Lehninger Principles of Biochemistry

1336 Pages·2012·79.02 MB·English

by  Albert Lehninger

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Media Connections
Below is a chapter-by-chapter list of the Chapter 5 Protein Function
media resources available on the Molecular Structure Tutorial: Oxygen-Binding
Instructor’s CD-ROM and website Proteins—Myoglobin: Oxygen Storage
www.courses.bfwpub.com/lehninger6e. Living Graphs:
Protein-Ligand Interactions
• Mechanism Animations (12 total) show key
Binding Curve for Myoglobin
reactions in detail.
Molecular Structure Tutorial: Oxygen-Binding
• Technique Animations (10 total) reveal the
Proteins—Hemoglobin: Oxygen Transport
experimental techniques available to
Living Graphs:
researchers today.
Cooperative Ligand Binding
• Living Graphs (15 total) allow students to
Hill Equation
alter the parameters in key equations and
graph the results. Molecular Structure Tutorials:
Oxygen-Binding Proteins—Hemoglobin Is
• Molecular Structure Tutorials (9 total) guide
Susceptible to Allosteric Regulation
students through concepts using three-
dimensional molecular models. Oxygen-Binding Proteins—Defects in Hb Lead
to Serious Genetic Disease
New animations will be added throughout the life
MHC Molecules
of the edition.
Technique Animation: Immunoblotting
Chapter 2 Water
Chapter 6 Enzymes
Living Graph: Henderson-Hasselbalch Equation
Living Graphs:
Chapter 3 Amino Acids, Peptides, and Proteins Michaelis-Menten Equation
Molecular Structure Tutorials: Protein Competitive Inhibitor
Architecture—Amino Acids
Uncompetitive Inhibitor
Technique Animation: SDS Gel Electrophoresis
Mixed Inhibitor
Mechanism Animation: Chymotrypsin
Chapter 4 The Three-Dimensional Structure of Proteins
Mechanism
Molecular Structure Tutorials:
Protein Architecture—Sequence and Primary Living Graph: Lineweaver-Burk Equation
Structure
Protein Architecture—The (cid:2) Helix Chapter 8 Nucleotides and Nucleic Acids
Molecular Structure Tutorial: Nucleotides, Build-
Protein Architecture—The (cid:3) Sheet
ing Blocks of Amino Acids
Protein Architecture—Turn
Technique Animation: Dideoxy Sequencing
Protein Architecture—Introduction to Tertiary of DNA
Structure
Protein Architecture—Tertiary Structure of Chapter 9 DNA-Based Information Technologies
Fibrous Proteins Molecular Structure Tutorial: Restriction
Endonucleases
Protein Architecture—Tertiary Structure of
Small Globular Proteins Technique Animations:
Plasmid Cloning
Protein Architecture—Tertiary Structure of
Large Globular Proteins Reporter Constructs
Protein Architecture—Quaternary Structure Polymerase Chain Reaction
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Synthesizing an Oligonucleotide Array Carbamoyl Phosphate Synthetase I Mechanism
Screening an Oligonucleotide Array for Patterns Argininosuccinate Synthetase Mechanism
of Gene Expression
Chapter 19 Oxidative Phosphorylation and
Yeast Two-Hybrid Systems
Photophosphorylation
Creating a Transgenic Mouse
Living Graph: Free-Energy Change for
Transport of an Ion
Chapter 11 Biological Membranes and Transport
Living Graphs: Molecular Structure Tutorial: Bacteriorhodopsin
Free-Energy Change for Transport
Chapter 20 Carbohydrate Biosynthesis in
Free-Energy Change for Transport of an Ion
Plants and Bacteria
Mechanism Animation: Rubisco Mechanism
Chapter 12 Biosignaling
Molecular Structure Tutorial: Trimeric G Proteins—
Chapter 22 Biosynthesis of Amino Acids, Nucleotides,
Molecular On/Off Switches
and Related Molecules
Mechanism Animations:
Chapter 13 Bioenergetics and Biochemical Reaction Types
Tryptophan Synthase Mechanism
Living Graphs:
Free-Energy Change Thymidylate Synthase Mechanism
Free-Energy of Hydrolysis of ATP
Chapter 24 Genes and Chromosomes
Animation: Three-Dimensional Packaging of
Chapter 14 Glycolysis, Gluconeogenesis, and the Pentose
Nuclear Chromosomes
Phosphate Pathway
Mechanism Animations:
Chapter 25 DNA Metabolism
Phosphohexose Isomerase Mechanism
Molecular Structure Tutorial: Restriction
Alcohol Dehydrogenase Mechanism
