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Coauthors
Peter L. Gross, MD, MSc, FRCP(C)

Associate Professor
Department of Medicine
McMaster University
Hamilton, Ontario, Canada
Molly Jacob MD, PhD

Professor and Head
Department of Biochemistry
Christian Medical College
Bagayam, Vellore, Tamil Nadu, India
Peter A. Mayes, PhD, DSc

Professor (Emeritus) of Veterinary Biochemistry
Royal Veterinary College
University of London
London, United Kingdom
Robert K. Murray, MD, PhD

Professor (Emeritus) of Biochemistry
University of Toronto
Toronto, Ontario, Canada
Margaret L. Rand, PhD

Senior Associate Scientist
Division of Haematology/Oncology
Hospital for Sick Children, Toronto, and Professor
7
University of Toronto, Toronto, Canada
Joe Varghese, PhD

Professor
Christian Medical College
Bagayam, Vellore, Tamil Nadu, India
8
Contents
Preface
SECTION
Structures & Functions of Proteins &
I Enzymes
1 Biochemistry & Medicine

Victor W. Rodwell, PhD, & Robert K. Murray, MD, PhD
2 Water & pH
Peter J. Kennelly, PhD & Victor W. Rodwell, PhD
3 Amino Acids & Peptides

4 Proteins: Determination of Primary Structure

5 Proteins: Higher Orders of Structure

SECTION
Enzymes: Kinetics, Mechanism,
9
Regulation, & Role of Transition Metals
II
6 Proteins: Myoglobin & Hemoglobin
7 Enzymes: Mechanism of Action

8 Enzymes: Kinetics
Victor W. Rodwell, PhD
9 Enzymes: Regulation of Activities

10 The Biochemical Roles of Transition Metals

Peter J. Kennelly, PhD
SECTION
Bioenergetics
III
11 Bioenergetics: The Role of ATP
Kathleen M. Botham, PhD, DSc & Peter A. Mayes, PhD, DSc
12 Biologic Oxidation
13 The Respiratory Chain & Oxidative Phosphorylation

SECTION
10
Metabolism of Carbohydrates
IV
14 Overview of Metabolism & the Provision of Metabolic Fuels
David A. Bender, PhD & Peter A. Mayes, PhD, DSc
15 Carbohydrates of Physiological Significance

16 The Citric Acid Cycle: The Central Pathway of Carbohydrate,

Lipid, & Amino Acid Metabolism
17 Glycolysis & the Oxidation of Pyruvate

18 Metabolism of Glycogen
19 Gluconeogenesis & the Control of Blood Glucose

20 The Pentose Phosphate Pathway & Other Pathways of Hexose

Metabolism
SECTION
Metabolism of Lipids
V
21 Lipids of Physiologic Significance
11
22 Oxidation of Fatty Acids: Ketogenesis
23 Biosynthesis of Fatty Acids & Eicosanoids

24 Metabolism of Acylglycerols & Sphingolipids

25 Lipid Transport & Storage

26 Cholesterol Synthesis, Transport, & Excretion

SECTION
Metabolism of Proteins & Amino Acids
VI
27 Biosynthesis of the Nutritionally Nonessential Amino Acids
28 Catabolism of Proteins & of Amino Acid Nitrogen

29 Catabolism of the Carbon Skeletons of Amino Acids

30 Conversion of Amino Acids to Specialized Products

31 Porphyrins & Bile Pigments

Victor W. Rodwell, PhD & Robert K. Murray, MD, PhD
12
SECTION
Structure, Function, & Replication of
VII Informational Macromolecules
32 Nucleotides
33 Metabolism of Purine & Pyrimidine Nucleotides

34 Nucleic Acid Structure & Function

P. Anthony Weil, PhD
35 DNA Organization, Replication, & Repair

36 RNA Synthesis, Processing, & Modification

37 Protein Synthesis & the Genetic Code

38 Regulation of Gene Expression

39 Molecular Genetics, Recombinant DNA, & Genomic

Technology
SECTION
Biochemistry of Extracellular &
VIII Intracellular Communication
13
40 Membranes: Structure & Function
41 The Diversity of the Endocrine System

42 Hormone Action & Signal Transduction

SECTION
Special Topics (A)
IX
43 Nutrition, Digestion, & Absorption
44 Micronutrients: Vitamins & Minerals

