Lehninger Principles of Biochemistry, Fourth Edition with CDROM

1125 Pages·2004·34.675 MB·English

by  David L. Nelson, Michael M. Cox

Lehninger Principles of Biochemistry
Fourth Edition
David L. Nelson (U. of Wisconsin–Madison)
Michael M. Cox (U. of Wisconsin–Madison)

1. The Foundations of Biochemistry
1.1 Cellular Foundations
1.2 Chemical Foundations
1.3 Physical Foundations
1.4 Genetic Foundations
1.5 Evolutionary Foundations
Distilled and reorganized from Chapters 1–3 of the previous edition, this overview
provides a refresher on the cellular, chemical, physical, genetic, and evolutionary
background to biochemistry, while orienting students toward what is unique about
biochemistry.

PART I. STRUCTURE AND CATALYSIS
2. Water
2.1 Weak Interactions in Aqueous Systems
2.2 Ionization of Water, Weak Acids, and Weak Bases
2.3 Buffering against pH Changes in Biological Systems
2.4 Water as a Reactant
2.5 The Fitness of the Aqueous Environment for Living Organisms
Includes new coverage of the concept of protein-bound water, illustrated with
molecular graphics.

3. Amino Acids, Peptides, and Proteins
3.1 Amino Acids
3.2 Peptides and Proteins
3.3 Working with Proteins
3.4 The Covalent Structure of Proteins
3.5 Protein Sequences and Evolution

Adds important new material on genomics and proteomics and their implications for
the study of protein structure, function, and evolution.

4. The Three-Dimensional Structure of Proteins
4.1 Overview of Protein Structure
4.2 Protein Secondary Structure
4.3 Protein Tertiary and Quaternary Structures
4.4 Protein Denaturation and Folding
Adds a new box on scurvy.

5. Protein Function
5.1 Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins
5.2 Complementary Interactions between Proteins and Ligands: The Immune
System and Immunoglobulins
5.3 Protein Interactions Modulated by Chemical Energy: Actin, Myosin, and
Molecular Motors
Adds a new box on carbon monoxide poisoning

6. Enzymes
6.1 An Introduction to Enzymes
6.2 How Enzymes Work
6.3 Enzyme Kinetics as An Approach to Understanding Mechanism
6.4 Examples of Enzymatic Reactions
6.5 Regulatory Enzymes
Offers a revised presentation of the mechanism of chymotrypsin (the first reaction
mechanism in the book), featuring a two-page figure that takes students through this
particular mechanism, while serving as a step-by-step guide to interpreting any
reaction mechanism
Features new coverage of the mechanism for lysozyme including the controversial
aspects of the mechanism and currently favored resolution based on work published in
2001.

7. Carbohydrates and Glycobiology
7.1 Monosaccharides and Disaccharides
7.2 Polysaccharides
7.3 Glycoconjugates: Proteoglycans, Glycoproteins, and Glycolipids
7.4 Carbohydrates as Informational Molecules: The Sugar Code
7.5 Working with Carbohydrates
Includes new section on polysaccharide conformations.
A striking new discussion of the "sugar code" looks at polysaccharides as
informational molecules, with detailed discussions of lectins, selectins, and
oligosaccharide-bearing hormones.
Features new material on structural heteropolysaccharides and proteoglycans
Covers recent techniques for carbohydrate analysis.

8. Nucleotides and Nucleic Acids
8.1 Some Basics
8.2 Nucleic Acid Structure
8.3 Nucleic Acid Chemistry
8.4 Other Functions of Nucleotides

9. DNA-Based Information Technologies
9.1 DNA Cloning: The Basics
9.2 From Genes to Genomes
9.3 From Genomes to Proteomes
9.4 Genome Alterations and New Products of Biotechnology
Introduces the human genome. Biochemical insights derived from the human
genome are integrated throughout the text.
Tracking the emergence of genomics and proteomics, this chapter establishes DNA
technology as a core topic and a path to understanding metabolism, signaling, and
other topics covered in the middle chapters of this edition. Includes up-to-date
coverage of microarrays, protein chips, comparative genomics, and techniques in
cloning and analysis.

