRequires
Metal Ions
Lysozlme UsesTWoSuccessiveNucleophilic
DisplacementReactions
An Understandingof EnzymeMechanismDrives

Important Advancesin Medicine

5.5Regulatory
Enzymes
A-llostericEnz)rmesUndergoConformational
Changesin Responseto ModulatorBinding
In Many Pathways,RegulatedStepsAre
Catalyzedby Allosteric Enzymes
The Kinetic Propertiesof Allosteric Enz;'rnes
Divergefrom Michaelis-MentenBehavior
SomeEnz5..rnes
are Regulatedby Reversible
CovalentModi-fication
PhosphorylGroupsAffect the Structure and
CatalyticActivity of En4rnes
Multiple PhosphorylationsAllow Exquisite
RegulatoryControi
SomeErz;'rnes and Other ProteinsAre Regulated
by Proteolltic Cleavageof an Enz5rmePrecursor
SomeRegulatoryEnzy.rnesUse SeveralRegulatory
Mechanisms

t97

201

20r
202
204

205
205

210
2\2
213
213
216

245
246
247
249
249

gates:
ns,Glycoproteins,
7.36lycoconju
Proteoglyca
252
andGlycolipids
Proteo$ycansAre Glycosaminoglycan-Containing
Macromoleculesof the Cell Surfaceand
252
Extracellular Matrix
GlycoproteinsHave CovalentlyAttached
255
Oligosaccharides
Are
Glycolipidsand Lipopolysaccharides

256
MembraneComponents

Molecules:
7.4(arbohydrates
asInformational
TheSugar(ode
Lectins Are ProteinsThat Readthe Sugar
Codeand MediateMany BiologicalProcesses
Lectin-CarbohydrateInteractionsAre Highly
Speciflcand Often Pollvalent

257
258
26I

220

Arids
8 Nucleotides
andNucleic

271

221

8.1Some
Basics

271

220

222
223
224

Nucleotidesand NucleicAcids Have
CharacteristicBasesand Pentoses
PhosphodiesterBondsLink Successive
Nucleotidesin NucleicAcids
The Propertiesof NucleotideBasesAffect the
Three-DimensionalStructure of NucleicAcids

8.2Nucleic
Acid
Structure

227

7.1Monosaccharides
andDisaccharides

23s

Disaccharides Contain a Glycosidic Bond

244

263

235

Box7-1Medicine:
Blood
Glucose
Measurements
inthe
Diagnosis
andTreatment
ofDiabetes

Are Stored
SomeHomopolysaccharides
Forms of Fuel
Serve
SomeHomopolysaccharides
Structural Roles
Steric Factorsand HydrogenBondingInfluence
Folding
Homopolysaccharide
Bacterialand Algal Cell WallsContainStructural
Heteropolysaccharides
Are Heteropolysaccharides
Glycosaminoglycans
of the ExtracellularMatrix

7.5Working
withCarbohydrates

7 Carbohydrates
andGlycobiology
The TWoFamiliesof Monosaccharides
Are
Aldosesand Ketoses
Monosaccharides
HaveAs].'rnmetricCenters
The CommonMonosaccharides
Have Cyclic
Structures
OrganismsContaina Variety of HexoseDerivatives
Monosaccharides
Are ReducingAgents

7.2Polysaccharides

236
236
238
240
24r

241
243

271
.tt7 ^

276

277

DNA Is a DoubleHelix that StoresGenetic
Information
278
DNA Can Occur in Different Three-Dimensional
Forms
280
Certain DNA SequencesAdopt UnusualStructures 28r
MessengerRNAsCodefor Po\peptide Chains
283
Many RNAsHaveMore ComplexThree-Dimensional
Structures
284

8.3Nucleic
Acid
Chemistry
Double-HelicalDNA and RNA Can Be Denatured
NucleicAcids from Different SoeciesCan
Form Hybrids
Nucleotidesand NucleicAcids Undergo
Nonenzl'rnaticTlansformations
SomeBasesof DNA Are Methylated
The Sequencesof Long DNA StrandsCan Be
Determined
The ChemicalSynthesisof DNA Has Been
Automated

287

287

289
292
292
294


8.4Other
Functions
ofNucleotides
NucleotidesCarry ChemicalEnergy in Ceils
Adenine NucleotidesAre Componentsof Marry
EnzSrme
Cofactors
SomeNucleotidesAre RegulatoryMolecules

296
296
to7

298

9 DNA-Based
Information
Terhnologies 3CI3
9.1DNA
Cloning:The
Basics
RestrictionEndonucleasesand DNA Ligase

Yield RecombinantDNA
CloningVectorsAllow Ampliflcationof Inserted
DNA Segments
Speci-flcDNA SequencesAre Detectableby
Hybridization
Expressionof ClonedGenesProduces
Large Quantitiesof Protein
Alterationsin ClonedGenesProduceModified
Proteins
Terminal TagsProvide Binding Sites for Affinity
Purification

9.2From
Genes
toGenomes
DNA LibrariesProvideSpecializedCataiogsof
GeneticInformation
The PolymeraseChainReactionAmpliflesSpeciic
DNA Sequences
GenomeSequencesProvidethe Ultimate
GeneticLibraries

304
304
307
310
3I2
3I2

315

315
Jl

r

317

319

9.3From
Genomes
to Proteomes

324

9.4Genome
Alterations
andNewProducts
ofBiotechnology
A BacterialPlant ParasiteAids Cloningin Plants
Manipulationof Animal Cell GenomesProvides
Information on ChromosomeStructure and
GeneExpression

Box9-2
Medicine:The
Human
Genome
andHuman
GeneTherapy

New TechnologiesPromiseto Expedite the
Discoveryof New Pharmaceuticals
RecombinantDNA TechnologyYieldsNew
Productsand Challenges

10Lipids
10.1Storage
Lipids
Fatty Acids Are HydrocarbonDerivatives
TfiacylglycerolsAre Fatty Acid Esters of Glyceroi
TtiacylglycerolsProvideStoredEnergy
and Insulation