David A. Bender, PhD
45 Free Radicals & Antioxidant Nutrients

46 Glycoproteins
David A. Bender, PhD & Robert K. Murray, MD, PhD
47 Metabolism of Xenobiotics
48 Clinical Biochemistry
SECTION
14
Special Topics (B)
X
49 Intracellular Traffic & Sorting of Proteins
Kathleen M. Botham, PhD, DSc & Robert K. Murray, MD, PhD
50 The Extracellular Matrix

Kathleen M. Botham, PhD, DSc & Robert K. Murray, MD, PhD
51 Muscle & the Cytoskeleton

Peter J. Kennelly, PhD and Robert K. Murray, MD, PhD
52 Plasma Proteins & Immunoglobulins

Peter J. Kennelly, PhD, Robert K. Murray, MD, PhD, Molly Jacob,
MBBS, MD, PhD & Joe Varghese, MBBS, MD
53 Red Blood Cells

Peter J. Kennelly, PhD & Robert K. Murray, MD, PhD
54 White Blood Cells

Peter J. Kennelly, PhD & Robert K. Murray, MD, PhD
SECTION
Special Topics (C)
XI
55 Hemostasis & Thrombosis
Peter L. Gross, MD, MSc, FRCP(C), P. Anthony Weil, PhD &
Margaret L. Rand, PhD
56 Cancer: An Overview
Molly Jacob, MD, PhD, Joe Varghese, PhD & P. Anthony Weil, PhD
15
57 The Biochemistry of Aging
Peter J. Kennelly, PhD
58 Biochemical Case Histories

The Answer Bank

Index
16
Preface
The authors and publishers are pleased to present the thirty-first edition of
Harper’s Illustrated Biochemistry. The first edition, entitled Harper’s
Biochemistry, was published in 1939 under the sole authorship of Dr
Harold Harper at the University of California School of Medicine, San
Francisco, California. Presently entitled Harper’s Illustrated Biochemistry,
the book continues, as originally intended, to provide a concise survey of
aspects of biochemistry most relevant to the study of medicine. Various
authors have contributed to subsequent editions of this medically oriented
biochemistry text, which is now observing its 79th year.
Cover Illustration for the Thirty-first Edition

The illustration on the cover of the thirty-first edition, the structure of Zika
virus protein determined at 3.8 Å resolution, was generously prepared and
provided by Lei Sun. The supporting data appeared in: Sirohi D, Chen Z,
Sun L, Klose T, Pierson TC, Rossmann MG, Kuhn RJ: “The 3.8 Å
resolution cryo-EM structure of Zika virus protein”, Science
2016;352:497-470. Together with the Zika virus, first recovered in the
Zika valley of Uganda, the viruses responsible for yellow fever, West Nile
fever, and dengue fever are members of the Flavivridae family of positive-
strand DNA viruses. The cover illustration indicates the resolving power
of cryo-electron microscopy (cryo-EM). More importantly, it recognizes
the medical significance of infection by the Zika virus, which in pregnant
women can result in a significant risk of congenital microcephaly and
associated severe mental impairment. While Zika virus typically is
transmitted by the bite of an infected mosquito, emerging evidence
suggests that under certain conditions the Zika virus may also be
transmitted between human subjects.
Changes in the Thirty-first Edition

17
As always, Harper’s Illustrated Biochemistry continues to emphasize the
close relationship of biochemistry to the understanding of diseases, their
pathology and the practice of medicine. The contents of most chapters
have been updated and provide to the reader the most current and pertinent
information. Toward that end, we have replaced Chapter 10
“Bioinformatics and Computational Biology,” most of whose programs
and topics (for example protein and nucleotide sequence comparisons and
in silico approaches in drug design) are available on line or are now
common knowledge. Its replacement, new Chapter 10 “Biochemistry of
Transition Metals,” incorporates material from several chapters, notably
those of blood cells and plasma, which contained extensive content on
metal ion adsorption and trafficking, especially of iron and copper. Since
approximately a third of all proteins are metalloproteins, new Chapter 10
explicitly addresses the importance and overall pervasiveness of transition
metals. Given the overlap with the topics of protein structure and of
enzyme reaction mechanisms, new Chapter 10 now follows the three
chapters on enzymes as the final chapter in Section II, now renamed
Enzymes: Kinetics, Mechanism, Regulation, & Role of Transition Metals.
Organization of the Book