Endonucleases
Thiamine Pyrophosphate Mechanism
Animation:
Nucleotide Polymerization by DNA Polymerase
Chapter 16 The Citric Acid Cycle
DNA Synthesis
Mechanism Animation: Citrate Synthase
Mechanism
Chapter 26 RNA Metabolism
Animation: mRNA Splicing
Chapter 17 Fatty Acid Catabolism
Mechanism Animation: Fatty Acyl–CoA Molecular Structure Tutorial: Hammerhead
Synthetase Mechanism Ribozyme
Animation: Life Cycle of an mRNA
Chapter 18 Amino Acid Oxidation and the Production of Urea
Mechanism Animations: Chapter 28 Regulation of Gene Expression
Pyridoxal Phosphate Reaction Mechanism Molecular Structure Tutorial: Lac Repressor
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Lehninger
Principles of Biochemistry
SIXTH EDITION
David L. Nelson Michael M. Cox
Professor of Biochemistry Professor of Biochemistry
University of Wisconsin–Madison University of Wisconsin–Madison
W. H. FREEMAN AND COMPANY • New York
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Publisher: SUSAN WINSLOW
Senior Acquisitions Editor: LAUREN SCHULTZ
Senior Developmental Editor: SUSAN MORAN
Developmental Editor: MATTHEW TONTONOZ
A ssociate Director of Marketing: DEBBIE CLARE
Marketing Director: JOHN BRITCH
Marketing Assistant LINDSAY NEFF
Media Editor: ALLISON MICHAEL
Managing Editor: PHILIP McCAFFREY
Project Editor: JANE O’NEILL
Photo Editor: TED SZCZEPANSKI
Photo Researcher: ELYSE RIEDER
Art Director: DIANA BLUME
Illustration Coordinator: JANICE DONNOLA
Illustrations: H . ADAM STEINBERG
and DRAGONFLY MEDIA GROUP
Molecular Graphics: H. ADAM STEINBERG
Production Manager: SUSAN WEIN
Composition: APTARA, INC.
Printing and binding: QUAD/GRAPHICS VERSAILLES
North American Edition
Cover image: The network of interactions in an animal mitochondrion. Each dot
represents a compound, and each line, an enzyme that interconverts the two com-
pounds. The major nodes include ADP, ATP, NAD(cid:2), and NADH. The image was
constructed with Cytoscape software by Anthony Smith in the laboratory of Alan
Robinson, Medical Research Council Mitochondrial Biology Unit, Cambridge, UK,
using data from MitoMiner (Smith, A.C., Blackshaw, J.A., & Robinson, A.J. (2012)
MitoMiner: a data warehouse for mitochondrial proteomics data. Nucleic Acids
Res. 40, D1160–D1167). Background: Transmission electron micrograph of inter-
scapular brown adipose cell from a bat. (Don W. Fawcett/Science Source/Photo
Researchers)
International Edition
Cover design: Dirk Kaufman
Cover image: Nastco/iStockphoto.com
Library of Congress Control Number: 2012948755
North American Edition International Edition
ISBN-13: 978-1-4292-3414-6 ISBN-13: 978-1-4641-0962-1
ISBN-10: 1-4292-3414-8 ISBN-10: 1-4641-0962-1
©2013, 2008, 2005, 2000 by W. H. Freeman and Company
All rights reserved
Printed in the United States of America
First printing
W. H. Freeman and Company Macmillan Higher Education
41 Madison Avenue Houndmills, Basingstoke
New York, NY 10010 RG21 6XS, England
www.whfreeman.com www.macmillanhighered.com/international
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To Our Teachers
Paul R. Burton
Albert Finholt
William P. Jencks
Eugene P. Kennedy
Homer Knoss
Arthur Kornberg
I. Robert Lehman
Earl K. Nelson
Wesley A. Pearson
David E. Sheppard
Harold B. White
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About the Authors
David L. Nelson
, born in Fairmont, Minnesota, received
his BS in Chemistry and Biology from St. Olaf College
in 1964 and earned his PhD in Biochemistry at Stan-
ford 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 in 1971 and became a
full professor of biochemistry in 1982. He was for eight
years 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 Paramecium. The enzymes of signal
transductions, including a variety of protein kinases,
are primary targets of study. His research group has
David L. Nelson and Michael M. Cox
used enzyme purification, immunological techniques,
electron microscopy, genetics, molecular biology, and
electrophysiology to study these processes.