10.2
Structural
Lipids
inMembranes
Are Derivativesof
Glycerophospholipids
PhosphatidicAcid
SomeGlycerophospholipidsHaveEther-Linked
Fatty Acids
CtrloroplastsContainGalactolipidsand Sulfolipids
ArchaeaContainUnique MembraneLipids
SphingolipidsAre Derivativesof Sphingosine
Sphingolipidsat Cell SurfacesAre Sitesof
BiologicalRecognition
Phospholipidsand SphingolipidsAre Degraded
In LySOSOmeS

e.) A

325
328

330
330

332

335
335
337

343
343
r)4r)

J40

.14r,

349
350
350
352
352
352
354
.JDi)

355

Accumulations
of
Box10-2
Medicine;
Abnormal
Inherited
Human
Diseases 356
Membrane
Lipids:Some
10.3
Lipids
asSignals,
Cofactors,
andPigments

313

347

Partial Hydrogenationof CookingOils Produces
347
Tfans Fatty Acids
WaxesServeas Energy Storesand Water Repellents 349

SterolsHaveFour FusedCarbonRhgs

Box9-1APotentWeapon
inForensic
Medicine
Sequenceor Structural Relationships
ProvideInformation on Protein Function
CellularExpressionPatternsCan Revealthe
CellularFunction of a Gene
Detection of Protein-ProteinInteractionsHelps to
Define Cellularand MolecularFunction

Fatheads
Box10-1Sperm
Whales:
oftheDeep

Phosphatidylinositolsand SphingosineDerivatives
Act as Intracellular Signals
EicosanoidsCarry Messagesto Nearby Cells
Steroid HormonesCarry MessagesbetweenTissues
VascularPlantsProduceThousandsof Volatile
Signals
VitaminsA and D Are HormonePrecursors
VitaminsE and K and the Lipid QuinonesAre
Oxidation-ReductionCofactors
DolicholsActivate SugarPrecursorsfor
Biosyrrthesis
Many Natural PigmentsAre Lipidic
ConjugatedDienes

withLipids

10.4
Working
Lipid Extraction RequiresOrganicSolvents
Adsorption ChromatographySeparatesLipids
of Different Polarity
Gas-LiquidChromatographyResolvesMixtures
of VolatileLipid Derivatives
Speciic HydrolysisAids in Determinationof
Lipid Structure
MassSpectrometryRevealsComplete
Lipid Structure
LipidomicsSeeksto CatalogAll Lipids and
Their Functions

andTransport
11Biological
Membranes

357
357
rJD''

359
359
360
361

363
363
364

365
365
365
365

371

ofMembranes372
andArchitecture
11.1
The(omposition
Each Tlpe of MembraneHas Characteristic
Lipids and Proteins
All BiologicalMembranesShareSome
FundamentalProperties
A Lipid Bilayer Is the BasicStructural
Element of Membranes
Three T$pesof MembraneProteinsDiffer in
Their Associationwith the Membrane
Many MembraneProteinsSpanthe Lipid Bilayer
Integral ProteinsAre Held in the Membraneby
HydrophobicInteractionswith Lipids

372
373
ary^

QNF

Q.7tr

.t 10


xx

[ontents

The Topologyof an Integral MembraneProtein Can
SometimesBe Predictedfrom Its Sequence
378
CovalentlyAttached Lipids Anchor Some
MembraneProteins
379

11.2Membrane
Dynamics

381

Acyl Groupsin the Bilayer Interior Are Ordered
to VaryingDegrees
381
TtansbilayerMovementof Lipids RequiresCatalysis 3 8 1
Lipids and ProteinsDiffuse Laterally in the Bilayer 383
Sphingolipidsand CholesterolCluster Togetherin
MembraneRafts

Box11-1Methods:
Atomic

Force
Microscopy
toVisualize
Membrane
Proteins
385
MembraneCurvatureand FusionAre Central to
ManyBiologicalProcesses
Integral Proteinsof the PlasmaMembraneAre
Involvedin SurfaceAdhesion,Signaling,and
Other CellularProcesses

Transport
I1"3Solute
across
Membranes
PassiveTransportIs Facilitatedby Membrane
Proteins
TfansportersCan Be Groupedinto Superfamilies
Basedon Their Structures
The GlucoseTtansporterof ErythrocytesMediates
PassiveT[ansport
The Chloride-BicarbonateExchangerCaLalyzes
ElectroneutralCotransportof Anionsacross
the PlasmaMembrane

387

388

389
390
391
391
393

Box11-2
Medicine:
Defective
Glu(ose
andWater
Transport
inTwoForms
ofDiabetes
394
Active Tfansport Resultsin SoluteMovement
againsta Concentrationor Electrochemical
Gradient
P-TlrpeATPasesUndergoPhosphorylationduring
Their CatalyticCycles
F-$rpe ATPasesAre Reversible,ATP-Driven
Proton Pumps
ABC TtansportersUseATP to Drive the Active
Tfansport of a Wide Variety of Substrates
Ion GradientsProvidethe Energy for Secondary
Active Transport

395
396

The p-AdrenergicReceptorSystem
Acts through the SecondMessengercAMP

Medicine.'G
Proteins:
Binary
Switches
in
Box12-2
Health
andDisease
SeveralMechanismsCauseTerminationof the
B-AdrenergicResponse
The B-AdrenergicReceptorIs Desensitizedby
Phosphorylationand by Associationwith
Arrestin
Cyclic AMP Acts as a SecondMessengerfor
Many RegulatoryMolecules
Diacylglycerol,Inositol Tf isphosphate,and,Caz*
HaveRelatedRolesas SecondMessengers

Methods:
FRET:
BiochemistryVisualized
ina
Box12-3
Living
Cell
CalciumIs a SecondMessengerThat May Be
Localizedin Spaceand Time

