Table Of ContentHarper's Illustrated Biochemistry, 28e
Robert K. Murray, David A Bender, Kathleen M. Botham , Peter J. Kennelly, Victor W.
Rodwell , P. Anthony Weil
Preface Copyright Authors
Chapter 1
Biochemistry & Medicine
Chapter 2
Water & pH
Section I. Structures & Functions of Proteins & Enzymes
Chapter 3
Amino Acids & Peptides
Chapter 4
Harper's Illustrated Biochemistry, 28e
Robert K. Murray, David A Bender, Kathleen M. Botham , Peter J. Kennelly, Victor W.
Rodwell , P. Anthony Weil
Preface Copyright Authors
Chapter 1
Biochemistry & Medicine
Chapter 2
Water & pH
Section I. Structures & Functions of Proteins & Enzymes
Chapter 3
Amino Acids & Peptides
Chapter 4
Proteins: Determination of Primary Structure
Chapter 5
Proteins: Higher Orders of Structure
Chapter 6
Proteins: Myoglobin & Hemoglobin
Chapter 7
Enzymes: Mechanism of Action
Chapter 8
Enzymes: Kinetics
Chapter 9
Enzymes: Regulation of Activities
Chapter 10
Bioinformatics & Computational Biology
Section II. Bioenergetics & the Metabolism of Carbohydrates & Lipids
Chapter 11
Bioenergetics: The Role of ATP
Chapter 12
Biologic Oxidation
Chapter 13
The Respiratory Chain & Oxidative Phosphorylation
Chapter 14
Carbohydrates of Physiologic Significance
Chapter 15
Lipids of Physiologic Significance
Chapter 16
Overview of Metabolism & the Provision of Metabolic Fuels
Chapter 17
The Citric Acid Cycle: The Catabolism of Acetyl-CoA
Chapter 18
Glycolysis & the Oxidation of Pyruvate
Chapter 19
Metabolism of Glycogen
Chapter 20
Gluconeogenesis & the Control of Blood Glucose
Chapter 21
The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism
Chapter 22
Oxidation of Fatty Acids: Ketogenesis
Chapter 23
Biosynthesis of Fatty Acids & Eicosanoids
Chapter 24
Metabolism of Acylglycerols & Sphingolipids
Chapter 25
Lipid Transport & Storage
Chapter 26
Cholesterol Synthesis, Transport, & Excretion
Section III. Metabolism of Proteins & Amino Acids
Chapter 27
Biosynthesis of the Nutritionally Nonessential Amino Acids
Chapter 28
Catabolism of Proteins & of Amino Acid Nitrogen
Chapter 29
Catabolism of the Carbon Skeletons of Amino Acids
Chapter 30
Conversion of Amino Acids to Specialized Products
Chapter 31
Porphyrins & Bile Pigments
Section IV. Structure, Function, & Replication of Informational
Macromolecules
Chapter 32
Nucleotides
Chapter 33
Metabolism of Purine & Pyrimidine Nucleotides
Chapter 34
Nucleic Acid Structure & Function
Chapter 35
DNA Organization, Replication, & Repair
Chapter 36
RNA Synthesis, Processing, & Modification
Chapter 37
Protein Synthesis & the Genetic Code
Chapter 38
Regulation of Gene Expression
Chapter 39
Molecular Genetics, Recombinant DNA, & Genomic Technology
Section V. Biochemistry of Extracellular & Intracellular Communication
Chapter 40
Membranes: Structure & Function
Chapter 41
The Diversity of the Endocrine System
Chapter 42
Hormone Action & Signal Transduction
Section VI. Special Topics
Chapter 43
Nutrition, Digestion, & Absorption
Chapter 44
Micronutrients: Vitamins & Minerals
Chapter 45
Free Radicals and Antioxidant Nutrients
Chapter 46
Intracellular Traffic & Sorting of Proteins
Chapter 47
Glycoproteins
Chapter 48
The Extracellular Matrix
Chapter 49
Muscle & the Cytoskeleton
Chapter 50
Plasma Proteins & Immunoglobulins
Chapter 51
Hemostasis & Thrombosis
Chapter 52
Red & White Blood Cells
Chapter 53
Metabolism of Xenobiotics
Chapter 54
Biochemical Case Histories
Appendix I
Appendix II
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Copyright Information
Harper's Illustrated Biochemistry, Twenty-Eighth Edition
Copyright © 2009 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in China. Except as permitted under
the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by
any means, or stored in a data base or retrieval system, without the prior written permission of the publisher.
