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

Peptides, and Proteins 4 The Three-Dimensional Strufiure of Proteins 5 Protein Funrtion 6 Enzymes 7 Carbohydrates and Glyrobiology 8 Nucleotides and Nucleic Acids 9 DNA-Based Information

Uni,uersity of Wi,sconsin-Madi,son

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W.H FREEMAN AND COMPANY

N e w Y o r k

4

APTARA,INC.

On the cover: RNA polymerase II from yeast, bound to DNA and in the act of transcribing it into RNA.

Library of Congress Control Number: 2007941224

All rights reserved Printed in the United States of America

To Our Teachers

PauL R Burton

Albert Fi,ntuolt Wi,LLi,am P Jencks Eugene P Kennedy Homer Knoss

ArtLtur Kornberg

L Robert Leltman EarL K, I{elson

Dauid E, Sh,eppard Harold B Wti,te

DaVid L NelSOn, born in Fairmont, Minnesora,

re-ceived 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 felLow at 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

trans-ductions 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,

tron microscopy, genetics, molecuiar biology, and

elec-trophysiology to 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

biochem-istry undergraduates in the life sciences He has also

taught a survey of biochemistry for nursing students,

and graduate courses on membrane structure and

func-tion 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 1991-1992 he was a visiting

profes-sor 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-mdergraduates and

to collect antique scientific instruments.

Biochem-'istry was a major influence in refocusing his fascination

with biology and inspiring him to pursue a career in

bio-chemistry 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

Wisconsin-Madison in 1983, and became a full professor of

biochemistry in 1992.

Cox's doctoral research was on general acid and

assay methods that are still in use, and illuminating the

cen-tral theme of his research

Mike Cox has coordinated a large and active

primary focus has been the mechanism of RecA

in the RecA system, and the regulation of tional DNA repair Part of the research program nowfocuses on organisms that exhibit an especially robust

Dave Nelson) the suwey of biochemistry to

struc-ture and topology, protein-DNA interactions, and the

has received awards for both his teaching and his

and the 1989 EIi Lilly Award in Biological Chemistry His

David [ Nelson and Michael M Cox

I n this twenty-flrst century a typical science education

sci-ence unstated, or relies on oversimplified definitions As

consider once again the 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

sci-ence flow directly from its reliance on ideas that can be

tested: information on natural phenomena that can be

foundational assumption that is often unstated but

cru-cial to the enterprise: that the laws governing forces and

phenomena existing in the universe are not subject to

this underlying assumption as the "postulate of

objectiv-ity." The natural world can therefore be understood by

applying a process of inquiry-the scientific method

Science could not succeed in a universe that played

tricks on us Other than the postulate of objectivity,

Scientrflc ideas take many forms The terms that

sci-entists use to describe these forms have meanings quite

provides an explanation for a body of experimental

thus a basis for further advance and innovation When a

scientiflc theory has been repeatedly tested and

a scientiflc idea is defined by whether or not it is

pub-lished in the scientiflc literature after peer review by

other working scientists About 16,000 peer-reviewed

scientific journals worldwide publish some 1.4 million

articles each year, a continuing rich harvest of

informa-tion that is the birthright of every human being

scientific method to understand the natural world

Merely having an advanced degree in a scientiflc

such a degree prevent one from making important

sci-entific contributions A scientist must be willing to

chal-lenge any idea when new findings demand it The ideas

that a scientist accepts must be based on measurable,

The scientific method is actually a collection of

hy-pothesis, then subjects it to experimental test Many of

that base pairjrg is the basis for information transfer in

Watson and Crick produced their DNA structurethrough a process of model bui,ldi,ng and calcula-t'ion No actual experiments were involved, althoughthe model building and calculations used data col-

dis-covery (Charles Darwin's 1831 voyage on H.M.S.Beagle among them) helped to map the planet, catalog

world Modern scientists follow a similar path whenthey explore the ocean depths or launch probes to

is hypothesi,s and deduct'ion Crick reasoned thatthere must be an adaptor molecule that facilitated

Not all paths to discovery involve planrung i,tg often plays a role The discovery of penicilJin byAlexander Fleming in 1928, and of RNA catalysts by

discov-eries, albeit by scientists well prepared to exploit them

biotech-nology, was developed by Kary Mullis afler a flash ofinspration dudng a road trip in northern Califomia in 1983.These many paths to scientiflc discovery can seemquite different, but they have some important things

in common They are focused on the natural world.They rely on reproducCble obseruat'ion anilor erperi-ment Nl of the ideas, insights, and experimental factsthat arise from these endeavors can be tested and

make new discoveries All lead to information that is

Understand-ing our universe requires hard work At the same time,

no human endeavor is more exciting and potentially

un-derstand some part of the natural world

first edition of Pnnctples oJ Bi,ochenuistry, v'ritten

Albert Lehninger twenty-flve years ago, has served as

the starting point and the model for our four subsequent

dis-covered, PCR technology introduced, and archaea

new protern structures even more frequently, and

Med-icine since that first edition of Prhrciples of Binchemistry

One major challenge of each edition has been to

re-flect the torrent of new information without making the

book overwhelming for students having their first

care-ful sifting aimed at emphasizing principles while still

conveying the excitement of current research and its

promise for the future The cover of this new edition

M a j o r R e c e n t A d v a n c e s i n Biochemistry

Every chapter has been thoroughly revised and

bio-chemistry including:

introduced earlier in the book (Chapter 1)

context of protein folding (Chapter 4)

r New section on pharmaceuticals developed from

(Chapter 6)

r New material on green fluorescent protein

(Chapter 9)

r New section on lipidomics (Chapter 10)

v i

We are at the threshold of a new molecular ogy in which processes such as membrane excitation,

manipu-lation Knowledge of the molecular structures of thehighly organized membrane complexes of oxidativephosphorylation and photophosphorylation, for exam-ple, will certainly bring deepened insight into those

in biochemical research and teaching Our book is notthe only thing that has acquired a touch of silver overthe years!)

maintain the qualities that made the original Lehninger

We have written together for twenty years and taught gether for almost twenty-flve Our thousands of students

have been an endless source of ideas about how to

rnspired us We hope that this twenty-flfth aruLiversary

Iove biochemistry as we do

by plants, and of bird feather pigments derivedfrom colored lipids in plant foods (Chapter 10)Expanded and updated section on lipid rafrts andcaveolae to rnclude new material on membranecurvature and the proteins that influence it, andintroducng amphitropic proteins and anmrlarIipids (Chapter 11)

New section on the emerging role of ribulose5-phosphate as a central regulator of $ycolysis

New Box 16-1, Moonlighting Erzymes: Proteinswith More Than One Job

New section on the role of transcription factors(PPARs) in regulation of lipid catabolism

Revised and updated section on fatty acidsynthase, including new structural information

Updated coverage of

the nitrogen cycle,

including new Box

Structure, and Histone

Variants describing the

role of histone

modification and

nucleosome deposition

in the transmission of

New information on the initiation of replication

introducing AAA+ ATPases and their functions

in replication and other aspects of DNA

New section on the expanded understanding of

the roles of RNA in cells (Chapter 26)

B i o c h e m i c a l M e t h o d s

An appreciation of biochemistry often

requires an understanding of how

bio-chemical information is obtained Some

of the new methods or updates described

in this edition are:

r Circular dicluoism (Chapter 4)

hemoglobin as an indicator of

(Chapter 7)

(Chap-ter 9)

r More on microarrays (Chapter 9)

purification (Chapter 9)

r PET combined with

CT scans to pinpoint cancer

(Chapter 14)

experiments (Chapter 24)

Preface

FIGURE 21-3 The structure offatty acid synthase type I systems

New information on the roles of RNA

in protein biosynthesis(Chapter 27)

New section on riboswitches(Chapter 28)

and development

tx

netic codes, for site-specific insertion of novelamino acids into proteins (Chapter 27)

Glutathione (GSH)

G€ne for tusion prctein

I

v Express tu8ion Foteh h a cell

flcuflt 9-12 The use of tagged proteins in protein cation The use of a CST tag is illustrated (a) Clu- tathione-s-transferase (CST) is a small enzyme (depicted here by the purple icon) that binds glutathione (a Sluta- mate residue to which a Cys-Cly dipeptide is attached at the carboxyl carbon of the Clu side chain, hence the ab- breviation CSH) (b) The CST tag is fused to the catr boxyl terminus of the target protein by Senetic engineering The tagged protein is expressed in host cells, and is present in the crude extract when the cells are lysed The extract is subjected to chromatography

purifi-on a column cpurifi-ontaining a medium with immobilized Slutathione The CsT{agged protein binds to the 8lu- tathione, retardinB its migration through the column, while the other proteins wash through rapidly The tagged protein is subsequently eluted from the column with a solution containing elevated salt concentration or free glutathione