12.3
ReceptorTyrosine
Kinases
Stimulationof the Insulin ReceptorInitiates a
Cascadeof Protein PhosphorylationReactions
The MembranePhospholipidPIP3Functionsat a
Branch in Insulin Signalhg
The JAK-STATSignalingSystemAlso Involves
TVrosineKinaseActivity
CrossTalk amongSignalingSystemsIs
Commonand Complex

(yclases,
12.4
Receptor
Guanylyl
cGMB
and
Protein
G
Kinase

400

404
406
407
407
410

410

12Biosignaling

419

12.1General
Features
ofSignal
Transduction
Box12-1Methods:Scatchard
Analysis
the
Quantifies
Receptor-Ligand
Interaction

419
42"1

423
423

425
430

430
431
432

434
436

439
439
441
443
444

445

12.5Multivalent
Proteins
Adaptor
andMembrane
Rafts446
Protein ModulesBind PhosphorylatedTlrr, Ser,or
Thr Residuesin Partner Proteins
MembraneRafts and CaveolaeSegregate
SignalingProteins

12.66atedlonChannels

Box11-3
Medicine:A
Defective
lon(hannelinCystic
Fibrosis401
AquaporinsForm Hydrophilic Tfansmembrane
Channelsfor the Passageof Water

Ion-SelectiveChannelsAllow RapidMovementof
IonsacrossMembranes
Ion-CharurelFunction Is MeasuredElectricallv
The Structure of a K+ CharurelRevealsthe
Basisfor Its Speci_flcity
GatedIon ChanneisAre Centralin Neuronal
Function
DefectiveIon CharmelsCanHaveSevere
Physiological
Consequences

12.2
Receptors
and
GProtein-(oupled
Second
Messengers

Ion ChannelsUnderlie Electrical Signalhg in
Excitable Cells
Voltage-GatedIon ChannelsProduce
NeuronalAction Potentials
The AcetylcholineReceptorIs a
Ligand-GatedIon Channel
NeuronsHaveReceptorChannelsThat
Respondto Different Neurotransmitters
ToxjnsTargetIon Charmels

446
449

449
449
45I
453
453
454

12,7
Integrins:
Bidirectional
Cell
Adhesion
Receptors455
12.8
Regulation
ofTranscription
bySteroid
Hormones456
12.9
Signaling
inMicroorganisms
andPlants
457
BacterialSignalingEntails Phosphorylationin a
TWo-Component
System
SignalingSystemsof PlantsHave Someof the Same
ComponentsUsedby Microbesand Mammals
Plants Detect Ethylene through a TWo-Component

Systemand a MAPK Cascade
ReceptorlikeProtein KinasesTlansduceSignalsfrom
Peptidesand Brassinosteroids

457
458
460
460


Contents xxi

12.10
Sensory
Transduction
inVision,
0lfaction,
andGustation
The VisualSystemUsesClassicGPCRMechanisms
Excited RhodopsinActs through the G Protein
Tlansducinto Reducethe cGMPConcentration
The Visual SignalIs Quickly Terminated
ConeCellsSpecializein Color Vision
VertebrateOlfactionand GustationUse
MechanismsSimilar to the Visual System

Box12-4Medicine:
Color
Blindness:
J0hn

Dalton's
Experiment
fromtheGrave
GPCRsofthe SensorySystemsShareSeveral
Featureswith GPCRsof HormoneSignaling
Systems

509
Boxl3-lFireflyFlashes:GlowingReportsofATP
461
462
463
+o+
40D

465

466
467

12.11
Regulation
oftheCell(yclebyProtein
Kinases 469
The Cell CycleHas Four Stages
469
Levelsof Cyclin-DependentProtein KinasesOscillate469
CDKsRegulateCeil Divisionby Phosphorylating
Critical Proteins
472

12.120ncogenes,
Tumor
5uppressor
Genes,
and
(ellDeath
Programmed
OncogenesAre Mutant Forms of the Genesfor
ProteinsThat Regulatethe Cell Cycte
Defectsin Certain GenesRemoveNormal
Restraintson Cell Division

Box'12-5
Medicine.'
Development
ofProtein
Kinase
Inhibitors
forCancer
Treatment
ApoptosisIs ProgrammedCell Suicide

473
473

477

489

13.1Bioenergetics
andThermodynamics

490

Biochemicaland ChemicalEouationsAre
Not Identical

13.3
Phosphoryl
Group
Transfers
andATP
The Free-EnergyChangefor ATP HydrolysisIs
Largeand Negative
Other PhosphorylatedCompoundsand Thioesters
Also HaveLarge Free Energiesof Hydrolysis
ATP ProvidesEnergy by Group Ttansfers,Not by
SimpieHydrolysrs
ATP DonatesPhosphoryl,Pyrophosphoryl,and
Adenylyl Groups
Assemblyof InformationalMacromolecules
RequiresEnergy

510
511

512

The Flow of ElectronsCan Do BiologicalWork

512
Oxidation-ReductionsCan Be Describedas
512
Half-Reactions
BiologicalOxidationsOften Involve Dehydrogenation513
ReductionPotentialsMeasureAfflnity for Electrons 5I4
StandardReductionPotentialsCanBe Usedto
CalculateFree-EnergyChange
515
CellularOxidation of Glucoseto CarbonDioxide
516
RequiresSpecializedElectron Carriers
A Few Tlpes of Coenzymesand ProteinsServeas
516
UniversalElectron Carriers
as
NADH and NADPHAct with Dehydrogenases
516
SolubleElectronCarriers
Dietary Deflciencyof Niacin, the Vitamin Form of
519
NAD and NADP,CausesPellagra
Flavin NucleotidesAre Tightly Bourd in
519
Flavoproteins

i 4 Glyeolysis,
Glucaneogenesis,
andthePentose
475

13Bioenergetics
andBiochemical
Reaction
Types
_

13.2Chemical
Logic
andCommon
Biochemical
Reactions

0xidation-Reduction
Reactions
13.4Biological

509

474

II BIOENERGETICS
ANDMETABOLISM 485

BiologicalEnergy TtansformationsObeythe
Laws of Thermodynamics
CellsRequireSourcesofFree Energy
StandardFree-EnergyChangeIs Directly
Relatedto the Equilibrium Constant
Actual Free-EnergyChangesDependon