10. Lipids
10.1 Storage Lipids
10.2 Structural Lipids in Membranes
10.3 Lipids as Signals, Cofactors, and Pigments
10.4 Working with Lipids
Integrates new topics specific to chloroplasts and archaebacteria
Adds material on lipids as signal molecules.

11. Biological Membranes and Transport
11.1 The Composition and Architecture of Membranes
11.2 Membrane Dynamics
11.3 Solute Transport across Membranes
Includes a description of membrane rafts and microdomains within membranes,
and a new box on the use of atomic force microscopy to visualize them.
Looks at the role of caveolins in the formation of membrane caveolae
Covers the investigation of hop diffusion of membrane lipids using FRAP
(fluorescence recovery after photobleaching)
Adds new details to the discussion of the mechanism of Ca2- ATPase (SERCA
pump), revealed by the recently available high-resolution view of its structure
Explores new facets of the mechanisms of the K+ selectivity filter, brought to light
by recent high-resolution structures of the K+ channel
Illuminates the structure, role, and mechanism of aquaporins with important new
details
Describes ABC transporters, with particular attention to the multidrug transporter
(MDR1)
Includes the newly solved structure of the lactose transporter of E. coli.

12. Biosignaling
12.1 Molecular Mechanisms of Signal Transduction
12.2 Gated Ion Channels
12.3 Receptor Enzymes
12.4 G Protein-Coupled Receptors and Second Messengers
12.5 Multivalent Scaffold Proteins and Membrane Rafts
12.6 Signaling in Microorganisms and Plants
12.7 Sensory Transduction in Vision, Olfaction, and Gustation
12.8 Regulation of Transcription by Steroid Hormones
12.9 Regulation of the Cell Cycle by Protein Kinases
12.10 Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death
Updates the previous edition's groundbreaking chapter to chart the continuing rapid
development of signaling research
Includes discussion on general mechanisms for activation of protein kinases in
cascades
Now covers the roles of membrane rafts and caveolae in signaling pathways,
including the activities of AKAPs (A Kinase Anchoring Proteins) and other scaffold
proteins
Examines the nature and conservation of families of multivalent protein binding
modules, which combine to create many discrete signaling pathways
Adds a new discussion of signaling in plants and bacteria, with comparison to
mammalian signaling pathways
Features a new box on visualizing biochemistry with fluorescence resonance energy
transfer (FRET) with green fluorescent protein (GFP)

PART II: BIOENERGETICS AND METABOLISM
13. Principles of Bioenergetics
13.1 Bioenergetics and Thermodynamics
13.2 Phosphoryl Group Transfers and ATP
13.3 Biological Oxidation-Reduction Reactions
Examines the increasing awareness of the multiple roles of polyphosphate
Adds a new discussion of niacin deficiency and pellagra.

14. Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway
14.1 Glycolysis
14.2 Feeder Pathways for Glycolysis
14.3 Fates of Pyruvate under Anaerobic Conditions: Fermentation
14.4 Gluconeogenesis
14.5 Pentose Phosphate Pathway of Glucose Oxidation
Now covers gluconeogenesis immediately after glycolysis, discussing their
relatedness, differences, and coordination and setting up the completely new chapter
on metabolic regulation that follows
Adds coverage of the mechanisms of phosphohexose isomerase and aldolase
Revises the presentation of the mechanism of glyceraldehyde 3-phosphate
dehydrogenase.