All 58 chapters of the thirty-first edition place major emphasis on the
medical relevance of biochemistry. Topics are organized under eleven
major headings. Both to assist study and to facilitate retention of the
contained information, Questions follow each Section. An Answer Bank
follows the Appendix.
Section I includes a brief history of biochemistry, and emphasizes the
interrelationships between biochemistry and medicine. Water, the
importance of homeostasis of intracellular pH are reviewed, and the
various orders of protein structure are addressed.
Section II begins with a chapter on hemoglobin. Four chapters next
address the kinetics, mechanism of action, and metabolic regulation of
enzymes, and the role of metal ions in multiple aspects of intermediary
metabolism.
Section III addresses bioenergetics and the role of high energy
phosphates in energy capture and transfer, the oxidation–reduction
reactions involved in biologic oxidation, and metabolic details of
energy capture via the respiratory chain and oxidative phosphorylation.
Section IV considers the metabolism of carbohydrates via glycolysis,
the citric acid cycle, the pentose phosphate pathway, glycogen
18
metabolism, gluconeogenesis, and the control of blood glucose.
Section V outlines the nature of simple and complex lipids, lipid
transport and storage, the biosynthesis and degradation of fatty acids
and more complex lipids, and the reactions and metabolic regulation of
cholesterol biosynthesis and transport in human subjects.
Section VI discusses protein catabolism, urea biosynthesis, and the
catabolism of amino acids and stresses the medically significant
metabolic disorders associated with their incomplete catabolism. The
final chapter considers the biochemistry of the porphyrins and bile
pigments.
Section VII first outlines the structure and function of nucleotides and
nucleic acids, then details DNA replication and repair, RNA synthesis
and modification, protein synthesis, the principles of recombinant DNA
technology, and the regulation of gene expression.
Section VIII considers aspects of extracellular and intracellular
communication. Specific topics include membrane structure and
function, the molecular bases of the actions of hormones, and signal
transduction.
Sections IX, X, & XI address fourteen topics of significant medical
importance.
Section IX discusses nutrition, digestion, and absorption,
micronutrients including vitamins free radicals and antioxidants,
glycoproteins, the metabolism of xenobiotics, and clinical
biochemistry.
Section X addresses intracellular traffic and the sorting of proteins, the
extracellular matrix, muscle and the cytoskeleton, plasma proteins and
immunoglobulins, and the biochemistry of red cells and of white cells.
Section XI includes hemostasis and thrombosis, an overview of cancer,
the biochemistry of aging, and a selection of case histories.
Acknowledgments
The authors thank Michael Weitz for his role in the planning of this edition
and Peter Boyle for overseeing its preparation for publication. We also
thank Surbhi Mittal and Jyoti Shaw at Cenveo Publisher Services for their
efforts in managing editing, typesetting, and artwork. We gratefully
acknowledge numerous suggestions and corrections received from
students and colleagues from around the world, especially those of Dr.
Karthikeyan Pethusamy of the All India Institute of Medical Sciences,
New Delhi, India.
19
Victor W. Rodwell
David A. Bender
Kathleen M. Botham
Peter J. Kennelly
P. Anthony Weil
20
SECTION
Structures & Functions of
I Proteins & Enzymes
CHAPTER
1
Biochemistry & Medicine
Victor W. Rodwell, PhD, & Robert K. Murray, MD, PhD
OBJECTIVES
After studying this chapter, you should be able to:
Understand the importance of the ability of cell-free extracts of

yeast to ferment sugars, an observation that enabled discovery of
the intermediates of fermentation, glycolysis, and other metabolic
pathways.
Appreciate the scope of biochemistry and its central role in the life
sciences, and that biochemistry and medicine are intimately
related disciplines.
Appreciate that biochemistry integrates knowledge of the chemical
processes in living cells with strategies to maintain health,
21
understand disease, identify potential therapies, and enhance our
understanding of the origins of life on earth.
Describe how genetic approaches have been critical for elucidating
many areas of biochemistry, and how the Human Genome Project
has furthered advances in numerous aspects of biology and
medicine.
BIOMEDICAL IMPORTANCE
Biochemistry and medicine enjoy a mutually cooperative relationship.
Biochemical studies have illuminated many aspects of health and disease,
and the study of various aspects of health and disease has opened up new
areas of biochemistry. The medical relevance of biochemistry both in
normal and abnormal situations is emphasized throughout this book.
Biochemistry makes significant contributions to the fields of cell biology,
physiology, immunology, microbiology, pharmacology, toxicology, and
epidemiology, as well as the fields of inflammation, cell injury, and
cancer. These close relationships emphasize that life, as we know it,
depends on biochemical reactions and processes.
DISCOVERY THAT A CELL-FREE EXTRACT OF