Reactantand Product Concentrations
StandardFree-EnergyChangesAre Additive

ATP EnergizesActive Ttansport and
MuscleContraction
Ttansphosphorylations
betweenNucleotides
Occurin All CellT$pes
InorganicPollphosphateIs a Potential
PhosphorylGroupDonor

Pathtruay
Pliosphate
14.1Glycolysis

5V7
528

528
An Overview:GlycolysisHas TWoPhases
The PreparatoryPhaseof GlycolysisRequiresATP 531
The PayoffPhaseof GlycolysisYieldsATP and NADH 535
The OverallBalanceSheetShowsa Net Gain of AIP 538
539
GlycolysisIs under Tight Regulation
GlucoseUptake Is Deflcientin Tlpe 1
539
DiabetesMellitus

490

491

inTumors
Suggests
Rate
ofGlycolysis
Box14-1Medicine:High
(hemotherapy
Facilitates
Diagnosis
540
for
and
Targets

49r

forGlycolysis
14.2Feeder
Pathways

493
494

495
500
501
501
504

Dietary Polysaccharidesand Disaccharides
UndergoHydrolysisto Monosaccharides
EndogenousGlycogenand StarchAre
Degradedby Phosphorolysis
Enter the Glycolytic
Other Monosaccharides
Pathwayat SeveralPoints

(onditions:
Anaelobic
under
14.3Fates
of Pyruvate
Ferrnentation
PyruvateIs the TerminalElectron Acceptor in
Lactic Acid Fermentation
Ethanol Is the ReducedProduct in Ethanol
Fermentation

Alligators,
andCoelacanths:
Box14-2Athletes,
ofOxygen
atLimiting
Concentrations
Glycolysis
Fermentations:
Box14-3Ethanol
Biofuels
Beer

andProducing
Brewing
Carries
ThiamineP1'rophosphate
"Active Acetaldehyde"Groups

543
543
544
545

546
546
547

548
549
549


-

.. l
xxtI

(ontents

and
15.3(oordinated
Regulation

ofGlycolysis
Gluconeogenesis

FermentationsAre Usedto ProduceSomeCommon
Foodsand Industrial Chemicals

14.4Gluconeogenesis
Conversionof P1'ruvateto Phosphoenolpyruvate
RequiresTWoExergonicReactions
Conversionof Fructose1,6-Bisphosphate
to
Fructose6-Phosphate
Is the SecondB5,pass
Conversionof GlucoseO-Phosphate
to
GlucoseIs the Third Bypass
Giuconeogenesis
Is EnergeticallyExpensive,but
Essential
Citric Acid CycleIntermediatesand SomeAmino
Acids Are Glucogenic
MammaisCannotConvertFatty Acids to Glucose
Glycolysisand Gluconeogenesis
Are Reciprocally
Regulated

551

ThatCatalyze
Box15-2 lsozymes:

Different
Proteins
theSame
Reaction
556
556

557

14.5Pentose
Phosphate
Pathway
ofGlucose
0xidation 558
Box14-4
Medicine;
WhyPythagoras
Wouldn't
EatFalafel:
Glucose
6-Phosphate
Dehydrogenase
Deficiency 559
The OxidativePhaseProducesPentose
Phosphatesand NADPH
The Nonoddative PhaseRecyclesPentose
Phosphates
to Glucose6-Phosphate
Wernicke-KorsakoffSyrrdromeIs Exacerbatedby a
Defect in Ttansketolase

Glucose6-Phosphate
Is Partitionedbetween
Glycolysisand the PentosePhosphatePathway

bbv

DO.l

15Principles
ofMetabolic
Regulation

559

15.1Regulation
ofMetabolic
Pathways

570

Cellsand OrganismsMaintain a Dynamic
SteadyState
Both the Amount and the Catalytic
Activity of an EnzymeCan Be Regulated
ReactionsFar from Equilibrium in CellsAre
CommonPohts of Regulation
Adenine NucleotidesPlay SpecialRolesin
Metabolc Regulation

15.2

Analysis
ofMetabolic
Control
The Contribution of Each Enz;.'rneto Flux through
a PathwayIs ExperimentallyMeasurable
The Control CoefflcientQuantiies the Effect of a
Changein Enz5.,rne
Activity on MetaboliteFIux
through a Pathway

Box15-1Methods:
ltretabolic
Control
Analysis:
Aspects
Quantitative

HexokinaseIsozJ..rnes
of Muscleand Liver Are
AffectedDifferentlyby Their Product,
GlucoseG-Phosphate

57r

582
583

584

HexokinaseIV (Glucokinase)and Glucose

6-PhosphataseAreTtanscriptionallyRegulated
585
Phosphofructokinase1 and Fructose
1,6-Bisphosphatase
Are ReciprocallyRegulated 585
Is a PotentAllosteric
Fructose2,6-Bisphosphate
RegulatorofPFK-I and FBPase-l
587
Xylulose5-PhosphateIs a Key Regulatorof
Carbohydrateand Fat Metabolism
588
The GlycolyticEnzl'rneP''ruvate KinaseIs
AllostericaliyInhibited by AIP
588
The GluconeogenicConversionof Py'ruvateto
PhosphoenolPlruvate Is Under Multiple
T!'pesof Regulation
590
TtanscriptionalRegulationof Glycolysisand
Gluconeogenesis
Changesthe Number of
Enz}''rneMolecules
590