New Chapter 15. Principles of Metabolic Regulation, Illustrated with Glucose and
Glycogen Metabolism
15.1 The Metabolism of Glycogen in Animals
15.2 Regulation of Metabolic Pathways
15.3 Coordinated Regulation of Glycolysis and Gluconeogenesis
15.4 Coordinated Regulation of Glycogen Synthesis and Breakdown
15.5 Analysis of Metabolic Control
Brings together the concepts and principles of metabolic regulation in one chapter
Concludes with the latest conceptual approaches to the regulation of metabolism,
including metabolic control analysis and contemporary methods for studying and
predicting the flux through metabolic pathways

16. The Citric Acid Cycle
16.1 Production of Acetyl-CoA (Activated Acetate)
16.2 Reactions of the Citric Acid Cycle
16.3 Regulation of the Citric Acid Cycle
16.4 The Glyoxylate Cycle
Expands and updates the presentation of the mechanism for pyruvate carboxylase.
Adds coverage of the mechanisms of isocitrate dehydrogenase and citrate
synthase.

17. Fatty Acid Catabolism
17.1 Digestion, Mobilization, and Transport of Fats
17.2 Oxidation of Fatty Acids
17.3 Ketone Bodies
Updates coverage of trifunctional protein
New section on the role of perilipin phosphorylation in the control of fat mobilization
New discussion of the role of acetyl-CoA in the integration of fatty acid oxidation
and synthesis
Updates coverage of the medical consequences of genetic defects in fatty acyl–CoA
dehydrogenases
Takes a fresh look at medical issues related to peroxisomes

18. Amino Acid Oxidation and the Production of Urea
18.1 Metabolic Fates of Amino Groups
18.2 Nitrogen Excretion and the Urea Cycle
18.3 Pathways of Amino Acid Degradation
Integrates the latest on regulation of reactions throughout the chapter, with new
material on genetic defects in urea cycle enzymes, and updated information on the
regulatory function of N-acetylglutamate synthase.
Reorganizes coverage of amino acid degradation to focus on the big picture
Adds new material on the relative importance of several degradative pathways
Includes a new description of the interplay of the pyridoxal phosphate and
tetrahydrofolate cofactors in serine and glycine metabolism

19. Oxidative Phosphorylation and Photophosphorylation
Oxidative Phosporylation
19.1 Electron-Transfer Reactions in Mitochondria
19.2 ATP Synthesis
19.3 Regulation of Oxidative Phosphorylation
19.4 Mitochondrial Genes: Their Origin and the Effects of Mutations
19.5 The Role of Mitochondria in Apoptosis and Oxidative Stress
Photosynthesis: Harvesting Light Energy
19.6 General Features of Photophosphorylation
19.7 Light Absorption
19.8 The Central Photochemical Event: Light-Driven Electron Flow
19.9 ATP Synthesis by Photophosphorylation
Adds a prominent new section on the roles of mitochondria in apoptosis and
oxidative stress
Now covers the role of IF1 in the inhibition of ATP synthase during ischemia
Includes revelatory details on the light-dependent pathways of electron transfer in
photosynthesis, based on newly available molecular structures

20. Carbohydrate Biosynthesis in Plants and Bacteria
20.1 Photosynthetic Carbohydrate Synthesis
20.2 Photorespiration and the C and CAM Pathways
4
20.3 Biosynthesis of Starch and Sucrose
20.4 Synthesis of Cell Wall Polysaccharides: Plant Cellulose and Bacterial
Peptidoglycan
20.5 Integration of Carbohydrate Metabolism in the Plant Cell
Reorganizes the coverage of photosynthesis and the C and CAM pathways
4
Adds a major new section on the synthesis of cellulose and bacterial peptidoglycan

21. Lipid Biosynthesis
21.1 Biosynthesis of Fatty Acids and Eicosanoids
21.2 Biosynthesis of Triacylglycerols
21.3 Biosynthesis of Membrane Phospholipids
21.4 Biosynthesis of Cholesterol, Steroids, and Isoprenoids
Features an important new section on glyceroneogenesis and the triacylglycerol
cycle between adipose tissue and liver, including their roles in fatty acid metabolism
(especially during starvation) and the emergence of thiazolidinediones as regulators of
glyceroneogenesis in the treatment of type II diabetes
Includes a timely new discussion on the regulation of cholesterol metabolism at the
genetic level, with consideration of sterol regulatory element-binding proteins
(SREBPs).