Dave Nelson has a distinguished record as a lec- particularly on the RecA protein, designing purification
turer and research supervisor. For 40 years he has and assay methods that are still in use, and illuminating
taught an intensive survey of biochemistry for advanced the process of DNA branch migration. Exploration of
biochemistry undergraduates in the life sciences. He the enzymes of genetic recombination has remained the
has also taught a survey of biochemistry for nursing central theme of his research.
students, and graduate courses on membrane struc- Mike Cox has coordinated a large and active research
ture and function and on molecular neurobiology. He team at Wisconsin, investigating the enzymology, topol-
has sponsored numerous PhD, MS, and undergraduate ogy, and energetics of genetic recombination. A primary
honors theses and has received awards for his outstand- focus has been the mechanism of RecA protein–mediated
ing teaching, including the Dreyfus Teacher–Scholar DNA strand exchange, the role of ATP in the RecA sys-
Award, the Atwood Distinguished Professorship, and tem, and the regulation of recombinational DNA repair.
the Unterkofler Excellence in Teaching Award from the Part of the research program now focuses on organisms
University of Wisconsin System. In 1991–1992 he was a that exhibit an especially robust capacity for DNA repair,
visiting professor of chemistry and biology at Spelman such as Deinococcus radiodurans, and the applications
College. His second love is history, and in his dotage he of those repair systems to biotechnology.
has begun to teach the history of biochemistry to under- For almost 30 years he has taught (with Dave
graduates and to collect antique scientific instruments Nelson) the survey of biochemistry to undergraduates
for use in a laboratory course he teaches. and has lectured in graduate courses on DNA structure
and topology, protein-DNA interactions, and the bio-
Michael M. Cox
was born in Wilmington, Delaware. In chemistry of recombination. More recent projects have
his first biochemistry course, Lehninger’s Biochemistry been the organization of a new course on professional
was a major influence in refocusing his fascination with responsibility for first-year graduate students and the
biology and inspiring him to pursue a career in biochem- establishment of a systematic program to draw talented
istry. After graduating from the University of Delaware biochemistry undergraduates into the laboratory at an
in 1974, Cox went to Brandeis University to do his doc- early stage of their collegiate career. He has received
toral work with William P. Jencks, and then to Stanford awards for both his teaching and his research, including
in 1979 for postdoctoral study with I. Robert Lehman. the Dreyfus Teacher–Scholar Award, the 1989 Eli Lilly
He moved to the University of Wisconsin–Madison in Award in Biological Chemistry, and the 2009 Regents
1983 and became a full professor of biochemistry in Teaching Excellence Award from the University of
1992. Wisconsin. He is also highly active in national efforts to
Cox’s doctoral research was on general acid and provide new guidelines for undergraduate biochemistry
base catalysis as a model for enzyme-catalyzed reac- education. His hobbies include turning 18 acres of Wis-
tions. At Stanford, he began work on the enzymes consin farmland into an arboretum, wine collecting, and
involved in genetic recombination. The work focused assisting in the design of laboratory buildings.
iv
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A Note on the Nature of Science
In this twenty-first century, a typical science education ideas that a scientist accepts must be based on measur-
often leaves the philosophical underpinnings of sci- able, reproducible observations, and the scientist must
ence unstated, or relies on oversimplified definitions. As report these observations with complete honesty.