Medicine;
Genetic
Mutations
ThatLead
Box15-3

to
Rare
Forms
ofDiabetes

593

15.4The
Metabolism
ofGlycogen
inAnimals

594

GlycogenBreakdownIs Catalyzedby Glycogen
Phosphorylase
Glucose1-PhosphateCanEnter Glycolysisor, in
Liver, ReplenishBlood Glucose
The SugarNucleotideUDP-GIucoseDonates
Glucosefor GlycogenSy'nthesis

Box15-4CarlandGertyCori:Pioneers
inGlycogen
Metabolism
andDisease
GlycogeninPrimes the Initial SugarResiduesin
Glycogen

595
596

596

598
601

Dtt
Dt+

575

577
578

578

579

The Elasticity CoefflcientIs Relatedto an Enzlme's
Responsiveness
to Changesin Metaboliteor
RegulatorConcentrations
580
The ResponseCoefflcientExpressesthe Effect of an
OutsideController on Flux through a Pathway Dtt 1
MetabolicControl AnalysisHas BeenApplied to
CarbohydrateMetabolism,with Surprising
Results
581
MetabolicControl AnalysisSuggestsa General
Methodfor IncreasingFlux through a Pathway

15.5(oordinated
Regulation
ofGlycogen
Synthesis
andBreakdown
602
GlycogenPhosphorylaseIs Regulated
Allostericallyand Hormonally
GlycogenSynthaseIs AJsoRegulatedby
Phosphorylationand Dephosphorylation
GlycogenSynthaseKinase3 MediatesSomeof the
Actions of Insulin
PhosphoproteinPhosphatase1 Is Centralto
GlycogenMetabolism
Allosteric and HormonalSignalsCoordinate
CarbohydrateMetabolismGlobally
Carbohydrateand Lipid MetabolismAre Integrated
bv Hormonaland Allosteric Mechanisms

603
605
606
606
606
608

16TheCitricAcidCycle

615

(Activated
16.1Production
ofAcetyl-CoA
Acetate)

6"t6

PytuvateIs Oxidizedto Acetyl-CoAand CO2
The Py'mvateDehydrogenaseComplexRequires
Five Coenzr.'rnes

oro
617


contents
F-"1
The PyruvateDehydrogenaseComplexConsists
of Three Distinct Enzymes
In SubstrateChanneling,IntermediatesNever
Leavethe EnzymeSurface

(ycle
16.2
Reactions
oftheCitric
Acid
The Citric Acid CycleHas Eight Steps

618
619

620
621.

Box16-1Moonlighting
Enzymes:
Proteins
withMore
Than
One
Job
624
Box16-2Synthases
andSynthetases;
Ligases
andLyases;
Kinases,
Phosphatases,
andPhosphorylases:
Yes,
the
Names
AreConfusing!
627
Box16-3Citrate:
ASymmetric
Molecule
ThatReacts

Asymmetrically
629
The Energy of Oxidationsin the CycleIs Efflciently
Conserved
630
Why Is the Oxidation of Acetate So Complicated? o,J 1
Citric Acid Cycle ComponentsAre Important
Bioslnthetic Intermediates
631
AnapleroticReactionsReplenishCitric Acid Cycle
Intermediates
631

Box16-4Gtrate
Synthase,
Soda
Pop,
andthe
World
Food
Supply
Biotin in Py'ruvateCarboxylaseCarriesCO2Groups

(ycle
16.3
Regulation
oftheCitric
Acid
Production of Acetyl-CoAby the Py'ruvate
DehydrogenaseComplexIs Regr_rlated

by
Allosteric and CovalentMechanisms
The Citric Acid CycleIs Regulatedat Its Three
ExergonicSteps
SubstrateCharmelingthrough MultienzSrme
ComplexesMay Occur in the Citric Acid Cycle
SomeMutationsin Enzy'rnesof the Citric Acid
Cycle Lead to Cancer

(ycle
16.4TheGlyoxylate
The GlyoxylateCycleProducesFour-Carbon
Compoundsfrom Acetate
The Citric Acid and GlyoxylateCyclesAre
CoordinatelyRegulated

17FattyAcidCatabolism

633
633
635

oJo

637
637

638
638
639

647
648

Dietary Fats Are Absorbedin the SmallIntestine
HormonesTtigger Mobilizationof Stored
Tliacylglycerols
Fatty Acids Are Activated and Ttansportedinto
Mitochondria

648

The B Oxidationof SaturatedFatty Acids Has
Four BasicSteps
The Four B-OxidationStepsAre Repeatedto Yield
Acetyl-CoAand ATP

(arryOutB 0xidation
Box17-1FatBears
inTheir
Sleep
Acetyl-CoACanBe Further Oxidizedin the
Citric Acid Cycle
Oxidation of UnsaturatedFatty Acids Requires
T\voAdditional Reactions

Btr:ARadicalSolution
toa
Box17-2(oenzyme
Problem

Perplexing
Fatty Acid OxidationIs Tightly Regulated
Tlanscription FactorsThm on the Synthesisof
Proteinsfor Lipid Catabolism
GeneticDefectsin Fatty Acyl-CoA
Dehydrogenases
CauseSeriousDisease
PeroxisomesAlso Carry Out p Oxidation
Plant Peroxisomesand GlyoxysomesUse
Acetyl-CoAfrom B Oxidationas a
BiosyntheticPrecursor
The B-OxidationEnzymesof Different Organelles
HaveDivergedduring Evolution
The ro Oxidationof Fatty Acids Occursin the
EndoplasmicReticulum
PhytanicAcid Undergoesa Oxidationin
Peroxisomes

0c/

658
obt,

660
bol

662

663
ooz+

664

666

17.3
Ketone
Bodies
Ketone Bodies,Formed in the Liver, Are
Exportedto Other Organsas Fuel
Ketone BodiesAre Overproducedin
Diabetesand during Starvation