Add gotein

EIub fusion plobin

x - Preface

M e d i c a l l y R e l e v a n t E x a m p l e s

This icon is used throughout the book to denote

material of special medical interest As teachers,

our goal is for students to learn biochemistry and to

understand its relevance to a healthier life and a

healthier planet We have included many new

exam-ples that relate biochemistry to medicine and to health

to this edition are:

for Cancer Tleatment

S p e c i a l T h e m e : U n d e r s t a n d i n g M e t a b o l i s m

Obesity and its medical

in the industrialized world, and we include new

mate-rial on the biochemical connections between obesity

and health throughout this edition Our focus on

dia-betes provides an integrating theme throughout the

chapters on metabolism and its control, and this will,

we hope, inspire some students to find solutions for

this disease Some of the sections and boxes that

highlight the interplay of metabolism, obesity, and

r Untreated Diabetes Produces Life-Threatenine Aci

dosis (Chapter 2)

hemoglobin glycation and AGEs and

their role in the pathology of advanced diabetes

Iitus (Chapter 14)

during Starvation (Chapter 17)

r Diabetes Can Result from Defects in the Mitochon

The Lipid Hypothesis and the Development ofStatins

of bacterial rnfections and cancer, includingmaterial on ciprofloxacin (the antibiotic effectivefor anthrax)

t h r o u g h 0 b e s i t y a n d D i a b e t e s

r Diabetes Mellitus Arises from Defects in Insulin

sensitivity and tlpe 2 diabetes

@ Fat synthesie

and storage Fatty acid oxidatioD

Stawation response

and storage Fatty acid oxidati Adipokineproduction Themogenesis

A d v a n c e s i n T e a c h i n g B i o c h e m i s t r y

have revised each chapter with an eye to helping students learn and master the

new problem-solving tools, a focus on organic chemistry foundations, and

highlighted key conventions

N e w P r o b l e m - 5 o l v i n g T o o l s

r New in-text Worked Examples help students improve their

most difficult equations

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 each chapter), con

F o c u s o n 0 r g a n i c ( h e m i s t r y F o u n d a t i o n s

r New Section 13.2, Chemical logic and common biochemical

reactions, discusses the common biochemical reaction types that

underlie all metabolic reactions.

r Mechanism figures feature step-by-step

introduced and explained in detail with the

the new problems focus on chemical

Key (onventions

and the biochemical literature are broken out of the

w r i t t e n f r o m 5 ' t o 3 ' e n d l e f t 1 n r i o h t )

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

f WORKED EXAMPII 1l-3 EnergeticsofPumping

bY SYnPort

lglumseli, Cahulal,e lhe maimm ': = mtio that can be

lglucosejour achieved by the plasma membrme Na*-glucose sym- porter of an epithelial cell, when [Na-]6 is 12 mM, [Nat]."1 is 145 ro, the membrme potential is -50 mV(inside negative), and the temperature is 37 'CSoltrtion: Using Equation 11-4 (p 396), we can calcu- late the energy inherent in an electrochemical Na+ gradient-that is, the cost of moving one Na- ion up this gradientl

AG ' _ R?lnry+ + zr a,r,

tNal,"

We then substitute standard values for-&, ?, and J, and the given values for [Na-] (expressed as molar concen- trations), +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.

AGt : (8 315 J/mol K)(3to rcm 1 45 x 10-'

1 2 x t o 2 + 1(96,500 JV.mol)(0 050 V)

= 11 2 kJ/mol This AGr is the potential energy per mole of Na- in the Na* $adient that is available to pmp glucose Given that two Na- ions pass dom their electrochemical gra- dient md into the cell for each glucose canied in by slmport, the energy available to pmp 1 mol of Llucose is2 x II2 kJ/mol = 22 4 kJ/mol We can now calculate the concentration ratio of Elucose that cm be achieved

by this pmp (from Equation l1-3, p 396):

lir"o""l.,, n,r = E:rs llorot ' t< u slo{(, - o ot

I S I cv"

CF

Gtyceraldehyde 3-phosphaE

of 8) when NAD+ iE bu4

ed is in the Eore readive,

thkago betuem the

(sthck by 4) releasiry fre se@nd pdud, l,g-bbphdphqly@me

o

active sik ud is replaced by another nolecule of NS+.

M e d i a a n d 5 u p p l e m e n t s

pro-vides instructors and students with innovative tools to

support a variety of teaching and learning approaches

All these resources are fully integrated with the style

and goals of the fifth edition textbook

eBook

This online version of the textbook

book, electronic study tools, and afull complement of student mediaspecifically created to support thetext The eBook also provides usefirlmaterial for instructors

r eBook study tools include instant navigation to arry

key-term definitions, and a spoken glossary

throughout the eBook, include animated enzyme

tutorials in Jmol, Protein Data Bank IDs in Jmol,

liv-ing graphs, and online quizzes (each described un

der "Additional Student Media" below)

r Instructor features include the ability to add

notes or files to any page and to share these

notes with students Notes may include text, Web

assign the entire text or a custom version of the

eBook

Additional Instructor Media

Instructors are provided with a comprehensive set

instructor media are available for download on the

book Web site (www.whfreeman.com/lehningerbe)

and on the Instructor Resource CDIDVD (ISBN

r Fully optimized JPEG flles of every flgure, photo,

and table in the text, with enhanced color, higher

resolution, and enlarged fonts The flles have been

reviewed by course instructors and tested in a

large lecture hall to ensure maximum clarity

and visibility The JPEGs are also offered in

chapter

available in an Overhead Thanspaxency Set (ISBN

visibil-ity in the lecture hall

r Animated Enzyme Mechanisms and AnimatedBiochemical Teehniques are available in Flash

list of animation topics on the inside front cover.)

r A list of Protein Data Bank IDs for the structures

new feature in this edition is an index to all tures in the Jmol interactive Web browser applet

struc-r Living Gstruc-raphs illuststruc-rate key equations fstruc-rom thetextbook, showing the graphic results of changingparameters

Word formats includes 150 multiple-choice and

of difflcr-rltv

Additional Student Media

Students are provided with media designed to enhancetheir understanding of biochemical principles and im-prove their problem-solving ability AII student media,along with the PDB Struetures and Living Graphs, arealso in the eBook, and many are available on the book

student media include:

r New Problem-SolvingVideos, created byScott Ensign of Utah StateUniversity proide24/7

two-part approach, each

key textbook problem senting a topic that students traditionally struggle to

problem-solving strategy and then applies the strategy to theproblem at hand in clear, concise steps Students can

wish until they firmly grasp not just the solution but

better and more confident at applying key strategies

as they solve other textbook and exam problems

r Student versions of the Animated EnzymeMechanisms and Animated BiochemicalTechniques help students understand key

For a complete list of animation topics, see theinside front cover

Jmol-Web browser applet, allow students to explore in

more depth the molecular structures included in

the textbook, including:

chal-lengrng multiple-choice questions for each chapter,

with automatic grading and text references and

feedback on all answers.

The Absolute, Ultimate Guide to Lehninger Principles of

Biochemistry, Fifth Edition, Study Guide ond Solutions

Manual, by Marcy Osgood (University of New Mexico

School of Medicine) and Karen Ocorr (University of

Ca lifornia, 5a n Diego); 1 - 4292-1241 -"1

The Absolute, Ult'imnte Guide combines an irmovative

study guide with a reliable solutions manual (providing

extended solutions to end-of-chapter problems) in one

Guide includes for each chapter:

r Major Coneepts: a roadmap through the chapter

r What to Review: questions that recap key points

from previous chapters

Preface [.t"]

Discussion Questions: provided foreach section; designed for individualreview, study groups, or classroomdiscussion

A Self-Tbst: "Do you know the terms?";crossword puzzles; multiple-choice,fact-driven questions; and questionsthat ask students to apply their newknowledge in new directions-plusanswers!

A c k n o w l e d g e m e n t s

This book is a team effort, and producing itwould be impossible without the outstandingpeople at W H Freeman and Company whosupported us at every step along the way.Randi Rossignol (Senior Editor) and l(ate Alu(Executive Editor) arranged reviews, made

taxget, and tried valiant$ (if not always successfully) tokeep us on schedr:le Our outstanding Project Editor, Liz

in spite of our missed deadlines and last-minute changes,and did so with her usual grace and skill We thankVicki Tomaselli for developing the design, and MarshaCohen for the beautiful layout We again had the good for-tune to work with Linda Strange, a superb copy editorwhohas edited all flve editions of Prirrci,plns of Binchenaistrg

Bi,ochenaistry) Her contributions are invaluable andenhance the text wherever she touches it We were alsoagain fortunate to have the contributions and insights ofMorgan Ryan, who worked with us on the third and fourtlteditions We thark photo researcher Dena Dgtlio Betz for

Clench for keeping the paper and files flowing among allparticipants in the project Our gratitude also goes toDebbie Clare, Associate Director of Marketing, for her cre-ativity and good humor in coordinating the sales andmarketing effort

In Madison, Brook Soltvedt is (and has been for allthe editions we have worked on) our first-line editor andcritic She is the first to see manuscript chapters, aids inmanuscript and art development, ensures internal con-sistency in content and nomenclature, and keeps us on

the fourth edition, Shelley Lusetti, now of New MexicoState University, read every word of the text in proofs,caught munerous mistakes, and made many suggestionsthat improved the book

The new art in this edition, including the new Iar graphics, was done by Adam Steinberg, here in Madi-

better and clearer illustrations This edition also containsmany molecular graphics produced for the third and

colleague We feel very fortunate to have such gifted

part-ners as Brook, Shelley, Adam, and Jean-Yves on our team.