you contemplate a career in science, it may be useful to The scientific method is actually a collection of
consider once again the terms science, scientist, and paths, all of which may lead to scientific discovery. In the
scientific method. hypothesis and experiment path, a scientist poses a
Science is both a way of thinking about the natural hypothesis, then subjects it to experimental test. Many of
world and the sum of the information and theory that the processes that biochemists work with every day were
result from such thinking. The power and success of discovered in this manner. The DNA structure elucidated
science flow directly from its reliance on ideas that can by James Watson and Francis Crick led to the hypothesis
be tested: information on natural phenomena that can that base pairing is the basis for information transfer in
be observed, measured, and reproduced and theories polynucleotide synthesis. This hypothesis helped inspire
that have predictive value. The progress of science rests the discovery of DNA and RNA polymerases.
on a foundational assumption that is often unstated but Watson and Crick produced their DNA structure
crucial to the enterprise: that the laws governing forces through a process of model building and calculation.
and phenomena existing in the universe are not subject No actual experiments were involved, although the model
to change. The Nobel laureate Jacques Monod referred building and calculations used data collected by other
to this underlying assumption as the “postulate of objec- scientists. Many adventurous scientists have applied the
tivity.” The natural world can therefore be understood process of exploration and observation as a path to dis-
by applying a process of inquiry—the scientific method. covery. Historical voyages of discovery (Charles Darwin’s
Science could not succeed in a universe that played 1831 voyage on H.M.S. Beagle among them) helped to
tricks on us. Other than the postulate of objectivity, sci- map the planet, catalog its living occupants, and change
ence makes no inviolate assumptions about the natural the way we view the world. Modern scientists follow
world. A useful scientific idea is one that (1) has been or a similar path when they explore the ocean depths or
can be reproducibly substantiated and (2) can be used launch probes to other planets. An analog of hypothesis
to accurately predict new phenomena. and experiment is hypothesis and deduction. Crick rea-
Scientific ideas take many forms. The terms that sci- soned that there must be an adaptor molecule that facili-
entists use to describe these forms have meanings quite tated translation of the information in messenger RNA
different from those applied by nonscientists. A hypoth- into protein. This adaptor hypothesis led to the discovery
esis is an idea or assumption that provides a reasonable of transfer RNA by Mahlon Hoagland and Paul Zamecnik.
and testable explanation for one or more observations, Not all paths to discovery involve planning. Serendip-
but it may lack extensive experimental substantiation. ity often plays a role. The discovery of penicillin by Alex-
A scientific theory is much more than a hunch. It is ander Fleming in 1928 and of RNA catalysts by Thomas
an idea that has been substantiated to some extent Cech in the early 1980s were both chance discoveries,
and provides an explanation for a body of experimental albeit by scientists well prepared to exploit them. Inspira-
observations. A theory can be tested and built upon and tion can also lead to important advances. The polymerase
is thus a basis for further advance and innovation. When chain reaction (PCR), now a central part of biotechnology,
a scientific theory has been repeatedly tested and vali- was developed by Kary Mullis after a flash of inspiration
dated on many fronts, it can be accepted as a fact. during a road trip in northern California in 1983.
In one important sense, what constitutes science These many paths to scientific discovery can seem
or a scientific idea is defined by whether or not it is quite different, but they have some important things in
published in the scientific literature after peer review by common. They are focused on the natural world. They
other working scientists. About 16,000 peer-reviewed rely on reproducible observation and/or experiment.
scientific journals worldwide publish some 1.4 million All of the ideas, insights, and experimental facts that
articles each year, a continuing rich harvest of informa- arise from these endeavors can be tested and repro-
tion that is the birthright of every human being. duced by scientists anywhere in the world. All can be
Scientists are individuals who rigorously apply used by other scientists to build new hypotheses and
the scientific method to understand the natural world. make new discoveries. All lead to information that is
Merely having an advanced degree in a scientific disci- properly included in the realm of science. Understand-
pline does not make one a scientist, nor does the lack ing our universe requires hard work. At the same time,
of such a degree prevent one from making important no human endeavor is more exciting and potentially
scientific contributions. A scientist must be willing to rewarding than trying, and occasionally succeeding, to
challenge any idea when new findings demand it. The understand some part of the natural world.