666
667

18Amino
Acid0xidation
andthe
Production
ofUrea

673

Fates
Groups
18.1
Metabolic
ofAmino

674

OJD

17.1
Digestion,
Mobilization,
andTransport
ofFats

17.20xidation
ofFatty
Acids

CompleteOxidation of Odd-NumberFatty
Acids RequiresThree Extra Reactions

649

650
652

Dietary Protein Is EnzymaticallyDegradedto
Amino Acids
Pyridoxal PhosphateParticipatesin the Ttansfer of
a-Amino Groupsto a-Ketoglutarate
GlutamateReleasesIts Amino GroupAs
Ammoniain the Liver

Assays

forTissue
Damage
Box18-1Medicine:
GlutamineTlansportsAmmoniain the
Bloodstream
Alanine TtansportsAmmoniafrom Skeletal
Musclesto the Liver
AmmoniaIs Toxic to Animals

Excretion
andtheUrea
Cycle
18.2
Nitrogen
Urea Is Producedfrom Ammoniain Five
Enz5rmaticStePs
The Citric Acid and Urea CvclesCan
Be Linked
The Activity of the Urea Cycle Is Regulatedat
T\woLevels
PathwayInterconnectionsReducethe Energetic
Cost of Urea Synthesis
GeneticDefectsin the Urea CycleCan Be

674
677
677
678
680
681

681

682
682
684
685

o

686

AcidDegradation
ofAmino
18.3Pathways

687

T .i fa-Throqtonin
!u!

r

rrr

!qlvrrr^!o

ODJ

oD4

655
ODD

SomeAmino Acids Are Convertedto Glucose
Othersto KetoneBodies
SeveralEnz].'rneCofactorsPlay Important
Rolesin Amino Acid Catabolism
Six Amino Acids Are Degradedto Py'ruvate
SevenAmino Acids Are Degradedto Acetyi-CoA

689
692
ovD


i

xxiv

, Contents

PhenylalanineCatabolismIs Genetically
Defectivein SomePeople
Five Amino Acids Are Convertedto
a-Ketoglutarate
Four Amino Acids Are Convertedto Succinyl-CoA

Box18-2
Medicine:
Scientific

Sleuths
Solve
a
Murder
Mystery
Branched-ChainAmino Acids Are Not
Degradedh the Liver
Asparagineand AspartateAre Degradedto
Oxaloacetate

bYft

698
699

700
70r
701

ATP-ProducingPathwaysAre
CoordinatelyRegulated

Mitochondria
inTherm0genesis,
Steroid
19.4
Synthesis,and
Apoptosis
UncoupledMitochondriain Brown Adipose
TissueProduceHeat

MitochondriaiP-450OxygenasesCatalyzeSteroid
Hydroxylations
MitochondriaAre Centralto the Initiation of
Apoptosis

734

735
736
736
737

Genes:Their
19.5
Mitochondrial
0rigin
andthe

19fixldative
Phosphorylaticn
and

Photophosphorylation

Effects
of Mutations

7U7

OXIDATIVE

PHOSPHORYLATION
19.1Electron-Transfer
Reactions
inMitochondria
ElectronsAre Funneledto UniversalElectron
Acceptors
ElectronsPassthrougha Seriesof
Membrane-Bound
Carriers
Electron CarriersFunction in Multienz;'rne
Complexes
MitochondrialComplexesMay Associatein
Respirasomes
The Energy of Electron Tfansfer Is Efflciently
Conservedin a ProtonGradient
ReactiveOxygenSpeciesAre Generatedduring
OxidativePhosphorylation
Plant MitochondriaHaveAiternative
Mechanismsfor OxidizingNADH

708
709

739
740
74r

712

19.6

Features
ofPhotophosphorylation742
General

718
718
720

72r

19.2ATP
Synthesis

723

OxidativePhosphorylationIs Regulatedby
CellularEnergy Needs
An Inhibitory Protein PreventsATP Hydrolysis
during Hlpoxia
Hypoxia Leadsto ROSProductionand Several
AdaptiveResponses

739

PHOIOSYNTHESIS:
HARVESTING
LIGHT
ENERGY

722

19.3Regulation
of0xidative
Phosphorylation

738

7r0

Box19-1Hot,
Stinking
Plants
andAlternative
Respiratory
Pathways
ATP SynthaseHas TWoFunctionalDomains,
Fo and Ft
ATP Is StabilizedRelativeto ADP on the
Surfaceof F1
The Proton GradientDrivesthe Releaseof
ATP from the Enz}.tneSurface
Each B Subunit of ATP SynthaseCanAssume
Three Di-fferentConformations
RotationalCatalysisIs Key to the Binding-Change
Mechanismfor ATP Synthesis
ChemiosmoticCouplingAllows Nonintegral
Stoichiometriesof 02 Consumptionand
ATP Synthesis
The Proton-MotiveForce Energizes
Active Transport

Shuttle SystemsIndirectly ConveyC5,'tosolic
NADH hto Mitochondriafor Oxidation

MitochondriaEvolvedfrom EndoslmrbioticBacteria
Mutationsin MitochondrialDNA Accumulate
throughout the Life of the Organism
SomeMutationsin MitochondrialGenomes
CauseDisease
DiabetesCan Resultfrom Defectsin the
Mitochondriaof PancreaticB Cells

725
725
726
726

729
730
/ dl

732
I t)r)

lJJ

lJO

in PlantsTakesPlacein
Photosy'nthesis
Chloroplasts

Light Drives Electron Flow in Chioroplasts

Light
Absorption
19.7
ChlorophyllsAbsorb Light Energy for
Photosynthesis
AccessoryPigmentsExtend the Rangeof Light
Absorption
ChlorophyllFunnelsthe AbsorbedEnergy to
ReactionCentersby Exciton Ttansfer

19.8TheCentral
Photochemical
Event:
Light-Driven
Electron
Flow
BacteriaHaveOne of Tlvo Tlpes of Single
PhotochemicalReactionCenter
Kinetic and ThermodynamicFactorsPrevent
the Dissipationof Energy by Internal
Conversion
In Plants,TWoReactionCentersAct in Tandem
Antenna ChlorophyllsAre Tightly Integratedwith
Electron Carriers
The Cytochromeb6lComplexLinks
PhotosystemsII and I
Cyclic Electron FIow betweenPSI and the
Cyochromeb6lComplexIncreasesthe