YEAST CAN FERMENT SUGAR
Although the ability of yeast to “ferment” various sugars to ethyl alcohol
has been known for millennia, only comparatively recently did this process
initiate the science of biochemistry. The great French microbiologist Louis
Pasteur maintained that fermentation could only occur in intact cells.
However, in 1899, the brothers Büchner discovered that fermentation
could occur in the absence of intact cells when they stored a yeast extract
in a crock of concentrated sugar solution, added as a preservative.
Overnight, the contents of the crock fermented, spilled over the laboratory
bench and floor, and dramatically demonstrated that fermentation can
proceed in the absence of an intact cell. This discovery unleashed an
avalanche of research that initiated the science of biochemistry.
Investigations revealed the vital roles of inorganic phosphate, ADP, ATP,
and NAD(H), and ultimately identified the phosphorylated sugars and the
chemical reactions and enzymes that convert glucose to pyruvate
(glycolysis) or to ethanol and CO2 (fermentation). Research beginning in
the 1930s identified the intermediates of the citric acid cycle and of urea
22
biosynthesis, and revealed the essential roles of certain vitamin-derived
cofactors or “coenzymes” such as thiamin pyrophosphate, riboflavin, and
ultimately coenzyme A, coenzyme Q, and cobamide coenzyme. The 1950s
revealed how complex carbohydrates are synthesized from, and broken
down into simple sugars, and the pathways for biosynthesis of pentoses,
and the catabolism of amino acids and fatty acids.
Investigators employed animal models, perfused intact organs, tissue
slices, cell homogenates and their subfractions, and subsequently purified
enzymes. Advances were enhanced by the development of analytical
ultracentrifugation, paper and other forms of chromatography, and the
post-World War II availability of radioisotopes, principally 14C, 3H, and
32P, as “tracers” to identify the intermediates in complex pathways such as
that of cholesterol biosynthesis. X-ray crystallography was then used to
solve the three-dimensional structures of numerous proteins,
polynucleotides, enzymes, and viruses. Genetic advances that followed the
realization that DNA was a double helix include the polymerase chain
reaction, and transgenic animals or those with gene knockouts. The
methods used to prepare, analyze, purify, and identify metabolites and the
activities of natural and recombinant enzymes and their three-dimensional
structures are discussed in the following chapters.
BIOCHEMISTRY & MEDICINE HAVE

PROVIDED MUTUAL ADVANCES
The two major concerns for workers in the health sciences—and
particularly physicians—are the understanding and maintenance of health
and effective treatment of disease. Biochemistry impacts both of these
fundamental concerns, and 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
(Figure 1–1). An early example of how investigation of protein structure
and function revealed the single difference in amino acid sequence
between normal hemoglobin and sickle cell hemoglobin. Subsequent
analysis of numerous variant sickle cell and other hemoglobins has
contributed significantly to our understanding of the structure and function
both of hemoglobin and of other proteins. During the early 1900s the
English physician Archibald Garrod studied patients with the relatively
rare disorders of alkaptonuria, albinism, cystinuria, and pentosuria, and
23
established that these conditions were genetically determined. Garrod
designated these conditions as inborn errors of metabolism. His insights
provided a foundation for the development of the field of human
biochemical genetics. A more recent example was investigation of the
genetic and molecular basis of familial hypercholesterolemia, a disease
that results in early-onset atherosclerosis. In addition to clarifying different
genetic mutations responsible for this disease, this provided a deeper
understanding of cell receptors and mechanisms of uptake, not only of
cholesterol but also of how other molecules cross cell membranes. Studies
of oncogenes and tumor suppressor genes in cancer cells have directed
attention to the molecular mechanisms involved in the control of normal
cell growth. These examples illustrate how the study of disease can open
up areas of basic biochemical research. Science provides physicians and
other workers in health care and biology with a foundation that impacts
practice, stimulates curiosity, and promotes the adoption of scientific
approaches for continued learning.
FIGURE 1–1 A two-way street connects biochemistry and medicine.