We are also deeply indebted to Brian White of the

Uni-versity 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:

Thomas O Baldwin, Uni,uersitg of Ari,zona

Vahe Bandari an, Uniu ersitg oJ Adzona

Sandra J Bonetti, Colorado State [Jniuersitg, Pueblo

Scott D Briggs, Purdue Uniuersi,ty

David Camerini, Uniuers'itg oJ CaliJorni,a, Irui,ne

Melanie Cocco, Uni,uersitg oJ Cali,Jontia, Irui,ne

Jeffrey Cohlberg, CaliJorni,a Stute [Jniuersi,tg, Lotzg Beach

Kim D Collins, Uniuersi,tg of Marytand

Gerald D Frenkel, Rutgers {Jni,uersi,tg

Perry Frey, Uni,uersi,tg oJ Wi,sconsin-M adi,son

Mart}'n Gurn, Teras A&M Uni,uersitg

Amy Hark, Muh,Ienberg CoILege

Peter Hinkle, Conwll Uniuersi,tg

P Shing Ho, Oregon State Uni,uersi,tA

Sir Hans Kornberg, Boston Uni,uersity

Ryan P LiegeI, Uniuersitg oJ Wi,sconsin-Madi,son

Andy C LiWang, Teras A&A,[ Uni,uersitg

Benjamin J McFarland, Seattle Pacifi,c Uni,uersi,ty

Scott C Mohr, Boston Uni,uersi,tg Kimberly Mowry, Brown Uniuersi,ty Leisha Mullins, Teras A&M Uni,uersi,tg

Allen W Nicholson, Temple Uni,uersi,ty Hiroshi Nikaido, Uni,uersitg of CaliJorni,a, Berkeley

Tom A Rapoport, Harvard Medi,ca| School

Mark Spaller, Wayne Sta,te Uni,uersi,tA Stephen Spiro, Uniuersitg oJ Teras at DaILo,s

Jon R Stultzfus, Mi,chigan State Uni,uersi,tg

Dean R ToIan, Boston Uni,uersi,ty

Ttacy Ware, Salem State CoLIege Susan Weintraub, Unintersi,tg oJ Teras, Health Sci,ence Csttter

We lack the space here to acknowledge all the other individuals whose special efforts went into this book.

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 com- ments and su ggestions 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.

David L NelsonMichael M Cox

January 2008

1 The Foundations of Biochemistry

2 Water

3 Amino Acids Peptides, and Proteins

4 The Three-Dimensional Strufiure of Proteins

5 Protein Funrtion

6 Enzymes

7 Carbohydrates and Glyrobiology

8 Nucleotides and Nucleic Acids

9 DNA-Based Information Technoloqies

10 Lipids

11 Biological Membranes and Transport

12 Biosignaling

II BIOENERGETICS AND METABOLISM

1 3 Bioenergetics and Biochemical Reaction Types

1 4 Glycolysis, Gluconeogenesis, and the Pentose

'15 Principles

16 The Citric Arid tyde

17 Fatty Acid (atabolism

18 Amino Acid 0xidation and the Production of Urea

1 9 Oxidative Phosphorylation and Photophosphorylation

20 ftrbohydrate Biosynthesis in Plants and Bacteria

28 Regulation ofGene Expression

1 The Foundations of Biochemistry

1.1 (ellular Foundations

Cells Are the Structural and Functional Units of All Living Organisms Cellular Dimensions Are 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 Organized by the Cytoskeleton and Is HigNy Dynamic

Cells Build Supramolecular Structures

In Vitro Studies May Overlook Important Interactions among Molecules

Biomolecules Are Compounds of Carbon with

Box 1-l MolecularWeight Molecular Mass,andTheir Conect Units

Constituents of Cells

by Configuration and Conformation

Box 1-2 louis Pasteurand 0ptical ActiuatyilnVino,Vefitus

lnteractions between Biomolecules Are Stereospeciic

485

489

527569

5 1 5

o l t

673

v07 773

80585190i

945

94797510211065't1 15

4 5

.7

8 I

Organisms Ttansform Energr and Matter

The Structure of DNA Allows for Its Replication

The Linear Sequence in DNA Encodes Proteins with

xv

1.5 Evolutionary Foundations

Allow Evolution

RNA or Related Precursors May Have Been the

First Genes and Catalysts

Biological Evolution Began More Than

Three and a Half Billion Years Ago

The First Cell Probably Used Inorganic Fuels

Eukaryotic Cells Evolved from Simpler

Relationships

Importance in Human Biology and Medicine

2 Water

2.1 Weak Interactions in Aqueous Systems

Hydrogen Bonding Gives Water lts

Water Forms Hydrogen Bonds with Polar Solutes

Water Interacts Electrostatically with

Charged Solutes

Unfavorable Changes in the Structure of Water

van der Waals Interactions Are Weak Interatomic

Attractions

Weak Interactions Are Crucial to Macromolecular

Structure and Function

Solutes Affect the Colligative Properties of

Aqueous Solutions

2.2 lonization of Water, Weak Acids, and Weak Bases

Pure Water Is Slightly Ionized

The Ionization of Water Is Expressed by an

Equilibrium Constant

OH-Concentrations

Weak Acids and Bases Have Characteristic

Titration Curves Reveal the pK of Weak Acids

2.3 Buffering against pH Changes in

Biological Systems

Buffers Are Mixtures of Weak Acids and Their

pH, pK., and Buffer Concentration

Weak Acids or Bases Buffer Cells and

Untreated Diabetes Produces

Box 2-1 Medicine:0n Being 0net Own Rabbit

(Don't Try This at Home!)

2.4 Water as a Reactant 2.5 The Fitness of the Aqueous Environment for Living 0rganisms

3 Amino Acids, Peptides, and Proteins

3.1 Amino Acids

Amino Acids Share Common Structural Features

L Stereoisomers

Box 3-1 Methods: Absorption of Lig ht by Molecules:

Ihe lambert-Beel Law

Uncommon Amino Acids Also Have Irnportant Functions

Amino Acids Can Act as Acids and Bases

Titration Curves Predict the Electric Charge of Amino Acids

Amino Acids Differ in Their Acid-Base Properties

3.2 Peptides and Proteins

Peptides Are Chains of Amino Acids

Ionization Behavior Biologically Active Peptides and Polypeptides Occur in a Vast Range of Sizes and Compositions

Some Proteins Contain Chemical Groups Other Than Amino Acids

3.3 Working with Proteins

Electrophoresis

65 65

333535

76

77 78

83 84

85

85 88

9 1

43

4345

47 47

49 50

3.4 The Structure of Proteins: Primary Structure 92

The Function of a Protein Depends on Its

4 The Three-Dimensional Strueture of Proteins 'll3 Protein Structure Affects How Ligands Bind

Hemoglobin Subunits Are Structurally Similar to Myoglobin

Binding Oxygen

Quantitatively

Box 5-1 Medicine:Cahon Monoxide:A Stealthy Killer

5.2 (omplementary lnteradions between Proteins and Ligands:The lmmune System and lmmunoglobulins

6 Enzymes

Contents xvii

160 160 162

1 6 3

1 5 8

1 5 8 159

4.1 0verview of Protein Structure

Weak Interactions

The Peptide Bond Is Rigid and Planar

4.2 Protein 5econdary Structure

The a Helix Is a Common Protein Secondary

Structure

Box 4-1 Methods:Knowing the Right Hand from the left

Amino Acid Sequence Affects Stability of the

a Helix

Chains into Sheets

B Tirrns Are Common in Proteins

4.3 Protein Tertiary and Quaternary Structures

Fibrous Proteins Are Adapted for a

Structural Function

Box 4-2 Permanent Waving ls Biochemical Engineering

Box4-3 Medicine:Why Sailors, Explorers, and College

Students Should Eat Their Fresh Fruits and Vegetables

Box 4-4 The Protein Data Bank

Structural Diversity Reflects Functional Diversity

in Globular Proteins

Myoglobin Provided Early Clues about the Complexity

Globular Proteins Have a Variety of

Tertiary Structures

Box4-5 Methods; Methods for Determining the

Three-Dimensi0nal Stlucture of a Protein

Protein Motifs Are the Basis for Protein

Structural Classiflcation

Protein Quaternary Structures Range from Simple

Dimers to Large Complexes

4.4 Protein Denaturation and Folding

Loss of Protein Structure Results in

Loss of Function

Tertiary Structure

Some Proteins Undergo Assisted Folding

Defects in Protein Folding May Be the Molecular

Basis for a Wide Range of Human Genetic

1 1 3rt4

\ 2 3125

174

5,1 Reversible Binding of a Protein to a Ligand:

0xygen-Binding Proteins

Oxygen Can Bind to a Heme Prosthetic Group

Myoglobin Has a Single Binding Site for Oxygen

Protein-Ligand Interactions Can Be Described

Quantitatively

Artibodies Have TWo Identical Antigen-Binding Sites 171

The Antibody-Antigen Interaction Is the Basis for a

5.3 Protein lnteractions Modulated by (hemical Energy: Actin, Myosin, and Molecular Motors

The Major Proteins of Muscle Are Myosin and Actin

Filaments into Ordered Structures Myosin Thick Filaments Slide along

1 8 3 6.1 An lntroduction to Enzymes

Most Enzymes Are Proteins

They Catalyze

6.2 How Enzymes Work

En4'rnes A-ffect Reaction Rates, Not Equilibria Reaction Rates and Equilibria Have Precise

Speciflcity and Catalysis Speciic Catalytic Groups Contribute to Catalysis

6.3 Enzyme Kinetics as an Approach to Understanding Mechanism

and Reaction Rate Can Be Expressed Quantitatively

126129r29t29

175

t75 176

t40

183

184

1 9 1 1.92

r84

1 8 6

1 8 6 188 188 189

r45147

1 5 3

1 5 4r54

194

194

1 9 5

Ivrrl Contents

Box 6-1 Transformations of the Michaelis-Menten Equation:

The Double-Reciprocal Plot

Activities

More Substrates

Pre-Steady State Kinetics Can Provide

Evidence for Specific Reaction Steps

Irreversible Inhibition

Box 6-2 Kinetic Tests for Determining lnhibition

Mechanisms

EnzSrme Activity Depends on pH

6.4 Examples of Enzymatic Reactions

and Deacyla[ion of a Ser Residue

Box 6-3 Evidence for Enzyme-Transition State

5.5 Regulatory Enzymes

The Kinetic Properties of Allosteric Enz;'rnes

Covalent Modi-fication

Phosphoryl Groups Affect the Structure and

Catalytic Activity of En4rnes

Regulatory Controi

Some Erz;'rnes and Other Proteins Are Regulated

Mechanisms

7 Carbohydrates and Glycobiology

Structures

Box 7-1 Medicine: Blood Glucose Measurements in the

Diagnosis and Treatment of Diabetes

Disaccharides Contain a Glycosidic Bond

7.3 6lycoconju gates: Proteoglyca ns, Glycoproteins,

Proteo$ycans Are Glycosaminoglycan-Containing

Lectins Are Proteins That Read the Sugar

7.5 Working with Carbohydrates 263

8 Nucleotides and Nucleic Arids

t97

20120r

202204

205

205210

2 \ 2213213216

Nucleotides and Nucleic Acids Have

Nucleotides in Nucleic Acids

271

2 7 1

.tt7 ^

8.2 Nucleic Acid Structure

DNA Is a Double Helix that Stores Genetic Information

DNA Can Occur in Different Three-Dimensional Forms

Many RNAs Have More Complex Three-Dimensional Structures

8.3 Nucleic Acid Chemistry

Form Hybrids Nucleotides and Nucleic Acids Undergo

Some Bases of DNA Are Methylated

28028r283284287287

289 292 292 294

241

243

8.4 Other Functions of Nucleotides

Nucleotides Carry Chemical Energy in Ceils

Some Nucleotides Are Regulatory Molecules

9 DNA-Based Information Terhnologies 3CI3

9.1 DNA Cloning:The Basics 304

Cloning Vectors Allow Ampliflcation of Inserted

Alterations in Cloned Genes Produce Modified

Terminal Tags Provide Binding Sites for Affinity

9.2 From Genes to Genomes 315

Waxes Serve as Energy Stores and Water Repellents 349

10.2 Structural Lipids in Membranes 349

In LySOSOmeS

Sterols Have Four Fused Carbon Rhgs

Box10-2 Medicine; Abnormal Accumulations of Membrane Lipids:Some Inherited Human Diseases 10.3 Lipids as Signals, Cofactors, and Pigments

Act as Intracellular Signals

Signals Vitamins A and D Are Hormone Precursors Vitamins E and K and the Lipid Quinones Are

10.4 Working with Lipids 363

Speciic Hydrolysis Aids in Determination of

11 Biological Membranes and Transport 371

11.1 The (omposition and Architecture of Membranes 372

Each Tlpe of Membrane Has Characteristic

A Lipid Bilayer Is the Basic Structural Element of Membranes

Many Membrane Proteins Span the Lipid Bilayer

Hydrophobic Interactions with Lipids

357

rJD''

359 359 360

3 6 1

DNA Sequences

Genetic Libraries

Box 9-1 A PotentWeapon in Forensic Medicine

Provide Information on Protein Function

Cellular Expression Patterns Can Reveal the

Cellular Function of a Gene

Detection of Protein-Protein Interactions Helps to

Define Cellular and Molecular Function

9.4 Genome Alterations and New Products

Box9-2 Medicine:The Human Genome and Human

10.1 Storage Lipids

Fatty Acids Are Hydrocarbon Derivatives

and Insulation

J l r

317

3 1 9 324

e.) A

325328

xx [ontents

The Topology of an Integral Membrane Protein Can

Covalently Attached Lipids Anchor Some

Membrane Proteins

Acyl Groups in the Bilayer Interior Are Ordered

to Varying Degrees

Lipids and Proteins Diffuse Laterally in the Bilayer

Membrane Rafts

Box 11-1 Methods: Atomic Force Microscopy to Visualize

Membrane Curvature and Fusion Are Central to

Integral Proteins of the Plasma Membrane Are

I1"3 Solute Transport across Membranes

Proteins

Tfansporters Can Be Grouped into Superfamilies

Box11-2 Medicine: Defective Glu(ose and Water Transport

in Two Forms of Diabetes

Active Tfansport Results in Solute Movement

against a Concentration or Electrochemical

Gradient

Their Catalytic Cycles

Proton Pumps

ABC Ttansporters Use ATP to Drive the Active

Tfansport of a Wide Variety of Substrates

Ion Gradients Provide the Energy for Secondary

Active Transport

Box11-3 Medicine:A Defective lon (hannel in Cystic Fibrosis

Aquaporins Form Hydrophilic Tfansmembrane

Basis for Its Speci_flcity

Function

12 Biosignaling

12.1 General Features ofSignal Transduction

Box 12-1 Methods:Scatchard Analysis Quantifies the

Receptor-Ligand Interaction

385

378 379

3 8 1

3 8 1

3 8 1 383

388

389390

3 9 1

3 9 1

12.2 G Protein-(oupled Receptors and

The p-Adrenergic Receptor System

Box12-2 Medicine.'G Proteins: Binary Switches in

Box12-3 Methods: FRET: BiochemistryVisualized in a

12.3 ReceptorTyrosine Kinases 439

Stimulation of the Insulin Receptor Initiates a

The Membrane Phospholipid PIP3 Functions at a

12.4 Receptor Guanylyl (yclases, cGMB and

12.5 Multivalent Adaptor Proteins and Membrane Rafts 446

The Acetylcholine Receptor Is a

12,7 Integrins: Bidirectional Cell Adhesion Receptors 455 12.8 Regulation of Transcription bySteroid Hormones 456 12.9 Signaling in Microorganisms and Plants 457

Plants Detect Ethylene through a TWo-Component

Receptorlike Protein Kinases Tlansduce Signals from

387

393394

395 396

400 401 404 406 407 407

4 1 0

4 1 0

419

4 1 942"1

1 2.10 Sensory Transduction in Vision,

0lfaction, and Gustation

The Visual System Uses Classic GPCR Mechanisms

Excited Rhodopsin Acts through the G Protein

Tlansducin to Reduce the cGMP Concentration

The Visual Signal Is Quickly Terminated

Vertebrate Olfaction and Gustation Use

Box 12-4 Medicine: Color Blindness: J0hn Dalton's

Experiment from the Grave

Systems

12.11 Regulation ofthe Cell (ycle by Protein Kinases 469

CDKs Regulate Ceil Division by Phosphorylating

Inorganic Pollphosphate Is a Potential

Biological Oxidations Often Involve Dehydrogenation 513 Reduction Potentials Measure Afflnity for Electrons 5I4 Standard Reduction Potentials Can Be Used to

Dietary Deflciency of Niacin, the Vitamin Form of

Flavin Nucleotides Are Tightly Bourd in

1 2.1 2 0ncogenes, Tumor 5uppressor Genes, and

Programmed (ell Death 473

461

462 463 +o+

500

5 0 1

493 494

Defects in Certain Genes Remove Normal

Box'12-5 Medicine.' Development of Protein

Kinase Inhibitors for Cancer Treatment

Apoptosis Is Programmed Cell Suicide

13 Bioenergetics and Biochemical

Reaction Types _

Laws of Thermodynamics

Standard Free-Energy Change Is Directly

Related to the Equilibrium Constant

Reactant and Product Concentrations

Not Identical

13.3 Phosphoryl Group Transfers and ATP

The Free-Energy Change for ATP Hydrolysis Is

Large and Negative

Also Have Large Free Energies of Hydrolysis

ATP Provides Energy by Group Ttansfers, Not by

i 4 Glyeolysis, Glucaneogenesis, and the Pentose

Pliosphate Pathtruay

The Overall Balance Sheet Shows a Net Gain of AIP 538

Box 14-1 Medicine:High Rate of Glycolysis in Tumors SuggestsTargets for (hemotherapy and Facilitates Diagnosis 540

1 4.3 Fates of Pyruvate under Anaelobic (onditions:

Pyruvate Is the Terminal Electron Acceptor in

Ethanol Is the Reduced Product in Ethanol

Box 1 4-2 Athletes, Alligators, and Coelacanths:

l

x x t I (o nte nts

Foods and Industrial Chemicals

Requires TWo Exergonic Reactions

Essential

Citric Acid Cycle Intermediates and Some Amino

Acids Are Glucogenic

Mammais Cannot Convert Fatty Acids to Glucose

Regulated

1 4.5 Pentose Phosphate Pathway of Glucose 0xidation

Box14-4 Medicine; Why Pythagoras Wouldn't Eat Falafel:

Glucose 6-Phosphate Dehydrogenase Deficiency

The Oxidative Phase Produces Pentose

Defect in Ttansketolase

15.1 Regulation of Metabolic Pathways

Steady State

Both the Amount and the Catalytic

Activity of an Enzyme Can Be Regulated

Common Pohts of Regulation

Adenine Nucleotides Play Special Roles in

Metabolc Regulation

15.2 Analysis of Metabolic Control

a Pathway Is Experimentally Measurable

The Control Coefflcient Quantiies the Effect of a

through a Pathway

Box 1 5-1 Methods: ltretabolic Control Analysis:

Quantitative Aspects

The Elasticity Coefflcient Is Related to an Enzlme's

Regulator Concentrations

Outside Controller on Flux through a Pathway

Metabolic Control Analysis Has Been Applied to

Results

Method for Increasing Flux through a Pathway

15 Principles of Metabolic Regulation 559

15.3 (oordinated Regulation of Glycolysis andGluconeogenesis

Box 1 5-2 lsozymes: Different Proteins That Catalyze

The Glycolytic Enzl'rne P''ruvate Kinase Is

Box15-3 Medicine; Genetic Mutations That Lead toRare Forms of Diabetes

15.4The Metabolism of Glycogen in Animals

Box 15-4 Carl and Gerty Cori: Pioneers in Glycogen

15.5 (oordinated Regulation of Glycogen Synthesis

Allosteric and Hormonal Signals Coordinate

582

584

5 5 1

556 556

570

59857r

16.1 Production of Acetyl-CoA (Activated Acetate)

Pytuvate Is Oxidized to Acetyl-CoA and CO2

Five Coenzr.'rnes

6"t6

o r o 617

5 8 1

The Pyruvate Dehydrogenase Complex Consists

of Three Distinct Enzymes

Leave the Enzyme Surface

16.2 Reactions of the Citric Acid (ycle

The Citric Acid Cycle Has Eight Steps

Box 16-1 Moonlighting Enzymes:

Proteins with More Than One Job

Box 16-2 Synthases and Synthetases; Ligases and Lyases;

Kinases, Phosphatases, and Phosphorylases: Yes, the

Box 16-3 Citrate: A Symmetric Molecule That Reacts

Asymmetrically

The Energy of Oxidations in the Cycle Is Efflciently

Conserved

Why Is the Oxidation of Acetate So Complicated?