Productionof ATP Relativeto NADPH
State TtansitionsChangethe Distribution of LHCII
betweenthe TWoPhotosystems
WaterIs Split by the Oxygen-EvolvingComplex

19.9ATP
Synthesis
byPhotophosphorylation
A Proton GradientCouolesElectron Flow and
Phosphorylation
The ApproximateStoichiometryof
PhotophosphorylationHas Been Established
The ATP Sy'nthaseof ChloroplastsIs Like That
of Mitochondria

743
743

744
745
747
747

749
749

75I
752
754
755

756
756
756

759
759
760
760


contents
[--l

19.10TheEvolution
of0xygenic
Photosynthesis 761
ChloroplastsEvolvedfrom Ancient
PhotosyntheticBacteria
In Halobacteri,um, aSingleProtein AbsorbsLight
and PumpsProtonsto Drive ATP S;,rrthesis

IOI

762

20Carbohydrate
Biosynthesis
in
Plants

andBacteria

773

Photosynthetic
20.1
Carbohydrate
Synthesis

773

PlastidsAre OrganellesUnique to Plant
Cellsand Algae
CarbonDioxide AssimilationOccursin
ThreeStages
Sy'nthesisof Each Ttiose Phosphatefrom CO2
RequiresSix NADPH and Nine ATP
A Tlansport SystemExports T?iosePhosphates
from the Chloroplastand Imports Phosphate
Four Enz)rmesof the Calvin CycleAre Indirectly
Activated by Light

774
TTb

Box21-1 Mixed-Function
Oxidases,
0xygenases,
and
P-450

Cytochrome

816

TB2

EicosanoidsAre Formed from 20-Carbon
PollrrnsaturatedFattyAcids

817

783
784

(AMPathways 786
20.2
Photorespiration
andtheCoand
PhotorespirationResuitsfrom Rubisco's
OxygenaseActivity
The SalvageofPhosphoglycolate
Is Costly
In CaPlants,CO2Fixation and RubiscoActivity
Are SpatiallySeparated
In CAM Plants,CO2Captureand RubiscoAction
Are TemporallySeparated

20.3
Biosynthesis
ofStarch

andSucrose

786
T8T
T8g
TgI

791

ADP-GlucoseIs the Substratefor Starch Slnthesis in
Plant Plastidsand for GlycogenSynthesisin
Bacteria
TgI
UDP-Glucose
Is the Substratefor Sucrose
Synthesish the Cytosolof Leaf Cells
Tg2
Conversionof Tfiose Phosphatesto Sucroseand
Starch Is Tightly Regulated
Tgz

20.4
Synthesis
ofCell
WallPolysaccharides:
Plant
Cellulose
andBacterial
Peptidoglyca
n

CelluloseIs Synthesizedby Supramolecular
Structuresin the PlasmaMembrane
Lipid-Linked Oligosaccharides
Are Precursorsfor
Bacterial Cell Wall S1'nthesis

20.5
lntegration
ofCarbohydrate
Metabolism
inthe
(ell
Plant
Gluconeogenesis
ConvertsFats and Proteinsto
Glucosein GerminatingSeeds
Poolsof CommonIntermediatesLink Pathwaysh
Different Organelles

794
Zgb

21.2
Biosynthesis
ofTriacylglycerols

820

Tliacylglycerolsand Glycerophospholipids
Are

Synthesizedfrom the SamePrecursors
820
TtiacylglycerolBiosy'nthesisin AnimalsIs ReguJated
by Hormones
821
AdiposeTissueGeneratesGlycerol3-Phosphateby
Glyceroneogenesis
822
ThiazolidinedionesTfeat Tlpe 2 Diabetes
by IncreasingGlyceroneogenesis
824

ofMembrane
21.3Biosynthesis
Phospholipids

824

CellsHaveTWoStrategiesfor Attaching Phospholipid
HeadGroups
824
PhospholipidSynthesisnE. coli,Employs
CDP-Diacylglycerol
825
EukaryotesSynthesizeAnionic Phospholipidsfrom
CDP-Diacylglycerol
827
Eukaryotic Pathwaysto Phosphatidylserine,
Phosphatidylethanolamine,
and

PhosphatidylcholineAre Interrelated
827
PlasmalogenSy'nthesisRequiresFormation of an
Ether-LinkedFatty Alcohol
829
Sphingolipidand GlycerophospholipidSynthesis
SharePrecursorsand SomeMechanisms
829
Polar Lipids Are Targetedto Speciflc
CellularMembranes
830

T96

797
798
799

21LipidBiosynthesis

80s

21.1Biosynthesis
of Fatty
Acids
andEicosanoids

805

Malonyl-CoAIs Formed from Acetyl-CoAand

Bicarbonate
Fatty Acid S5.nthesis
Proceedsin a Repeating
ReactionSequence

The MammalianFatty Acid SynthaseHas
Multiple Active Sites
808
Fatty Acid SynthaseReceivesthe Acetyl and
MalonylGroups
The Fatty Acid Slnthase ReactionsAre
Repeatedto Form Palmitate
811
Fatty Acid Slnthesis Occursin the Cytosolof Many
Organismsbut ir the Chloroplastsof Plants
811
Acetate Is Shuttled out of Mitochondriaas Citrate
813
Fatty Acid BiosynthesisIs Tightly Regulated
8I4
Long-ChainSaturatedFatty Acids Are S5,'nthesized
from Palmitate
814
Desaturationof Fatty Acids Requiresa
Mixed-FunctionOxidase
815

805
806

21.4Biosynthesis
ofCholesterol,
Steroids,
andlsoprenoids

831

CholesterolIs Madefrom Acetyl-CoAin
Four Stages
832
836
CholesterolHas SeveralFates
Cholesteroland Other Lipids Are Carriedon Plasma
Lipoproteins
836