Previous editions copyright © 2006, 2003 by The McGraw-Hill Companies, Inc.; 2000, 1996, 1993, 1990 by Appleton &
Lange; copyright © 1988 by Lange Medical Publications.
ISBN 978-0-07-162591-3
Notice
Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in
treatment and drug therapy are required. The authors and the publisher of this work have checked with sources
believed to be reliable in their efforts to provide information that is complete and generally in accord with the
standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical
sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or
publication of this work warrants that the information contained herein is in every respect accurate or complete, and
they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information
contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For
example and in particular, readers are advised to check the product information sheet included in the package of each
drug they plan to administer to be certain that the information contained in this work is accurate and that changes
have not been made in the recommended dose or in the contraindications for administration. This recommendation is
of particular importance in connection with new or infrequently used drugs.
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Authors
Robert K. Murray, MD, PhD
Professor (Emeritus) of Biochemistry
University of Toronto
Toronto, Ontario
David A. Bender, PhD
Sub-Dean
University College Medical School
Senior Lecturer in Biochemistry
Department of Structural and Molecular Biology and Division of Medical Education
University College London
Kathleen M. Botham, PhD, DSc
Professor of Biochemistry
Royal Veterinary College
University of London
Peter J. Kennelly, PhD
Professor and Head
Department of Biochemistry
Virginia Polytechnic Institute and State University
Blacksburg, Virginia
Victor W. Rodwell, PhD
Emeritus Professor of Biochemistry
Purdue University
West Lafayette, Indiana
P. Anthony Weil, PhD
Professor of Molecular Physiology and Biophysics
Vanderbilt University School of Medicine
Nashville, Tennessee
Co-Authors
Daryl K. Granner, MD
Emeritus Professor of Molecular Physiology and Biophysics and Medicine, Vanderbilt University, Nashville, Tennessee
Peter L. Gross, MD, MSc, FRCP(C)
Associate Professor, Department of Medicine, McMaster University, Hamilton, Ontario
Frederick W. Keeley, PhD
Associate Director and Senior Scientist, Research Institute, Hospital for Sick Children, Toronto, and Professor,
Department of Biochemistry, University of Toronto, Toronto, Ontario
Peter A. Mayes, PhD, DSc
Emeritus Professor of Veterinary Biochemistry, Royal Veterinary College, University of London, London
Margaret L. Rand, PhD
Associate Senior Scientist, Hospital for Sick Children, Toronto, and Professor, Departments of Laboratory Medicine &
Pathobiology and Biochemistry, University of Toronto, Toronto, Ontario
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Preface
The authors and publisher are pleased to present the twentyeighth edition of Harper's Illustrated Biochemistry. This
edition features for the first time multiple color images, many entirely new, that vividly emphasize the ever-increasing
complexity of biochemical knowledge. The cover picture of green fluorescent protein (GFP), which recognizes the
award of the 2008 Nobel Prize in Chemistry to Martin Chalfie, Roger Y. Tsien, and Osamu Shimomura, reflects the
book's emphasis on new developments. Together with its derivatives, GFP fulfills an ever-widening role in tracking
protein movement in intact cells and tissues, and has multiple applications to cell biology, biochemistry and medicine.
In this edition, we bid a regretful farewell to long-time author and editor, Daryl Granner. In 1983, in preparation for
the 20th edition, Daryl was asked to write new chapters on the endocrine system and the molecular mechanism of
hormones, which he did with great success. He assumed responsibility for the chapters on membranes, protein
synthesis and molecular biology in the 21st edition, and wrote a highly informative new chapter on the then emerging
field of recombinant DNA technology. Over the ensuing 25 years, through the 27th edition, Daryl continuously revised
his chapters to provide concise, instructive descriptions of these rapidly changing, complex fields. Daryl's editorial
colleagues express their gratitude for his many invaluable contributions as an author, editor and a friend, and wish him
all the best in his future endeavors.