Bioslnthetic Intermediates

Anaplerotic Reactions Replenish Citric Acid Cycle

Intermediates

Box 1 6-4 Gtrate Synthase, Soda Pop, and the

World Food Supply

16.3 Regulation of the Citric Acid (ycle

Production of Acetyl-CoA by the Py'ruvate

Allosteric and Covalent Mechanisms

The Citric Acid Cycle Is Regulated at Its Three

Cycle Lead to Cancer

16.4 The Glyoxylate (ycle

The Glyoxylate Cycle Produces Four-Carbon

The Citric Acid and Glyoxylate Cycles Are

Coordinately Regulated

17 Fatty Acid Catabolism

17.1 Digestion, Mobilization, and Transport of Fats

Dietary Fats Are Absorbed in the Small Intestine

Hormones Ttigger Mobilization of Stored

Tliacylglycerols

Fatty Acids Are Activated and Ttansported into

Mitochondria

17.2 0xidation of Fatty Acids

The B Oxidation of Saturated Fatty Acids Has

Four Basic Steps

The Four B-Oxidation Steps Are Repeated to Yield

Acetyl-CoA and ATP

Box 17-1 Fat Bears (arry Out B 0xidation in Their Sleep

Acetyl-CoA Can Be Further Oxidized in the

Citric Acid Cycle

Oxidation of Unsaturated Fatty Acids Requires

T\vo Additional Reactions

Genetic Defects in Fatty Acyl-CoA

Acetyl-CoA from B Oxidation as a Biosynthetic Precursor

The B-Oxidation Enzymes of Different Organelles Have Diverged during Evolution

The ro Oxidation of Fatty Acids Occurs in the

18.1 Metabolic Fates of Amino Groups

Dietary Protein Is Enzymatically Degraded to Amino Acids

a-Amino Groups to a-Ketoglutarate

Ammonia in the Liver

Box 18-1 Medicine: Assays forTissue Damage

Glutamine Tlansports Ammonia in the Bloodstream

Alanine Ttansports Ammonia from Skeletal Muscles to the Liver

Ammonia Is Toxic to Animals

18.2 Nitrogen Excretion and the Urea Cycle

Urea Is Produced from Ammonia in Five

Cost of Urea Synthesis Genetic Defects in the Urea Cycle Can Be

T i fa - T h r o q t o n i n o

! u ! r r r r ! q l v r r r ^ ! o

1 8.3 Pathways of Amino Acid Degradation

Some Amino Acids Are Converted to Glucose Others to Ketone Bodies

Roles in Amino Acid Catabolism Six Amino Acids Are Degraded to Py'ruvate Seven Amino Acids Are Degraded to Acetyi-CoA

o,J 1

6 3 1

6 3 1

Ketone Bodies, Formed in the Liver, Are

633633635

6 8 1 681

682

682 684 685

650652

i x x i v , C o n t e n t s

Defective in Some People

Five Amino Acids Are Converted to

a-Ketoglutarate

Four Amino Acids Are Converted to Succinyl-CoA

Box18-2 Medicine: Scientific Sleuths Solve a

Degraded h the Liver

Oxaloacetate

19 fixldative Phosphorylaticn and

Photophosphorylation

19.1 Electron-Transfer Reactions in Mitochondria

Electrons Are Funneled to Universal Electron

The Energy of Electron Tfansfer Is Efflciently

Oxidative Phosphorylation

Plant Mitochondria Have Aiternative

Box 1 9-1 Hot, Stinking Plants and Alternative

ATP from the Enz}.tne Surface

Each B Subunit of ATP Synthase Can Assume

ATP Synthesis

The Proton-Motive Force Energizes

Active Transport

NADH hto Mitochondria for Oxidation

Cellular Energy Needs

An Inhibitory Protein Prevents ATP Hydrolysis

70070r

Uncoupled Mitochondria in Brown Adipose

Mutations in Mitochondrial DNA Accumulate throughout the Life of the Organism Some Mutations in Mitochondrial Genomes

72r722723

742

743 743

725 725 726 726

729 730

19.8 The Central Photochemical Event:

Light-Driven Electron Flow

Bacteria Have One of Tlvo Tlpes of Single

the Dissipation of Energy by Internal

Cyclic Electron FIow between PSI and the

A Proton Gradient Couoles Electron Flow and

732

I t ) r )

l J J

1 9.1 0 The Evolution of 0xygenic Photosynthesis

Photosynthetic Bacteria

In Halobacteri,um, aSingle Protein Absorbs Light

and Pumps Protons to Drive ATP S;,rrthesis

20 Carbohydrate Biosynthesis in

Plants and Bacteria

20.1 Photosynthetic Carbohydrate Synthesis 773

Carbon Dioxide Assimilation Occurs in

20.2 Photorespiration and the Coand (AM Pathways 786

In Ca Plants, CO2 Fixation and Rubisco Activity

In CAM Plants, CO2 Capture and Rubisco Action

20.3 Biosynthesis of Starch and Sucrose 791

Plant Plastids and for Glycogen Synthesis in

20.4 Synthesis of Cell Wall Polysaccharides:

Plant Cellulose and Bacterial Peptidoglyca n 794

20.5 lntegration of Carbohydrate Metabolism in the

Pools of Common Intermediates Link Pathways h

21 Lipid Biosynthesis

21.1 Biosynthesis of Fatty Acids and Eicosanoids

Multiple Active Sites

Malonyl Groups

Fatty Acid Slnthesis Occurs in the Cytosol of Many

21.3 Biosynthesis of Membrane Phospholipids 824

Polar Lipids Are Targeted to Speciflc

84r

805805

I xxvr ] Contents

Steroid Hormones Are Formed by Side-Chain

Cleavage and Oxidation of Cholesterol

Intermediates in Cholesterol Bioslmthesis Have

Many Alternative Fates

22 Biosynthesis of Amino Acids, Nucleotides,

and Related Molecules

The Nitrogen Cycle Maintains a Pool of

Biologically Available Nitrogen

Box 22-1 Unusual Lifestyles ofthe 0bscure but Abundant

Ammonia Is Incorporated hto Biomolecules

through Glutamate and Glutamine

Point in Nitrogen Metabolism

Acids and Nucleotides

22.2 Biosynthesis of Amino Acids

a-Ketoglutarate Gives Rise to Glutamate,

G l r r t : m i n p P r o l i n c r n d A r o i n i n e

Serine, Glycine, and Cysteine Are Derived from

Py'ruvate

Biosl'nthesis

Allosteric Regulation

22.3 Molecules Derived from Amino Acids

Box22-2 Medicine;0n Kings and Vampires

Heme Is the Source of Bile Pigments

Amino Acids Are Precursors of Creatine and

Glutathione

o-Amino Acids Are Found Primarily in Bacteria

Aromatic Amino Acids Are Precursors of Manv

Plant Substances

Biological Amines Are Products of Amino Acid

Decarboxylation

Box22-3 Medicine; Curing African Sleeping Sicknes with

a Biochemical Trojan Horse

Arginine Is the Precursor for Biological

22.4 Biosynthesis and Degradation of Nucleotides

De Novo Purine Nucleotide Synthesis

Begins with PRPP

Feedback Inhibition

Pyrimidhe Nucleotides Are Made from Aspartate,

in the Nucleotide Biosynthetic Pathways

23 Hormonal Regulation and Integration

Box 23-1 Medicine: How ls a Hormone Discovered?