Knowledge of the biochemical topics listed above the green line of the
diagram has clarified our understanding of the diseases shown below the
green line. Conversely, analyses of the diseases 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.
BIOCHEMICAL PROCESSES UNDERLIE

HUMAN HEALTH
Biochemical Research Impacts Nutrition &
Preventive Medicine
24
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 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 survival under pressure from both
internal and external challenges. The maintenance of health requires
optimal dietary intake of vitamins, certain amino acids and fatty acids,
various minerals, and water. Understanding nutrition depends to a great
extent on knowledge of biochemistry, and the sciences of biochemistry
and nutrition share a focus on these chemicals. Recent increasing emphasis
on systematic attempts to maintain health and forestall disease, or
preventive medicine, includes nutritional approaches to the prevention of
diseases such as atherosclerosis and cancer.
Most Diseases Have a Biochemical Basis

Apart from infectious organisms and environmental pollutants, many
diseases are manifestations of abnormalities in genes, proteins, chemical
reactions, or biochemical processes, each of which can adversely affect
one or more critical biochemical functions. Examples of disturbances in
human biochemistry responsible for diseases or other debilitating
conditions include electrolyte imbalance, defective nutrient ingestion or
absorption, hormonal imbalances, toxic chemicals or biologic agents, and
DNA-based genetic disorders. To address these challenges, biochemical
research continues to be interwoven with studies in disciplines such as
genetics, cell biology, immunology, nutrition, pathology, and
pharmacology. In addition, many biochemists are vitally interested in
contributing to solutions to key issues such as the ultimate survival of
mankind, and educating the public to support use of the scientific method
in solving environmental and other major problems that confront our
civilization.
Impact of the Human Genome Project on

Biochemistry, Biology, & Medicine
Initially unanticipated rapid progress in the late 1990s in sequencing the
human genome led in the mid-2000s to the announcement that over 90%
of the genome had been sequenced. This effort was headed by the
International Human Genome Sequencing Consortium and by Celera
25
Genomics. Except for a few gaps, the sequence of the entire human
genome was completed in 2003, just 50 years after the description of the
double-helical nature of DNA by Watson and Crick. The implications for
biochemistry, medicine, and indeed for all of biology, are virtually
unlimited. For example, the ability to isolate and sequence a gene and to
investigate its structure and function by sequencing and “gene knockout”
experiments have revealed previously unknown genes and their products,
and new insights have been gained concerning human evolution and
procedures for identifying disease-related genes.
Major advances in biochemistry and understanding human health and
disease continue to be made by mutation of the genomes of model
organisms such as yeast, the fruit fly Drosophila melanogaster, the
roundworm Caenorhabditis elegans, and the zebra fish, all organisms that
can be genetically manipulated to provide insight into the functions of
individual genes. These advances can potentially provide clues to curing
human diseases such as cancer and Alzheimer disease. Figure 1–2
highlights areas that have developed or accelerated as a direct result of
progress made in the Human Genome Project (HGP). New “-omics” fields
focus on comprehensive study of the structures and functions of the
molecules with which each is concerned. The products of genes (RNA
molecules and proteins) are being studied using the techniques of
transcriptomics and proteomics. A spectacular example of the speed of
progress in transcriptomics is the explosion of knowledge about small
RNA molecules as regulators of gene activity. Other -omics fields include
glycomics, lipidomics, metabolomics, nutrigenomics, and
pharmacogenomics. To keep pace with the information generated,
bioinformatics has received much attention. Other related fields to which
the impetus from the HGP has carried over are biotechnology,
bioengineering, biophysics, and bioethics. Definitions of these -omics
fields and other terms appear in the Glossary of this chapter.
Nanotechnology is an active area, which, for example, may provide novel
methods of diagnosis and treatment for cancer and other disorders. Stem
cell biology is at the center of much current research. Gene therapy has
yet to deliver the promise that it appears to offer, but it seems probable that
ultimately will occur. Many new molecular diagnostic tests have
developed in areas such as genetic, microbiologic, and immunologic
testing and diagnosis. Systems biology is also burgeoning. The outcomes
of research in the various areas mentioned above will impact tremendously
the future of biology, medicine, and the health sciences. Synthetic biology
offers the potential for creating living organisms, initially small bacteria,
26
from genetic material in vitro that might carry out specific tasks such as
cleansing petroleum spills. All of the above make the 21st century an
exhilarating time to be directly involved in biology and medicine.
FIGURE 1–2 The Human Genome Project (HGP) has influenced