David Bender, Kathleen Botham, Peter Kennelly, and Anthony Weil, formerly co-authors, are now full authors. Rob
Murray gratefully acknowledges the major contributions of Peter Gross, Fred Keeley, and Margaret Rand to specific
chapters, and thanks Reinhart Reithmeier, Alan Volchuk, and David B. Williams for reviewing and making invaluable
suggestions for the revision of Chapters 40 and 46. In addition, he is grateful to Kasra Haghighat and Mohammad
Rassouli-Rashti for reading and suggesting improvements to Chapter 54.
Changes in the Twenty-Eighth Edition
Consistent with our goal of providing students with a text that describes and illustrates biochemistry in a
comprehensive, concise, and readily accessible manner, the authors have incorporated substantial new material in this
edition. Many new figures and tables have been added. Every chapter has been revised, updated and in several
instances substantially rewritten to incorporate the latest advances in both knowledge and technology of importance to
the understanding and practice of medicine.
Two new chapters have been added. Chapter 45, entitled “Free Radicals and Antioxidant Nutrients,” describes the
sources of free radicals; their damaging effects on DNA, proteins, and lipids; and their roles in causing diseases such
as cancer and atherosclerosis. The role of antioxidants in counteracting their deleterious effects is assessed.
Chapter 54, entitled “Biochemical Case Histories,” provides extensive presentations of 16 pathophysiologic conditions:
adenosine deaminase deficiency, Alzheimer disease, cholera, colorectal cancer, cystic fibrosis, diabetic ketoacidosis,
Duchenne muscular dystrophy, ethanol intoxication, gout, hereditary hemochromatosis, hypothyroidism, kwashiorkor
(and protein-energy malnutrition), myocardial infarction, obesity, osteoporosis, and xeroderma pigmentosum.
Important new features of medical interest include:
Influence of the Human Genome Project on various biomedical fields.
Re-write of the use of enzymes in medical diagnosis.
New material on computer-aided drug discovery.
Compilation of some conformational diseases.
New material on advanced glycation end-products and their importance in diabetes mellitus.
New material on the attachment of influenza virus to human cells.
Some major challenges facing medicine.
The following topics that have been added to various chapters are of basic biochemical interest:
Expanded coverage of mass spectrometry, a key analytical method in contemporary biochemistry.
New figures revealing various aspects of protein structure.
Expanded coverage of active sites of enzymes and transition states.
New information on methods of assaying enzymes.
Expanded coverage of aspects of enzyme kinetics.
New information on micro- and silencing RNAs.
New information on eukaryotic transcription mechanisms, including the biogenesis of mRNA and the role of
nucleosomes.
Description of activities of miRNAs.
New material on Next Generation Sequencing (NGS) platforms.
New material on the Chromatin Immunoprecipitation (CHIP) technology and its uses.
New information on subcellular localization of key signaling enzymes (kinases, phosphatases).
New information on how hormones affect gene transcription.
Every chapter begins with a summary of the biomedical importance of its contents and concludes with a summary
reviewing the major topics covered.
Organization of the Book
Following two introductory chapters (“Biochemistry and Medicine” and “Water and pH”), the text is divided into six
main sections. All sections and chapters emphasize the medical relevance of biochemistry.
Section I addresses the structures and functions of proteins and enzymes. Because almost all of the reactions in cells
are catalyzed by enzymes, it is vital to understand the properties of enzymes before considering other topics. This
section also contains a chapter on bioinformatics and computational biology, reflecting the increasing importance of
these topics in modern biochemistry, biology and medicine.
Section II explains how various cellular reactions either utilize or release energy, and traces the pathways by which
carbohydrates and lipids are synthesized and degraded. Also described are the many functions of these two classes of
molecules.
Section III deals with the amino acids, their many metabolic fates, certain key features of protein catabolism, and the
biochemistry of the porphyrins and bile pigments.
Section IV describes the structures and functions of the nucleotides and nucleic acids, and includes topics such as
DNA replication and repair, RNA synthesis and modification, protein synthesis, the principles of recombinant DNA and
genomic technology, and new understanding of how gene expression is regulated.
Section V deals with aspects of extracellular and intracellular communication. Topics include membrane structure and
function, the molecular bases of the actions of hormones, and the key field of signal transduction.