22. Biosynthesis of Amino Acids, Nucleotides, and Related Molecules
22.1 Overview of Nitrogen Metabolism
22.2 Biosynthesis of Amino Acids
22.3 Molecules Derived from Amino Acids
22.4 Biosynthesis and Degradation of Nucleotides
Adds material on the regulation of nitrogen metabolism at the level of transcription
Significantly expands coverage of synthesis and degradation of heme

23. Integration and Hormonal Regulation of Mammalian Metabolism
23.1 Tissue-Specific Metabolism: The Division of Labor
23.2 Hormonal Regulation of Fuel Metabolism
23.3 Long Term Regulation of Body Mass
23.4 Hormones: Diverse Structures for Diverse Functions
Reorganized presentation leads students through the complex interactions of
integrated metabolism step by step
Features extensively revised coverage of insulin and glucagon metabolism that
includes the integration of carbohydrate and fat metabolism
New discussion of the role of AMP-dependent protein kinase in metabolic
integration
Updates coverage of the fast-moving field of obesity, regulation of body mass, and
the leptin and adiponectin regulatory systems
Adds a discussion of Ghrelin and PYY3-36 as regulators of short-term eating
behavior
Covers the effects of diet on the regulation of gene expression, considering the role
of peroxisome proliferator-activated receptors (PPARs)

PART III. INFORMATION PATHWAYS
24. Genes and Chromosomes
24.1 Chromosomal Elements
24.2 DNA Supercoiling
24.3 The Structure of Chromosomes
Integrates important new material on the structure of chromosomes, including the
roles of SMC proteins and cohesins, the features of chromosomal DNA, and the
organization of genes in DNA

25. DNA Metabolism
25.1 DNA Replication
25.2 DNA Repair
25.3 DNA Recombination
Adds a section on the "replication factories" of bacterial DNA
Includes latest perspectives on DNA recombination and repair

26. RNA Metabolism
26.1 DNA-Dependent Synthesis of RNA
26.2 RNA Processing
26.3 RNA-Dependent Synthesis of RNA and DNA
Updates coverage on mechanisms of mRNA processing
Adds a subsection on the 5' cap of eukaryotic mRNAs
Adds important new information about the structure of bacterial RNA polymerase
and its mechanism of action.

27. Protein Metabolism
27.1 The Genetic Code
27.2 Protein Synthesis
27.3 Protein Targeting and Degradation
Includes a presentation and analysis of the long-awaited structure of the ribosome-
-one of the most important updates in this new edition
Adds a new box on the evolutionary significance of ribozyme-catalyzed peptide
synthesis.