v
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Preface
As we complete our work on this sixth edition of to the molecular mechanisms of disease, highlighting the
Lehninger Principles of Biochemistry, we are again special role that biochemistry plays in advancing human
struck by the remarkable changes in the field of biochem- health and welfare. A special theme is the metabolic basis
istry that have occurred between editions. The sheer of diabetes and the factors that predispose to the disease.
volume of new information from high-throughput DNA This theme is interwoven through many chapters and
sequencing, x-ray crystallography, and the manipulation serves to integrate the discussion of metabolism. We also
of genes and gene expression, to cite only three examples, underscore the importance of evolution to biochemistry.
challenges both the seasoned researcher and the first-time Evolutionary theory is the bedrock upon which all biologi-
biochemistry student. Our goal here is to strike a balance: cal sciences rest, and we have not wasted opportunities to
to include new and exciting research findings without highlight its important role in our discipline.
making the book overwhelming for students. The primary To a significant degree, research progress in bio-
criterion for inclusion is that the new finding helps to illus- chemistry runs in parallel with the development of bet-
trate an important principle of biochemistry. ter tools and techniques. We have therefore highlighted
The image on our cover, a map of the known meta- some of these crucial developments. Chapter 9, DNA-
bolic transformations in a mitochondrion, illustrates the Based Information Technologies, in particular, has been
richness of factual material now available about bio- significantly revised to include the latest advances in
chemical transformations. We can no longer treat meta- genomics and next-generation sequencing.
bolic “pathways” as though they occurred in isolation; a Finally, we have devoted considerable attention to
single metabolite may be simultaneously part of many making the text and the art even more useful to stu-
pathways in a three-dimensional network of metabolic dents learning biochemistry for the first time. To those
transformations. Biochemical research focuses more and familiar with the book, some of these changes will be
more upon the interactions among these pathways, the obvious as soon as you crack the cover.
regulation of their interactions at the level of gene and With every revision of this textbook, we have striven
protein, and the effects of regulation upon the activities to maintain the qualities that made the original Lehninger
of a whole cell or organism. text a classic—clear writing, careful explanations of diffi-
This edition of LPOB reflects these realities. Much of cult concepts, and insightful communication to students
the new material that we have added reflects our increas- of the ways in which biochemistry is understood and
ingly sophisticated understanding of regulatory mecha- practiced today. The authors have written together for
nisms, including those involved in altering the synthesis almost 25 years and taught introductory biochemistry
of enzymes and their degradation, those responsible for together for nearly 30. Our thousands of students at the
the control and timing of DNA synthesis and the cell University of Wisconsin–Madison over those years have
cycle, and those that integrate the metabolism of car- been an endless source of ideas about how to present
bohydrates, fats, and proteins over time in response to biochemistry more clearly; they have enlightened and
changes in the environment and in different cell types. inspired us. We hope that this sixth edition of Lehninger
Even as we strive to incorporate the latest major will in turn enlighten and inspire current students of bio-
advances, certain hallmarks of the book remain unchanged. chemistry everywhere, and perhaps lead some of them to
We continue to emphasize the relevance of biochemistry love biochemistry as we do.
New Art (a)Folding intermediate (b)
delivered by Hsp70-ADP
GroES
The most obvious change to the book is the
completely revamped art program. Our goal
7ATP ATP ADP ADP
throughout has been to improve pedagogy, GroEL ATP ATP ATP ATP hydrolysisADP ADP
ATP ATP ATP ATP
ADP ADP
drawing on modern graphic resources to make ADP ADP 7ADP 7Pi
our subject as clear as humanly possible. Many
figures illustrate new topics, and much of the
or
art has been reconceived and modernized in
Slow-folding Native
style. Defining features of the new art program intermediate protein
include:
7Pi 7ADP ADP ADP ADP ADP
u Smarter renditions of classic figures ADP ADP ADP ADP
ADP ADP
are easier to interpret and learn from; ADP ADP ATP ATP ATP ATP ATP
ADP ADP hydrolysis ATP ATP ATP 7
Chaperonins in protein folding GroES Fdoelldivienrge idn tbeyr mHsepd7ia0te-ADP
vi
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Preface vii
1dePgrraodteaitnion 9Excess u Figures that pair molecular models with
yields ketone schematic cartoons, generated specifically for
glucogenic bodies
amino acids. inen udr iunpe. this book, use shapes and color schemes that are
internally consistent;
2 Urea 4 Glucose 8Ketone bodies are 5 Fatty acids
tois tehxep koirdtneedy tiso ethxpe obrrtaeidn bleoxopdosrttreeda mvia t oth tehe ad(iipmopsoer ttiesdsu fero)m are u Figures with numbered, annotated steps help
and excreted via the brain, which uses oxidized as fuel,
in urine. bloodstream. them as fuel. producing acetyl-CoA. explain complex processes; in many cases, we
have moved descriptive text out of the legends
Urea Glucose Ketone bodies and into the figure itself;
Pi Acetoacetyl-CoA Fatty acids
NH3 Glucose u Summary figures help the student to keep the
6-phosphate 7Acetyl-CoA accumulation big picture in mind while learning the specifics.