Section VI discusses twelve special topics: nutrition, digestion and absorption; vitamins and minerals; free radicals
and antioxidants; intracellular trafficking and sorting of proteins; glycoproteins; the extracellular matrix; muscle and
the cytoskeleton; plasma proteins and immunoglobulins; hemostasis and thrombosis; red and white blood cells; the
metabolism of xenobiotics; and 16 biochemically oriented case histories. The latter chapter concludes with a brief
Epilog indicating some major challenges for medicine in whose solution biochemistry and related disciplines will play
key roles.
Appendix I contains a list of laboratory results relevant to the cases discussed in Chapter 54.
Appendix II contains a list of useful web sites and a list of biochemical journals or journals with considerable
biochemical content.
Acknowledgments
The authors thank Michael Weitz for his vital role in the planning and actualization of this edition. It has been a
pleasure to work with him. We are also very grateful to Kim Davis for her highly professional supervising of the editing
of the text, to Sherri Souffrance for supervising its production, to Elise Langdon for its design, and to Margaret
Webster-Shapiro for her work on the cover art. We warmly acknowledge the work of the artists, typesetters, and other
individuals not known to us who participated in the production of the twenty-eighth edition of Harper's Illustrated
Biochemistry. In particular, we are very grateful to Joanne Jay of Newgen North America for her central role in the
management of the entire project and to Joseph Varghese of Thomson Digital for his skilled supervision of the large
amount of art work that was necessary for this edition.
Suggestions from students and colleagues around the world have been most helpful in the formulation of this edition.
We look forward to receiving similar input in the future.
Robert K. Murray, Toronto, Ontario, Canada
David A. Bender, London, UK
Kathleen M. Botham, London, UK
Peter J. Kennelly, Blacksburg, Virginia, USA
Victor W. Rodwell, West Lafayette, Indiana, USA
P. Anthony Weil, Nashville, Tennessee, USA
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Copyright © The McGraw-Hill Companies. All rights reserved.
Harper's Illustrated Biochemistry, 28e > Chapter 1. Biochemistry & Medicine >
BIOCHEMISTRY & MEDICINE: INTRODUCTION
Biochemistry can be defined as the science of the chemical basis of life (Gk bios "life"). The cell is the
structural unit of living systems. Thus, biochemistry can also be described as the science of the chemical
constituents of living cells and of the reactions and processes they undergo. By this definition, biochemistry
encompasses large areas of cell biology, molecular biology, and molecular genetics.
The Aim of Biochemistry Is to Describe & Explain, in Molecular
Terms, All Chemical Processes of Living Cells
The major objective of biochemistry is the complete understanding, at the molecular level, of all of the
chemical processes associated with living cells. To achieve this objective, biochemists have sought to isolate
the numerous molecules found in cells, determine their structures, and analyze how they function. Many
techniques have been used for these purposes; some of them are summarized in Table 1–1.
Table 1–1. The Principal Methods and Preparations Used in Biochemical
Laboratories
Methods for Separating and Purifying Biomolecules1
Salt fractionation (eg, precipitation of proteins with ammonium sulfate)
Chromatography: Paper, ion exchange, affinity, thin-layer, gas–liquid, high-pressure liquid, gel filtration
Electrophoresis: Paper, high-voltage, agarose, cellulose acetate, starch gel, polyacrylamide gel, SDS-
polyacrylamide gel
Ultracentrifugation
Methods for Determining Biomolecular Structures
Elemental analysis
UV, visible, infrared, and NMR spectroscopy
Use of acid or alkaline hydrolysis to degrade the biomolecule under study into its basic constituents
Use of a battery of enzymes of known specificity to degrade the biomolecule under study (eg, proteases,
nucleases, glycosidases)
Mass spectrometry
Specific sequencing methods (eg, for proteins and nucleic acids)
X-ray crystallography
Preparations for Studying Biochemical Processes
Whole animal (includes transgenic animals and animals with gene knockouts)
Isolated perfused organ
Tissue slice
Whole cells
Homogenate
Isolated cell organelles
Subfractionation of organelles
Purified metabolites and enzymes
Isolated genes (including polymerase chain reaction and site-directed mutagenesis)
1Most of these methods are suitable for analyzing the components present in cell homogenates and other
biochemical preparations. The sequential use of several techniques will generally permit purification of most
biomolecules. The reader is referred to texts on methods of biochemical research for details.