28. Regulation of Gene Expression
28.1 Principles of Gene Regulation
28.2 Regulation of Gene Expression in Prokaryotes
28.3 Regulation of Gene Expression in Eukaryotes
Adds a new section on RNA interference (RNAi), including the medical potential of
gene silencing.
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1
chapter
THE FOUNDATIONS
OF BIOCHEMISTRY
1.1 Cellular Foundations 3 life arose—simple microorganisms with the ability to ex-
tract energy from organic compounds or from sunlight,
1.2 Chemical Foundations 12
which they used to make a vast array of more complex
1.3 Physical Foundations 21
biomoleculesfrom the simple elements and compounds
1.4 Genetic Foundations 28 on the Earth’s surface.
Biochemistry asks how the remarkable properties
1.5 Evolutionary Foundations 31
of living organisms arise from the thousands of differ-
ent lifeless biomolecules. When these molecules are iso-
With the cell,biology discovered its atom...To lated and examined individually, they conform to all the
characterize life,it was henceforth essential to study the physical and chemical laws that describe the behavior
cell and analyze its structure: to single out the common of inanimate matter—as do all the processes occurring
in living organisms. The study of biochemistry shows
denominators,necessary for the life of every cell;
how the collections of inanimate molecules that consti-
alternatively,to identify differences associated with the
tute living organisms interact to maintain and perpetu-
performance of special functions.
ate life animated solely by the physical and chemical
—François Jacob,La logique du vivant: une histoire de l’hérédité laws that govern the nonliving universe.
(The Logic of Life: A History of Heredity),1970 Yet organisms possess extraordinary attributes,
properties that distinguish them from other collections
We must,however,acknowledge,as it seems to me,that of matter. What are these distinguishing features of liv-
ing organisms?
man with all his noble qualities...still bears in his
bodily frame the indelible stamp of his lowly origin. A high degree of chemical complexity and
—Charles Darwin,The Descent of Man,1871 microscopic organization. Thousands of differ-
ent molecules make up a cell’s intricate internal
structures (Fig. 1–1a). Each has its characteristic
F
ifteen to twenty billion years ago, the universe arose sequence of subunits, its unique three-dimensional
as a cataclysmic eruption of hot, energy-rich sub- structure, and its highly specific selection of
atomic particles. Within seconds, the simplest elements binding partners in the cell.
(hydrogen and helium) were formed. As the universe Systems for extracting, transforming, and
expanded and cooled, material condensed under the in- using energy from the environment (Fig.
fluence of gravity to form stars. Some stars became 1–1b), enabling organisms to build and maintain
enormous and then exploded as supernovae, releasing their intricate structures and to do mechanical,
the energy needed to fuse simpler atomic nuclei into the chemical, osmotic, and electrical work. Inanimate
more complex elements. Thus were produced, over bil- matter tends, rather, to decay toward a more
lions of years, the Earth itself and the chemical elements disordered state, to come to equilibrium with its
found on the Earth today. About four billion years ago, surroundings.
1
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2 Chapter 1 The Foundations of Biochemistry
This is true not only of macroscopic structures,
such as leaves and stems or hearts and lungs, but
also of microscopic intracellular structures and indi-
vidual chemical compounds. The interplay among
the chemical components of a living organism is dy-
namic; changes in one component cause coordinat-
ing or compensating changes in another, with the
whole ensemble displaying a character beyond that
of its individual parts. The collection of molecules
carries out a program, the end result of which is
reproduction of the program and self-perpetuation
(a)
of that collection of molecules—in short, life.
A history of evolutionary change. Organisms
change their inherited life strategies to survive
in new circumstances. The result of eons of
evolution is an enormous diversity of life forms,
superficially very different (Fig. 1–2) but
fundamentally related through their shared ancestry.
Despite these common properties, and the funda-
mental unity of life they reveal, very few generalizations
(b) about living organisms are absolutely correct for every
organism under every condition; there is enormous di-
versity. The range of habitats in which organisms live,
from hot springs to Arctic tundra, from animal intestines
to college dormitories, is matched by a correspondingly
wide range of specific biochemical adaptations, achieved
(c)
FIGURE 1–1 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.
A capacity for precise self-replication and
self-assembly (Fig. 1–1c). A single bacterial cell
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
FIGURE 1–2 Diverse living organisms share common chemical fea-
directed entirely from information contained
tures. Birds, beasts, plants, and soil microorganisms share with hu-