many disciplines and areas of research. Biochemistry is not listed since
it predates commencement of the HGP, but disciplines such as
bioinformatics, genomics, glycomics, lipidomics, metabolomics, molecular
diagnostics, proteomics, and transcriptomics are nevertheless active areas
of biochemical research.
SUMMARY
Biochemistry is the science concerned with the molecules present in
living organisms, individual chemical reactions and their enzyme
catalysts, and the expression and regulation of each metabolic process.
Biochemistry has become the basic language of all biologic sciences.
Despite the focus on human biochemistry in this text, biochemistry
concerns the entire spectrum of life forms, from viruses, bacteria, and
plants to complex eukaryotes such as human beings.
Biochemistry, medicine, and other health care disciplines are
intimately related. Health in all species depends on a harmonious
balance of the biochemical reactions occurring in the body, while
disease reflects abnormalities in biomolecules, biochemical reactions,
27
or biochemical processes.
Advances in biochemical knowledge have illuminated many areas of
medicine, and the study of diseases has often revealed previously
unsuspected aspects of biochemistry.
Biochemical approaches are often fundamental in illuminating the
causes of diseases and in designing appropriate therapy. Biochemical
laboratory tests also represent an integral component of diagnosis and
monitoring of treatment.
A sound knowledge of biochemistry and of other related basic
disciplines is essential for the rational practice of medicine and related
health sciences.
Results of the HGP and of research in related areas will have a
profound influence on the future of biology, medicine, and other
health sciences.
Genomic research on model organisms such as yeast, the fruit fly D.
melanogaster, the roundworm C. elegans, and the zebra fish provides
insight into understanding human diseases.
GLOSSARY
Bioengineering: The application of engineering to biology and medicine.
Bioethics: The area of ethics that is concerned with the application of
moral and ethical principles to biology and medicine.
Bioinformatics: The discipline concerned with the collection, storage, and
analysis of biologic data, for example, DNA, RNA, and protein
sequences.
Biophysics: The application of physics and its techniques to biology and
medicine.
Biotechnology: The field in which biochemical, engineering, and other
approaches are combined to develop biologic products of use in
medicine and industry.
Gene Therapy: Applies to the use of genetically engineered genes to treat
various diseases.
Genomics: The genome is the complete set of genes of an organism, and
genomics is the in-depth study of the structures and functions of
genomes.
Glycomics: The glycome is the total complement of simple and complex
carbohydrates in an organism. Glycomics is the systematic study of the
structures and functions of glycomes such as the human glycome.
28
Lipidomics: The lipidome is the complete complement of lipids found in
an organism. Lipidomics is the in-depth study of the structures and
functions of all members of the lipidome and their interactions, in both
health and disease.
Metabolomics: The metabolome is the complete complement of
metabolites (small molecules involved in metabolism) present in an
organism. Metabolomics is the in-depth study of their structures,
functions, and changes in various metabolic states.
Molecular Diagnostics: Refers to the use of molecular approaches such as
DNA probes to assist in the diagnosis of various biochemical, genetic,
immunologic, microbiologic, and other medical conditions.
Nanotechnology: The development and application to medicine and to
other areas of devices such as nanoshells, which are only a few
nanometers in size (10–9 m = 1 nm).
Nutrigenomics: The systematic study of the effects of nutrients on genetic
expression and of the effects of genetic variations on the metabolism of
nutrients.
Pharmacogenomics: The use of genomic information and technologies to
optimize the discovery and development of new drugs and drug targets.
Proteomics: The proteome is the complete complement of proteins of an
organism. Proteomics is the systematic study of the structures and
functions of proteomes and their variations in health and disease.
Stem Cell Biology: Stem cells are undifferentiated cells that have the
potential to self-renew and to differentiate into any of the adult cells of
an organism. Stem cell biology concerns the biology of stem cells and
their potential for treating various diseases.
Synthetic Biology: The field that combines biomolecular techniques with
engineering approaches to build new biologic functions and systems.
Systems Biology: The field concerns complex biologic systems studied as
integrated entities.
Transcriptomics: The comprehensive study of the transcriptome, the
complete set of RNA transcripts produced by the genome during a
fixed period of time.
APPENDIX
Shown are selected examples of databases that assemble, annotate, and
analyze data of biomedical importance.
ENCODE: ENCyclopedia Of DNA Elements. A collaborative effort that
29
combines laboratory and computational approaches to identify every
functional element in the human genome.
GenBank: Protein sequence database of the National Institutes of Health
(NIH) stores all known biologic nucleotide sequences and their
translations in a searchable form.
HapMap: Haplotype Map, an international effort to identify single
nucleotide polymorphisms (SNPs) associated with common human
diseases and differential responses to pharmaceuticals.
ISDB: International Sequence DataBase that incorporates DNA databases
of Japan and of the European Molecular Biology Laboratory (EMBL).
PDB: Protein DataBase. Three-dimensional structures of proteins,
polynucleotides, and other macromolecules, including proteins bound
to substrates, inhibitors, or other proteins.
30
CHAPTER
2
Water & pH
OBJECTIVES
After studying this chapter, you should be able to:
Describe the properties of water that account for its surface