favors ketone body synthesis.
Amino Phosphoenol- Acetyl-CoA
acids pyruvate
6 Lack of oxaloacetate
3Citric acid cycle prevents acetyl-CoA entry
intermediates into the citric acid cycle;
are diverted to acetyl-CoA accumulates.
gluconeogenesis.
Oxaloacetate Citrate
Fuel metabolism in the liver during prolonged fasting or in uncontrolled
diabetes mellitus
Updated Genomics
(a)
Add blocked, fluorescently Remove labels and
Munoddeerrsnt angdeinnogm oifc bitoecchhenmiqiustersy . hIna vteh ist readnitsifoonr,m weed hoavuer labeleCd nucleotides. bwlalbaosechlke;i ndag dn dgu rcbolleuoopctskid;eeds,. Rbwleaomschko;iv naegd ldga rbboeluolspc ska;endd, Rbleomckoivneg lgarboeulsp sa;nd
dramatically updated our coverage of genomic methods AT CAGT AC CAGT labeled nuCcleotides. CAGT wlabasehle; da dndu cblleooctkideeds,. CAGT
G G C T G C A G C C G C
and their applications. Chapter 9, DNA-Based Informa- T A G T A T T A A T A
tion Technologies, has been completely revised to Thymine nucle3o(cid:2)tideGT 3(cid:2) AGT G CAGT GT CAGT
icnhcaoprtpeorrsa htea vteh bee leant euspt dgaetnedo mtoic r emfleetcht oaddsv.a Mncaensy g aoitnheedr acaodnlddo errd eo;c bfolsuredorervedes.dcent ACT Aacaodndlddeo enrrd eion;c befols urnedourervcedelse.dcoetindteACT Cacodyldtooersd oi;n bfelsu enorurvceelsdec3oe(cid:2)tnidte ACT Guanine nucle3o(cid:2)tidGeACT
from these methods. Among the new genomic methods G G and recorded. G acodldoerd o; bflsueorrveesdcentG
C C C and recorded. C
discussed in this edition are: A A A A
5(cid:2) 5(cid:2) 5(cid:2) 5(cid:2)
u Next-generation DNA sequencing, including the (b)dNTP incorporated
Illumina and 454 sequencing methods and TACGGTCTC:
platforms (Chapter 9) CCCCCCAGT:
u Applications of genomics, including the use of (c)
haplotypes to trace human migrations and
phylogenetics to locate human genes associated
with inherited diseases (Chapter 9)
u Forensic genotyping and the use of personalized
genomics in medicine (Chapter 9) Next-generation reversible terminator sequencing
New Science
(a) (c)
Every chapter has been thoroughly revised and updated
Cyclin A
to include both the most important advances in bio-
chemistry and information needed in a modern bio- N terminus
C terminus
chemistry text. Among the new and updated topics in
Sirtuin
this edition are:
u Prebiotic evolution, black smokers, and the RNA
(b)
world (Chapter 1) 1.0 CBP bromo
domain
u Intrinsically disordered proteins (Chapter 4) DR score0.5
N
u Transition-state analogs and irreversible inhibition PO s100B( b b )
(Chapter 6) 0.00 100 200 300 400
Amino acid residues
u Blood coagulation pathways in the context of Binding of the intrinsically disordered carboxyl terminus of p53
enzymatic regulation (Chapter 6) to its binding partners