Predict
Incidence
of
Box2l-2Medicine:
ApoE
Alleles
Alzheimer's
Disease

839

CholesterylEstersEnter Cellsby
Endocltosis
Receptor-Mediated

CholesterolBiosynthesisIs Regulatedat
SeveralLevels

84r

Medicine:The
LipidHypothesis
and
Box21-3
ofStatins
theDevelopment

842


TJ

I

xxvr Contents
]
Steroid Hormones Are Formed by Side-Chain
Cleavage and Oxidation of Cholesterol
Intermediates in Cholesterol Bioslmthesis Have
Many Alternative Fates

845

22Biosynthesis
ofAmino

Acids,
Nucleotides,
andRelated
Molecules
851
22.1Overview
of Nitrogen
Metabolism
The Nitrogen CycleMaintainsa Pool of
BiologicallyAvailableNitrogen
Nitrogenls Fixed by Enzyrnesof the
NitrogenaseComplex

852

22.2
Biosynthesis
ofAmino
Acids

857
857

859

860

a-KetoglutarateGivesRiseto Glutamate,
Glrrt:minp

Prolinc

rnd

Aroinine

Serine,Glycine,and CysteineAre Derivedfrom
3-Phosnhoslveerat
e
Three Nonessentialand Six EssentialAmino
Acids Are Slnthesizedfrom Oxaloacetateand
Py'ruvate
ChorismateIs a Key Intermediatein the Synthesis
of Tf5.ptophan,Phenylalanine,and T!'rosine
Histidine Biosy'nthesisUsesPrecursorsof Purine
Biosl'nthesis
Amino Acid Biosy'nthesisIs under
Allosteric Regulation

861

872

873

GlycineIs a Precursorof Porphytins

873

HemeIs the Sourceof Bile Pigments

Amino Acids Are Precursorsof Creatineand
Glutathione
o-Amino Acids Are Found Primarily in Bacteria
Aromatic Amino Acids Are Precursorsof Manv
Plant Substances
BiologicalAminesAre Productsof Amino Acid
Decarboxylation

Box22-3
Medicine;
Curing
African
Sleeping
with
Sicknes
a Biochemical
Trojan
Horse
Arginine Is the Precursorfor Biological
S1'nthesisof Nitric Oxide

22.4Biosynthesis
andDegradation
of Nucleotides
De Novo Purine NucleotideSynthesis
Beginswith PRPP
Purine NucleotideBios5,'nthesis
Is Regulatedby
FeedbackInhibition
Pyrimidhe NucleotidesAre Madefrom Aspartate,

PRPP,and CarbamoylPhosphate
Pytimidine NucleotideBiosynthesisIs
Regulatedby FeedbackInhibition

892
893
893

Regulation
andIntegration
23Hormonal
Metabolism
ofMammalian

901

for
23.1
Hormones:
Diverse
Structures
Functions
Diverse

901

The Detection and Purificationof Hormones
Requiresa Bioassay

902

Discovered?
Howlsa Hormone
Box23-1Medicine:
Insulin
TheArduous
Pathto
Purified

903

HormonesAct through SpeciflcHigh-Affinity
CellularReceptors
HormonesAre ChemicallyDiverse
HormoneReleaseIs Regulatedby a Hierarchyof
Neuronaland HormonalSignals

904
906
909

ofLabor 912
23.2Tissue-5pecific
Metabolism:The
Division

22.3
Molecules
Derived
fromAmino

Acids
Box22-2
Medicine;0n
Kings
andVampires

888
890

852

Box22-1Unusual
Lifestyles
ofthe0bscure
butAbundant 853
AmmoniaIs Incorporatedhto Biomolecules
through Glutamateand Glutamine
GlutamineSynthetaseIs a Primary Regulatory
Point in Nitrogen Metabolism
SeveralClassesof ReactionsPlay Special
Rolesin the Biosyrrthesisof Amino
Acids and Nucleotides

NucleosideMonophosphatesAre Convertedto
NucleosideTfiphosphates
RibonucleotidesAre the Precursorsof
Deoxyribonucleotides
ThymidylateIs Derivedfrom dCDPand dUMP
Degradationof Purinesand PyrimidinesProduces
Uric Acid and Urea,Respectively

Purine and Py'rimidineBasesAre Recycledby
SalvagePathways
ExcessUric Acid CausesGout
Many ChemotherapeuticAgentsTargetEnz;nnes
in the NucleotideBiosyntheticPathways

875
875
876
877

880
882

882
883
885
886
887

The Liver Processesand DistributesNutrients
AdiposeTissuesStore and Supply Fatty Acids
Brown AdiposeTissueIs Thermogenic
MusclesUseATP for MechanicalWork
The Brain UsesEnergy for Ttansmissionof
Electrical Impulses
Blood CarriesOxygen,Metabolites,and Hormones

Regulation
ofFuelMetabolism

23.3Hormonal
Insulin CountersHigh Blood Glucose
PancreaticB CellsSecreteInsulin in Responseto
Changesin BloodGlucose
GlucagonCountersLow BloodGlucose
During Fastingand Starvation,Metabolism
Shifts to ProvideFuel for the Brain
EpinephrineSignalsImpendingActivity
Cortisol SignalsStress,Inciuding Low
BloodGlucose
DiabetesMellitus Arisesfrom Defectsin
Insulin Productionor Action

Mass
23.4
Obesity
andtheRegulation
ofBody
AdiposeTissueHas Important
EndocrineFunctions
Leptin StimulatesProduction of Anorexigenic
PeptideHormones
Leptin T?iggersa SignalingCascadeThat
RegulatesGeneExpression
The Leptin SystemMay HaveEvolvedto
Regulatethe StarvationResponse

912
916
917

918
920
920

922
922
923
925
926
928
929
o90

930
930
932
933
934