tension, viscosity, liquid state at ambient temperature, and solvent
power.
Use structural formulas to represent several organic compounds
that can serve as hydrogen bond donors or acceptors.
Explain the role played by entropy in the orientation, in an
aqueous environment, of the polar and nonpolar regions of
macromolecules.
Indicate the quantitative contributions of salt bridges, hydrophobic
interactions, and van der Waals forces to the stability of
macromolecules.
Explain the relationship of pH to acidity, alkalinity, and the
quantitative determinants that characterize weak and strong acids.
Calculate the shift in pH that accompanies the addition of a given
quantity of acid or base to the pH of a buffered solution.
Describe what buffers do, how they do it, and the conditions under
which a buffer is most effective under physiologic or other
31
conditions.
Illustrate how the Henderson-Hasselbalch equation can be used to
calculate the net charge on a polyelectrolyte at a given pH.
BIOMEDICAL IMPORTANCE
Water is the predominant chemical component of living organisms. Its
unique physical properties, which include the ability to solvate a wide
range of organic and inorganic molecules, derive from water’s dipolar
structure and exceptional capacity for forming hydrogen bonds. The
manner in which water interacts with a solvated biomolecule influences
the structure both of the biomolecule and of water itself. An excellent
nucleophile, water is a reactant or product in many metabolic reactions.
Regulation of water balance depends upon hypothalamic mechanisms that
control thirst, on antidiuretic hormone (ADH), on retention or excretion of
water by the kidneys, and on evaporative loss. Nephrogenic diabetes
insipidus, which involves the inability to concentrate urine or adjust to
subtle changes in extracellular fluid osmolarity, results from the
unresponsiveness of renal tubular osmoreceptors to ADH.
Water has a slight propensity to dissociate into hydroxide ions and
protons. The concentration of protons, or acidity, of aqueous solutions is
generally reported using the logarithmic pH scale. Bicarbonate and other
buffers normally maintain the pH of extracellular fluid between 7.35 and
7.45. Suspected disturbances of acid-base balance are verified by
measuring the pH of arterial blood and the CO2 content of venous blood.
Causes of acidosis (blood pH <7.35) include diabetic ketosis and lactic
acidosis. Alkalosis (pH >7.45) may follow vomiting of acidic gastric
contents.
WATER IS AN IDEAL BIOLOGIC SOLVENT

Water Molecules Form Dipoles
A water molecule is an irregular, slightly skewed tetrahedron with oxygen
at its center (Figure 2–1). The two hydrogens and the unshared electrons
of the remaining two sp3-hybridized orbitals occupy the corners of the
tetrahedron. The 105° angle between the two hydrogen atoms differs
slightly from the ideal tetrahedral angle, 109.5°. Ammonia is also
tetrahedral, with a 107° angle between its three hydrogens. The strongly
32
electronegative oxygen atom in a water molecule attracts electrons away
from the hydrogen nuclei, leaving them with a partial positive charge,
while its two unshared electron pairs constitute a region of local negative
charge.
FIGURE 2–1 The water molecule has tetrahedral geometry.
A molecule with electrical charge distributed asymmetrically about its

structure is referred to as a dipole. Water’s strong dipole is responsible for
its high dielectric constant. As described quantitatively by Coulomb’s
law, the strength of interaction F between oppositely charged particles is
inversely proportionate to the dielectric constant ε of the surrounding
medium. The dielectric constant for a vacuum is essentially unity; for
hexane it is 1.9; for ethanol, 24.3; and for water at 25°C, 78.5. Water
therefore greatly decreases the force of attraction between charged and
polar species relative to water-free environments with lower dielectric
constants. Its strong dipole and high dielectric constant enable water to
dissolve large quantities of charged compounds such as salts.
Water Molecules Form Hydrogen Bonds