within the genetic material of the original cell.
mans the same basic structural units (cells) and the same kinds of
Mechanisms for sensing and responding to
macromolecules (DNA, RNA, proteins) made up of the same kinds of
alterations in their surroundings, constantly
monomeric subunits (nucleotides, amino acids). They utilize the same
adjusting to these changes by adapting their
pathways for synthesis of cellular components, share the same genetic
internal chemistry.
code, and derive from the same evolutionary ancestors. Shown here
Defined functions for each of their compo- is a detail from “The Garden of Eden,” by Jan van Kessel the Younger
nents and regulated interactions among them. (1626–1679).
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1.1 Cellular Foundations 3
within a common chemical framework. For the sake of Nucleus (eukaryotes)
clarity, in this book we sometimes risk certain general- or nucleoid (bacteria)
Contains genetic material–DNA and
izations, which, though not perfect, remain useful; we
associated proteins. Nucleus is
also frequently point out the exceptions that illuminate membrane-bounded.
scientific generalizations.
Plasma membrane
Biochemistry describes in molecular terms the struc-
Tough, flexible lipid bilayer.
tures, mechanisms, and chemical processes shared by Selectively permeable to
all organisms and provides organizing principles that polar substances. Includes
membrane proteins that
underlie life in all its diverse forms, principles we refer
function in transport,
to collectively as the molecular logic of life. Although in signal reception,
biochemistry provides important insights and practical and as enzymes.
applications in medicine, agriculture, nutrition, and
industry, its ultimate concern is with the wonder of life
itself.
In this introductory chapter, then, we describe
(briefly!) the cellular, chemical, physical (thermody-
namic), and genetic backgrounds to biochemistry and
the overarching principle of evolution—the develop-
ment over generations of the properties of living cells.
Cytoplasm
As you read through the book, you may find it helpful
Aqueous cell contents and
to refer back to this chapter at intervals to refresh your suspended particles
memory of this background material. and organelles.
1.1 Cellular Foundations centrifuge at 150,000 g
The unity and diversity of organisms become apparent Supernatant: cytosol
even at the cellular level. The smallest organisms consist Concentrated solution
of enzymes, RNA,
of single cells and are microscopic. Larger, multicellular
monomeric subunits,
organisms contain many different types of cells, which metabolites,
vary in size, shape, and specialized function. Despite inorganic ions.
these obvious differences, all cells of the simplest and
Pellet: particles and organelles
most complex organisms share certain fundamental
Ribosomes, storage granules,
properties, which can be seen at the biochemical level. mitochondria, chloroplasts, lysosomes,
endoplasmic reticulum.
Cells Are the Structural and Functional Units of All
FIGURE 1–3 The universal features of living cells. All cells have a
Living Organisms
nucleus or nucleoid, a plasma membrane, and cytoplasm. The cytosol
Cells of all kinds share certain structural features (Fig. is defined as that portion of the cytoplasm that remains in the super-
1–3). The plasma membranedefines the periphery of natant after centrifugation of a cell extract at 150,000 g for 1 hour.
the cell, separating its contents from the surroundings.
It is composed of lipid and protein molecules that form The internal volume bounded by the plasma mem-
a thin, tough, pliable, hydrophobic barrier around the brane, the cytoplasm (Fig. 1–3), is composed of an
cell. The membrane is a barrier to the free passage of aqueous solution, the cytosol, and a variety of sus-
inorganic ions and most other charged or polar com- pended particles with specific functions. The cytosol is
pounds. Transport proteins in the plasma membrane al- a highly concentrated solution containing enzymes and
low the passage of certain ions and molecules; receptor the RNA molecules that encode them; the components
proteins transmit signals into the cell; and membrane (amino acids and nucleotides) from which these macro-
enzymes participate in some reaction pathways. Be- molecules are assembled; hundreds of small organic
cause the individual lipids and proteins of the plasma molecules called metabolites,intermediates in biosyn-
membrane are not covalently linked, the entire struc- thetic and degradative pathways; coenzymes, com-
ture is remarkably flexible, allowing changes in the pounds essential to many enzyme-catalyzed reactions;
shape and size of the cell. As a cell grows, newly made inorganic ions; and ribosomes, small particles (com-
lipid and protein molecules are inserted into its plasma posed of protein and RNA molecules) that are the sites
membrane; cell division produces two cells, each with its of protein synthesis.
own membrane. This growth and cell division (fission) All cells have, for at least some part of their life, ei-
occurs without loss of membrane integrity. ther a nucleus or a nucleoid, in which the genome—