23.2 Tissue-5pecific Metabolism:The Division of Labor

Adipose Tissues Store and Supply Fatty Acids Brown Adipose Tissue Is Thermogenic

Electrical Impulses

23.3 Hormonal Regulation of Fuel Metabolism

Insulin Counters High Blood Glucose

During Fasting and Starvation, Metabolism Shifts to Provide Fuel for the Brain

Blood Glucose Diabetes Mellitus Arises from Defects in Insulin Production or Action

23.4 Obesity and the Regulation of Body Mass 930

Adipose Tissue Has Important

Leptin Stimulates Production of Anorexigenic

The Leptin System May Have Evolved to

888 890

852

892 893 893

9 1 8 920 920

922

922 923 925 926 928 929

880

882

882

883 885 886 887

Insulin Acts in the Arcuate Nucleus to

Regulate Eating and Energy Conservation

Adiponectin Acts through AMPK to Increase

Insulin Sensitivity

Central to Maintaining Body Mass

Short-Term Eating Behavior Is Influenced by

Ghrelin and PYY3_36

23.5 Obesity, the Metabolic Syndrome, and

In Tlpe 2 Diabetes the Tissues Become

Insensitive to Insulin

Replication in Eukaryotic Cells Is Both

The Interaction of Replication Forks with DNA

934 934 936

938

24.1 Chromosomal Elements

Polypeptide Chains and RNAs

Contain Them

Very Compiex

24.2 DNA Supercoiling

Most Cellular DNA Is Underwound

DNA Underwinding Is Defined by Topological

Linking Number

Linking Number of DNA

Box 24-1 Medicine: Curing Disease by Inhibiting

Topoisomerases

DNA Compaction Requires a Special Form of

Supercoiling

24.3 The Structure of Chromosomes

Histones Are Small, Basic Proteins

Box 24-2 Medicine: Epigenetics, Nucleosome

Structure, and Histone Variants

A-ll Aspects of DNA Metabolism Come Together to

938 939

945 947

1001100310031004

966

o A q

970

26.1 DNA-Dependent Synthesis of RNA

Box 26-1 Methods: RNA Polymerase Leaves ltsFootprint on a Promoter

RNA Synthesis

1022r022r025

10261028r029

25.1 DNA Replication

DNA Replication Follows a Set of

Fundamental Rules

Replication Is Very Accurate

E coli, Has at Least Five DNA Polrrmerases

Eukaryotic Cells Have Three Kinds of Nuclear

Protein Factors for lts Activity

26.2 RNA Processing

Eukaryotic mRNAs Are Capped at the 5' End Both Introns and Exons Are Ttanscribed from DNAinto RNA

Eukaryotic mRNAs Have a Distinctive 3' End Structure

A Gene Can Give Rise to Multiple Products by Differential RNA Processinq

975

10301033

1033

10341035103610391040

977

9 7 7

o 7 0

979 980 982

Events in RNA Metabolism

RNAlike Polynners

26.3 RNA-Dependent Synthesis ofRNA and DNA

Viral RNA

May Have a Common Evolutionary Origin

Box26-2 Medicinej Fighting AlD5 with Inhibitors of

Some Viral RNAs Are Replicated by

Biochemical Evolution

Box26-3 Methods: The SEIEX Method for Generating

RNA Polymers with New Functions

Box 26-4 An Expanding RNA Universe Filled with

27 Protein Metabolism

27.1 The Genetic (ode

The Genetic Code Was Cracked Using Arti-flcial

mRNA Templates

Box27-'l Exceptions That Prove the Rule:

Natural Variations in the Genetic Code

Wobble Allows Some tRNAs to Recognize

More than One Codon

Tlanslational Frameshifting and RNA Editing

A-ffect How the Code Is Read

27.2 Protein Synthesis

Machine

Box27-2 From an RNA World to a Protein World

Ttansfer RNAs Have Characteristic

Structural Features

Correct Amino Acids to Their tRNAs

Box 27-3 Natural and Unnatural Expansion ofthe

Stage 4: Termination of Polypeptide Synthesis

Requires a Special Signal

Antibiotics and Toxins

27.3 Protein Targeting and Degradation

Eukaryotic Proteins Begins in the

Small RNAs in Cis or in Ttans

Genetic Recombination

Positively Regulated DNA-Binding Activators and Coactivators Facilitate Assembly of the General Transcriotion Factors

The Lac Operon Is Subject to Negative Regulation 1119 Regulatory Proteins Have Discrete DNA-Binding

Regulatory Proteins Also Have Protein-Protein

28.2 Regulation of Gene Expression in Bacteria 1126

r042

1 0 4 5 1045 1048 1049

1 050

1050

1 0 5 1t052

1053

1 0 5 6105610581060

1065

1096 1098

1 0751075r076

1 0 7 81079

1 0 8 110851088

1 0 9 11094r094

28.3 Regulation ofGene Expression in Eukaryotes 1136

Ttanscriptionally Active Chromatin Is Structurally

NucleosomalDisplacement/Repositioning 1137 Many Eukaryotic Promoters Are

1 130

I I 3 2I134

1 1 3 8

I 1 3 8

Are Subject to Both Positive and Negative

Tfanscription Activators Have a Modular Structure lI42

Contents I xxix I

RNA Interference

'v vr

bout fifteen billion years ago, the universe arose as

a cataclysmic eruption of hot, energy-rich

sub-atomic particles Within seconds, the simplest

elements (hydrogen and helium) were formed As the

universe expanded and cooled, material condensed

under the influence of gravity to form stars Some stars

became enormous and then exploded as supernovae,

releasing the energy needed to fuse simpler atomic

nuclei into the more complex elements Thus were

pro-duced, over billions of years, Earth itself and the

chemical elements found on Earth today About four

bil-lion years ago, life arose-simple microorganisms with

the ability to extract energy from chemical compounds

and, later, from sunlight, which they used to make a vast

array of more complex biomolecules from the simple

elements and compounds on the Earth's surface.

Biochemistry asks how the remarkable properties of

living organisms arise from the thousands of different

examined individually, they conform to all the physical

and chemical laws that describe the behavior of

organisms The study of biochemistry shows how the

collections of inanimate molecules that constitute living

organisms interact to maintain and perpetuate life

animated solely by the physical and chemical laws that

govern the nonliving universe

Yet organisms possess extraordinary attributes,

properties that distinguish them from other collections

of matter What are these distinguishing features ofIMng organisms?

A hrgh degree of chemical complexity and croscopic organization Thousands of differentmolecules make up a cell's intricate internal struc-tures (Fig l-la) These include very long pol}rmers,

urLique three-dimensional structure, and its higNyspecific selection of binding partners in the cell

Systems for extraeting, tlansforming, and ing energy from the environment (Fig 1- lb), en-

all matter to decay toward a more disordered state,

to come to equilibrium with its surroundings

Defined functions for each of an organism'scomponents and regulated interactions arnongthem This is true not only of macroscopic struc-tures, such as leaves and stems or hearts and lungs,but also of microscopic intracellular structuresand individual chemical compounds The interplay

whole ensemble displaying a character beyond that

of its individual parts The collection of moleculescarries out a program, the end result of which is re-

that collection of molecules-in short, life

Mechanisms for sensing and responding to terations in their surroundings, constantly ad-justing to these changes by adapting their internalchemistry or their location in the environment

self-assembly (Fig 1-1c) A single bacterial cell

(c) FIGURE l-1 Some characteristics of living matter (a) Microscopic

complexity and organization are apparent in this colorized thin

sec-tion of vertebrate muscle tissue, viewed with the electron microscope.

(b) A prairie falcon acquires nutrients by consuming a smaller bird.

(c) Biological reproduction occurs with near-perfect fidelity.

placed in a sterile nutrient medium can give rise to

a billion identical "daughter" cells in 24 hours Each

cell contains thousands of different molecules,

some extremely complex; yet each bacterium is a

faithful copy of the original, its construction

di-rected entirely from information contained in the

genetic material of the original cell

A capacity to change over time by gradual

evo-lution Organisms change their inherited life

cir-cumstances The result of eons of evolution is an

enorrnous diversity of Me forms, superflcially very

different (Fig 1-2) but fundamentally related

through their shared ancestry This fundamental

molecu-lar level in the simimolecu-larity of gene sequences and

protein structures

Despite these common properties, and the

funda-mental unity of life they reveal, it is difflcult to make

generalizations about living organisms Earth has an

from hot springs to Arctic tundra, from animal intestines

to college dormitories, is matched by a correspondingly

within a corrmon chemical framework For the sake ofclarity, in this book we sometimes risk certain general-izations, which, though not perfect, remain useftil; wealso frequently point out the exceptions to these gener-alizations, which can prove illuminating

Biochemistry describes in molecular terms the

underlie life in all its diverse forms, principles we refer

to collectively as the molecular logi,c oJ life I.Jthorghbiochemistry provides important insights and practicalapplications in medicine, agriculture, nutrition, andindustry, its ultimate concern is with the wonder oflife itself

In this introductory chapter we give an overview

of the cellular, chemical, physical, and genetic grounds to biochemistry and the overarching principle

back-of evolution-the development over generations back-ofthe properties of living cells As you read through thebook, you may find it helpful to refer back to this chap-ter at intervals to refresh your memory of this back-ground material

1.1 (ellularFoundations

The unity and diversity of organisms become apparent

of single cells and are microscopic Larger, multicellularorganisms contain many different types of cells, whichvary in size, shape, and specialized function Despite

FIGURE 1-2 Diverse living organisms share common chemical features Birds, beasts, plants, and soil microorganisms share with humans the same basic structural units (cells) and the same kinds of macromolecules(DNA, RNA, proteins) made up of the same kinds of monomeric subunits (nucleotides, amino acids) They utilize the same pathways for synthesis

of cellular components, share the same genetic code, and derive from the same evolutionary ancestors Shown here is a detail from "The Carden of Eden," bylan van Kessel theYounger (1626-1679).

these obvious differences, all cells of the simplest and

most complex organisms share certain fundamental

{e[is Are the Strurturai afid Falnrti*n*f Uni{s cl{

Altl-iuing Organi*ms

Cells of all kinds share certain structural features

(f ig [-3) The plasma membrane defines the

pe-riphery of the cell, separating its contents from the

that form a thin, tough, pliable, hydrophobic barrier

around the cell The membrane is a barrier to the free

receptor proteins transmit signals into the cell; and

membrane enzpes participate in some reaction

path-Nucleus (eukaryotes)

or nucleoid (bacteria, archaea) Contains genetic material-DNA and associated proteins Nucleus is membrane-enclosed.

Plasma membrane Tough, fledble lipid bilayer.