A Knowledge of Biochemistry Is Essential to All Life Sciences
The biochemistry of the nucleic acids lies at the heart of genetics; in turn, the use of genetic approaches
has been critical for elucidating many areas of biochemistry. Physiology, the study of body function,
overlaps with biochemistry almost completely. Immunology employs numerous biochemical techniques,
and many immunologic approaches have found wide use by biochemists. Pharmacology and pharmacy
rest on a sound knowledge of biochemistry and physiology; in particular, most drugs are metabolized by
enzyme-catalyzed reactions. Poisons act on biochemical reactions or processes; this is the subject matter of
toxicology. Biochemical approaches are being used increasingly to study basic aspects of pathology (the
study of disease), such as inflammation, cell injury, and cancer. Many workers in microbiology, zoology,
and botany employ biochemical approaches almost exclusively. These relationships are not surprising,
because life as we know it depends on biochemical reactions and processes. In fact, the old barriers among
the life sciences are breaking down, and biochemistry is increasingly becoming their common language.
A Reciprocal Relationship Between Biochemistry & Medicine Has
Stimulated Mutual Advances
The two major concerns for workers in the health sciences—and particularly physicians—are the
understanding and maintenance of health and the understanding and effective treatment of diseases.
Biochemistry impacts enormously on both of these fundamental concerns of medicine. In fact, the
interrelationship of biochemistry and medicine is a wide, two-way street. Biochemical studies have
illuminated many aspects of health and disease, and conversely, the study of various aspects of health and
disease has opened up new areas of biochemistry. Some examples of this two-way street are shown in
Figure 1–1. For instance, knowledge of protein structure and function was necessary to elucidate the single
biochemical difference between normal hemoglobin and sickle cell hemoglobin. On the other hand, analysis
of sickle cell hemoglobin has contributed significantly to our understanding of the structure and function of
both normal hemoglobin and other proteins. Analogous examples of reciprocal benefit between biochemistry
and medicine could be cited for the other paired items shown in Figure 1–1. Another example is the
pioneering work of Archibald Garrod, a physician in England during the early 1900s. He studied patients
with a number of relatively rare disorders (alkaptonuria, albinism, cystinuria, and pentosuria; these are
described in later chapters) and established that these conditions were genetically determined. Garrod
designated these conditions as inborn errors of metabolism. His insights provided a major foundation for
the development of the field of human biochemical genetics. More recent efforts to understand the basis of
the genetic disease known as familial hypercholesterolemia, which results in severe atherosclerosis at
an early age, have led to dramatic progress in understanding of cell receptors and of mechanisms of uptake
of cholesterol into cells. Studies of oncogenes in cancer cells have directed attention to the molecular
mechanisms involved in the control of normal cell growth. These and many other examples emphasize how
the study of disease can open up areas of cell function for basic biochemical research.
Figure 1–1.
Examples of the two-way street connecting biochemistry and medicine. Knowledge of the biochemical molecules
shown in the top part of the diagram has clarified our understanding of the diseases shown on the bottom half—and
conversely, analyses of the diseases shown below have cast light on many areas of biochemistry. Note that sickle
cell anemia is a genetic disease and that both atherosclerosis and diabetes mellitus have genetic components.
The relationship between medicine and biochemistry has important implications for the former. As long as
medical treatment is firmly grounded in the knowledge of biochemistry and other basic sciences, the
practice of medicine will have a rational basis that can be adapted to accommodate new knowledge. This
contrasts with unorthodox health cults and at least some "alternative medicine" practices that are often
founded on little more than myth and wishful thinking and generally lack any intellectual basis.
NORMAL BIOCHEMICAL PROCESSES ARE THE BASIS OF HEALTH
The World Health Organization (WHO) defines health as a state of "complete physical, mental and social
well-being and not merely the absence of disease and infirmity." From a strictly biochemical viewpoint,
health may be considered that situation in which all of the many thousands of intra- and extracellular
reactions that occur in the body are proceeding at rates commensurate with the organism's maximal
survival in the physiologic state. However, this is an extremely reductionist view, and it should be apparent
that caring for the health of patients requires not only a wide knowledge of biologic principles but also of
psychologic and social principles.