Selectively permeable to polar substances Includes membrane proteins that

1 1 C e l l u l a r F o u n d a t i o n s 3

ways Because the individual lipids and proteins of theplasma membrane are not covalently lirked, the entire

shape and size of the cell As a cell grows, newly madelipid and protein molecules are inserted into its plasmamembrane; cell division produces two cells, each withits own membrane This growth and cell division (fls-sion) occurs without loss of membrane integrity

The internal volume enclosed by the plasma

aque-ous solution, the c5rtosol, and a variety of suspendedparticles with specific functions The cytosol is a highly

molecules that encode them; the components (aminoacids and nucleotides) from which these macromoleculesare assembled; hundreds of small organic moleculescalled metabolites, intermediates in biosynthetic and

proteins no longer needed by the cell

All cells have, for at least some part of their life,either a nucleus or a nucleoid, in which the genome-

not separated from the cytoplasm by a membrane; the

Cells with nuclear envelopes make up the large group

grouped together as prokaryotes (Greek pro,

dis-tinct groups, Bacteria and Archaea, described below

{ellu}ar ftimensions Are [innited by Dlffusion

Animal and plant cells are typically 5 to 100 pm in

2 g,m long (see the inside back cover for information onunits and their abbreviations) What limits the dimen-sions of a cell? The Iower limit is probably set by theminimum number of each type of biomolecule required

by the cell The smallest cells, certain bacteria known as

take up a substantial fraction of the volume in a

The upper limit of cell size is probably set by the

For example, a bacterial cell that depends on consuming reactions for energy production must obtainmolecular oxygen by diffusion from the surroundingmedium through its plasma membrane The cell is sosmall, and the ratio of its surface area to its volume is soIarge, that every part of its cytoplasm is easily reached

Aqueous cell contents and suspended particles and organelles.

FI6URE 1 - 3 The universal features of living cells, All cells have a

nu-cleus or nucleoid, a plasma membrane, and cytoplasm The cytosol is

defined as that portion ofthe cytoplasm that remains in the supernatant

after gentle breakage of the plasma membrane and centrifugation of

the resulting extract at 1 50,000 g for .l hour.

Entamoebae Slime

molds

Halophiles

Eukarya Animals

Green

nonsulfur bacteria

Phototrophe (energy from light)

Pyrod.ictium\Thermococcus"

\ \ celer

Plants Ciliates

Thermotogales

FIGURE 1-4 Phylogeny of the three domains of life Phylogenetic

rela-tionships are often illustrated by a "family tree" of this type The basis for

this tree is the similarity in nucleotide sequences of the ribosomal RNAs

of each group; the more similar the sequence, the closer the location of

the branches, with the distance between branches representing the

de-gree of difference bretween two sequences Phylogenetic trees can also

me-tabolism consumes 02 faster than diffusion can supply

There Are Three Distinct Domains of Life

All living organisms fall into one of three Iarge groups

(domains) that define three branches of evolution from

Flagellates Trichomonads

Microsporidia Diplomonads

be constructed from similarities across species of the amino acid quences of a single protein For example, sequences of the protein CroEL (a bacterial protein that assists in protein folding) were compared

se-to generate the tree in Figure 3-32 The tree in Figure 3-33 is a sensus" tree, which uses several comparisons such as these to make the best estimates of evolutionary relatedness of a group of organisms.

"con-a common progenitor (Fig 1-4) TWo l"con-arge groups of

genetic and biochemical grounds: Bacteria andArchaea Bacteria inhabit soils, surface waters, and

lakes, hot springs, highly acidic bogs, and the ocean

and Bacteria diverged early in evolution AII eukaryotic

Reduced fuel Oxidized fuel Lithotrophs

Heterotrophs (carbon from organic compounds) Purple bacteria Green bacteria

Sulfur bacteria Hydrogen bacteria

Most bacteria All nonphototrophic eukaryotes All organisms

t l G U R E l - 5 O r g a n i s m s c a n b e c l a s s i f i e d a c c o r d i n g t o t h e i r s o u r c e o f e n e r g y ( s u n l i g h t o r o x i d i z a b l e c h e m i c a l

compounds) and their source of carbon for the synthesis of cellular material.

evolved from the same branch that gave rise to the

Within the domains of Archaea and Bacteria are

habitats with a plentiful supply of oxygen, some resident

organisms derive energy from the transfer of electrons

from fuel molecules to oxygen Other environments are

anaerobic, virtually devoid of oxygen, and

transferring electrons to nitrate (forming N2), sulfate

(forming H2S), or CO2 (forming CH+) Many organisms

that have evolved in anaerobic environments are

Oth-ers are facultatzue anaerobes, able to live with or

without oxygen

ob-tain the energy and carbon they need for q,rrthesizing

sunlight, and chemotrophs derive their energy from

lithotrophs, oxidize inorganic fuels-HS- to Su

for example Organotrophs oxidize a wide array of

Pho-totrophs and chemotrophs may also be divided into

those that can obtain all needed carbon from CO2

(au-totrophs) and those that require organic nutrients

(heterotrophs)

Esrhe ia rolils the Most-Studied Bacterium

E coli, is a usually harmless inhabitant of the human

intestinal tract The E coli, cell is about 2 pm long and

outer membrane and an inner plasma membrane that

a pol;'rner (peptidoglycan) that gives the cell its shape

and rigidity The plasma membrane and the layers

out-side it constitute the cell envelope We should note

here that in archaea, rigidity is conferred by a different

FIGURE 1 -6 Common structural features of bacterial cells Because of

differences in cell envelope structure, some bacteria (gram-positive

bacteria) retain Cram's stain (introduced by Hans Christian Cram in

1BB2), and others (gram-negative bacteria) do not f coli is

gram-negative Cyanobacteria are distinguished by their extensive internal

membrane system, which is the site of photosynthetic pigments

Al-though the cell envelopes of archaea and gram-positive bacteria look

similar under the electron microscope, the structures of the membrane

lipids and the polysaccharides are distinctly different (see Fig 10-.12).

L 1 C e l l u l a r F o u n d a t i o n s 5

have a similar architecture, but the lipids are strikinglydifferent from those ofbacteria (see Fig 10-12)

Ribosomes Bacterial ribosomes are smaller than eukaryotic ribosomes, but serve the same functron-

Nucleoid Contains a single, simple, long circular DNA molecule.

Pili Provide points of adhesion to surface of

* other cells.

Cell envelope Structure varies with type of bacteria.

Gram-negative bacteria Outer membrane;

extensive internal membrane system with photosynthetic pigments

Archaea

No outer membrane;

pseudopeptidoglycan layer outside plasma membrane

Flagella

" Propel cellthrough itssurroundings.

The cytoplasm of -O coli, contains about 15,000

organic compounds of molecular weight less than 1,000

(a) Animal cell

Nuclear envelope segregates

chromatin (DNA + protein)

from cytoplasm

(metabolites and cofactors), and a variety of inorganic

DNA, and the cytoplasm (like that of most bacteria)

Ribosomes are synthesizing machines Peroxisome oxidizes fattv acids

protein-Cytoskeleton supports cell, aids

in movement of organelles

me degrades intracellular Ttansport vesicle shuttles lipids and proteins between ER, Golgi, and plasma membrane

Golgi complex processes, packages, and targets proteins to other organelles or for export

Smooth endoplasmic reticulum (SER) is site of lipid synthesis and drug metabolism

Nucleolus is site of ribosomal RNA synthesis

Nucleus contains the genes (chromatin) Plasma membrane separates cell

from environment, regulates

movement of materials into and

out of cell

Chloroplast harvests sunlight,

produces ATP and carbohydrates

Thylakoids are site of

light-driven ATP synthesis

Cell wall provides shape and

rigidity; protects cell from

osmotic swelling

Rough endoplasmic reticulum (RER) is site of much protein synthesis

Mitochondrion oxidizes fuels to produce ATP

Nuclear envelope Ribosomes Cytoskeleton

Golgi complex

Starch granule temporarily stores

carbohydrate products of

photosynthesis

Vacuole degrades and recycles macromolecules, stores metabolites

FIGURE 1-7 Eukaryotic cell structure Schematic illustrations of two

major types of eukaryotic cell: (a) a representative animal cell and

(b) a representative plant cell Plant cells are usually .l 0 to .l 00 pm in

diameter-largerthan animal cells, which typically rangefrom 5 to 30 pm

Plasmodesma provides path between two plant cells

Cell wall of adjacent cell

Glyoxysome contains enzJrmes of the glyoxylate cycle

ft) Plant cell Structures labeled in red are unique to either animal or plant cells Eukaryotic microorganisms (such as protists and fungi) have structuressimilar to those in plant and animal cells, but many also contain spe- cialized orsanelles not illustrated here.

called plasmids In nature, some plasmids confer

resis-tance to toxins and antibiotics in the environment In

the laboratory, these DNA segments are especially

amenable to experimental marupulation and are powerful

Most bacteria (including E coli,) exist as individual

myxobac-teria, for example) show simple social behavior, forming

many-celled aggregates

Eukaryotic Cells Have a Variety of Membranous 0rganelles,

Which Can Be lsolated for Study

$pical eukaryotic cells (Fig l-7) are much larger than

bacteria-commonly 5 to 100 pm in diameter, with cell

volumes a thousand to a million times larger than those

eukary-otes are the nucleus and a variety of membrane-enclosedorganelles with speciflc functions: mitochondria, endo-

cytoplasm of many cells are granules or droplets taining stored nutrients such as starch and fat

con-In a major advance in biochemistry, Albert Claude,Christian de Duve, and George Palade developed meth-

each other-an essential step in investigating theirstructures and functions In a typical cell fractionation(Fig 1-8), cells or tissues in solution are gently dis-rupted by physical shear This treatment ruptures theplasma membrane but leaves most of the organelles

FIGURE 1-8 Subcellular fractionation of tissue A tissue such as liver

is first mechanically homogenized to break cells and disperse their contents in an aqueous buffer The sucrose medium has an osmotic pressure similar to that in organelles, thus balancing diffusion of water into and out of the organelles, which would swell and burst in a solu- tion of lower osmolarity (see Fig 2-12) (a) The large and small parti- cles in the suspension can be separated by centrifugation at different speeds, or (b) particles of different density can be separated by isopyc- nic centrifugation In isopycnic centrifugation, a centrifuge tube is filled with a solution, the density of which increases from top to bot- tom; a solute such as sucrose is dissolved at different concentrations to produce the density gradient When a mixture of organelles is layered

on top of the density gradient and the tube is centrifuged at high speed, individual organelles sediment until their buoyant density exactly matches that in the gradient Each layer can be collected separately.

(b) Isopycnic (sucrose-density) centrifugation

Less dense component

f

Centrifugation

f

contalns mlcrosomes (fragments of ER), small vesicles

!i:.: l

Pellet contains ribosomes, large

Pellet | | proteins

More dense component

8 7

Sucrose

intact The homogenate is then centrifuged; organelles

such as nuclei, mitochondria, and lysosomes differ in

size and therefore sediment at different rates

Differential centrifugation results in a rough

frac-tionation of the cytoplasmic contents, which may be

further purified by isopycnic ("same density")

centrifu-gation In this procedure, organelles of different

buoy-ant densities (the result of different ratios of lipid and

protein in each type of organelle) are separated by

cen-trifugation through a column of solvent with graded

density By carefully removing material from each

re-gion of the gradient and observing it with a microscope,

of each organelle and obtain purifled organelles for

chloro-plasts contain photosynthetic pigments The isolation of

an organelle enriched in a certain enzyrne is often the

first step in the purification of that enzyme

The (ytoplasm ls Organized by the (ytoskeleton and ls

Highly Dynamic

filaments crisscrossing the eukaryotic cell, forming

cyto-FIGURE 1 - 9 The three types of cytoskeletal fitaments: actin fitaments,

microtubules, and intermediate filaments Cellular structures can be

labeled with an antibody (that recognizes a characteristic protein)

co-valently attached to a fluorescent compound The stained structures are

visible when the cell is viewed with a fluorescence microscope (a)

En-dothelial cells from the bovine pulmonary artery Bundles of actin

fila-ments called "stress fibers" are stained red; microtubules, radiating

skeleton There are three general types of cytoplasmic

about 6 to 22 run), composition, and specific function

cyto-plasm and shape to the cell Actin fllaments and

of the whole cell

Each type of cytoskeletal component is composed

to form fllaments of uniform thickness These filamentsare not permanent structures; they undergo constant

into filaments Their locations in cells are not rigidlyfixed but may change dramatically with mitosis, cytoki-

flla-ments are regulated by other proteins, which serve toIink or bundle the filaments or to move cltoplasmic

The picture that emerges from this brief survey ofeukaryotic cell structure is of a cell with a meshwork ofstructural flbers and a complex system of membrane-enclosed compartments (Fig 1-7) The fllaments disas-

vesicles bud from one organelle and fuse with another.Organelles move through the cytoplasm along protein

from the cell center, are stained green; and chromosomes (in the cleus) are stained blue (b) A newt lung cell undergoing mitosis Micro- tubules (green), attached to structures called kinetochores (yellow) onthe condensed chromosomes (blue), pull the chromosomes to oppositepoles, or centrosomes (magenta), of the cell Intermediate filaments,made of keratin (red), maintain the structure of the cell.

coo

* l H3N-?-H 9H,

CHO

l

-SH Cysteine

?oo-H3N-?-H

OH

Tyrosine

(b) The componente of nucleic acids

fllaments, their motion powered by energy-dependent

motor proteins The endomembrane system

segre-gates specific metabolic processes and provides

transport (out of and into cells, respectively) that

in-volve membrane fusion and flssion, provide paths

be-tween the cytoplasm and surrounding medium, allowing

uptake of extracellular materials

(a) Some of the amino acids of proteins

1 1 ( e l l u l a r F o u n d a t i o n s I

L - l

Although complex, this organization of the plasm is far from random The motion and positioning of

regulation, and at certain stages in its life, a eukaryotic

reversible, and subject to regulation in response tovarious intracellular and extracellular signals

(ells Build Supramoletular Structures

Macromolecules and their monomeric subunits differ

oxygen-carrying protein of erythrocytes (red blood cells), sists of nearly 600 amino acid subunits in four long chains,

5.5 nm in diameter In turn, proteins are much smaller

FIGURE 1-10 The organic compounds from which most cellular terials are constructed: the ABCs of biochemistry Shown here are (a) six of the 20 amino acids from which all proteins are built (the side chains are shaded pink); (b) the five nitrogenous bases, two five- carbon sugars, and phosphate ion from which all nucleic acids are built; (c) five components of membrane lipids; and (d) o-glucose, the simple sugar from which most carbohydrates are derived Note that phosphate is a component of both nucleic acids and membrane lipids (c) Some components of lipids

?H,OH

CHOH

I

cH2oH Glycerol

j',

cHr 11- at2cH2oHCHs

CHg Oleate

(d) The parent sugar

HHO

H O H a-p-Glucose

NH"

t NAcs

-t i l ozc'-*,.cH

H Cytosine

Level 4:

The cell and ite organelles

FIGURE 1-11 Structural hierarchy in the molecular organization of

cells The nucleus of this plant cell is an organelle containing several

types of supramolecular complexes, including chromatin Chromatin

with the light microscope Figure 1-11 illustrates the

structural hierarchy in cellular organization

are held together by noncovalent interactions-much

weaker, individually, than covalent bonds Among these

noncovalent interactions are hydrogen bonds (between

polar groups), ionic interactions (between charged

groups), hydrophobic interactions (among nonpolar

interac-tions (London forces)-all of which have energies much

smaller than those of covalent bonds These

numbers of weak interactions between macromolecules

producing their unique structures

In Vitro Studies May Overlook lmportant Interactions

among Molecules

tube), without interference from other molecules

pres-ent in the intact cell-that is, in vivo ("in the living')

A1-though this approach has been remarkably revealing, we

must keep in mind that the inside of a cell is quite

differ-ent from the inside of a test tube The "interfering"

com-ponents eliminated by puriflcation may be critical to the

biological function or regulation of the molecule purified

For example, in vitro studies of pure erzyrnes are

com-monly done at very low enzyme concentrations in

thor-oughly stirred aqueous solutions In the cell, an enz).Tne

Level 3: Level 2: Level 1:

Supranolecular Macromoleculee Monomericunitscomplexes

sugars

*W+

consists of two types of macromolecules, DNA and many different proteins, each made up of simple subunits.

thou-sands of other proteins, some of which bind to that z5rme and influence its activity Some enz}nnes arecomponents of multienzyme complexes in which reac-tants are channeled from one enzyrne to another, neverentering the bulk solvent Diffusion is hindered in thegel-like cytosol, and the cytosolic composition variesthroughout the cell In short, a $ven molecule may be-have quite differently in the cell and in vitro A central

biomol-ecules-to understand function in vivo as well as in vitro

S U M M A R Y 1 1 C e l l u l a r F o u n d a t i o n s

have a cytosol containing metabolites, coenzymes,

genes contained within a nucleoid (bacteria and

nucleoid, and plasmids Eukaryotic cells have a

that give cells shape and rigidity and serve as rails

the cell

t3 AI

Za Ge 32 G€

33 Ag

u

ll€ Br 36 Kr

42 Mo 43

Tc Ru

t6

nh 46Pd

t 7 AS 48

cd

l9 In

71 Ir

l 1

TI

, 2 Pb

83 Bi

84 Po 86

noncovalent interactions and form a hierarchy of

When individual molecules are removed from these

important in the living cell may be lost

1.2 Chemical Foundations

had concluded that the composition of living matter is

strikrgly djfferent from that of the inanimate world

An-toine-Laurent Lavoisier (1743-1794) noted the relative

chemical simplicity of the "mineral world" and contrasted

it with the complexity of the "plant and animal worlds"; the

During the flrst half of the twentieth century

yeast and in animal muscle cells revealed remarkable

chemical similarities in these two apparently very

differ-ent cell types; the breakdown of glucose in yeast and

muscle celis nvolved the same 10 chemical

or-ganisms have confirmed the generality of this

observa-tion, neatly summarized in 1954 by Jacques Monod:

cur-rent understanding that all organisms share a common

FIGURE 1-12 Elements essential to animal life and health Bulk elements (shaded orange) arestructural components of cells and tissues and are required in the diet in gram quantities daily For trace elements (shaded bright yellow), the re- quirements are much smaller: for humans, a few milligrams per day of Fe, Cu, and Zn, even less of the others The elemental requirements for plants and microorganisms are similar to those shown here; the ways in which they acquire these ele- ments vary.

uni-versality of chemical intermediates and transformations,

Fewer than 30 of the more than 90 naturally

se-lenium, 34 (FiS l-12) The four most abundant

number of atoms, are hydrogen, oxygen, nitrogen, and

of efflciently forming one, two, three, and four bonds,

repre-sent a miniscule fraction of the weight of the human body,but all are essential to life, usually because they are es-sential to the function of specific proteins, including

depend-ent on four iron ions that make up only 0.3% of its mass

Biomolecules Are Compounds of (arhon with a Variety of Functional Groups

The chemistry of living organisms is organized aroundcarbon, which accounts for more than half the dryweight of cells Carbon can form single bonds with hy-drogen atoms, and both single and double bonds with

sig-nificance in biology is the ability of carbon atoms to form

FIGURE 1-13 Versatility of carbon bonding Carbon can form covalent single, double, and triple bonds (all bonds in red), particularly with other carbon atoms Triple bonds are rare