A partially unshielded hydrogen nucleus covalently bound to an electron-
withdrawing oxygen or nitrogen atom can interact with an unshared
electron pair on another oxygen or nitrogen atom to form a hydrogen
bond. Since water molecules contain both of these features, hydrogen
bonding favors the self-association of water molecules into ordered arrays
(Figure 2–2). Hydrogen bonding profoundly influences the physical
properties of water and accounts for its relatively high viscosity, surface
tension, and boiling point. On average, each molecule in liquid water
associates through hydrogen bonds with 3.5 others. These bonds are both
relatively weak and transient, with a half-life of a few picoseconds.
Rupture of a hydrogen bond in liquid water requires only about 4.5
33
kcal/mol, less than 5% of the energy required to rupture a covalent O—H
bond.
FIGURE 2–2 Water molecules self-associate via hydrogen bonds.

Shown are the association of two water molecules (left) and a hydrogen-
bonded cluster of four water molecules (right). Notice that water can serve
simultaneously both as a hydrogen donor and as a hydrogen acceptor.
Hydrogen bonding enables water to dissolve many organic

biomolecules that contain functional groups which can participate in
hydrogen bonding. The oxygen atoms of aldehydes, ketones, and amides,
for example, provide lone pairs of electrons that can serve as hydrogen
acceptors. Alcohols, carboxylic acids, and amines can serve both as
hydrogen acceptors and as donors of unshielded hydrogen atoms for
formation of hydrogen bonds (Figure 2–3).
FIGURE 2–3 Additional polar groups participate in hydrogen

bonding. Shown are hydrogen bonds formed between alcohol and water,
between two molecules of ethanol, and between the peptide carbonyl
oxygen and the peptide nitrogen hydrogen of an adjacent amino acid.
34
INTERACTION WITH WATER INFLUENCES
THE STRUCTURE OF BIOMOLECULES
Covalent and Noncovalent Bonds Stabilize Biologic
Molecules
The covalent bond is the strongest force that holds molecules together
(Table 2–1). Noncovalent forces, while of lesser magnitude, make
significant contributions to the structure, stability, and functional
competence of macromolecules in living cells. These forces, which can be
either attractive or repulsive, involve interactions both within the
biomolecule and between it and the water that forms the principal
component of the surrounding environment.
TABLE 2–1 Bond Energies for Atoms of Biologic Significance
Biomolecules Fold to Position Polar & Charged

Groups on Their Surfaces
Most biomolecules are amphipathic; that is, they possess regions rich in
charged or polar functional groups as well as regions with hydrophobic
character. Proteins tend to fold with the R-groups of amino acids with
hydrophobic side chains in the interior. Amino acids with charged or polar
amino acid side chains (eg, arginine, glutamate, serine, see Table 3–1)
generally are present on the surface in contact with water. A similar
pattern prevails in a phospholipid bilayer where the charged “head groups”
of phosphatidylserine or phosphatidylethanolamine contact water while
35
their hydrophobic fatty acyl side chains cluster together, excluding water
(see Figure 40–5). This pattern maximizes the opportunities for the
formation of energetically favorable charge-dipole, dipole-dipole, and
hydrogen bonding interactions between polar groups on the biomolecule
and water. It also minimizes energetically unfavorable contacts between
water and hydrophobic groups.
Hydrophobic Interactions
Hydrophobic interaction refers to the tendency of nonpolar compounds to
self-associate in an aqueous environment. This self-association is driven
neither by mutual attraction nor by what are sometimes incorrectly referred
to as “hydrophobic bonds.” Self-association minimizes the disruption of
energetically favorable interactions between the surrounding water
molecules.
While the hydrogens of nonpolar groups such as the methylene groups
of hydrocarbons do not form hydrogen bonds, they do affect the structure
of the water that surrounds them. Water molecules adjacent to a
hydrophobic group are restricted in the number of orientations (degrees of
freedom) that permit them to participate in the maximum number of
energetically favorable hydrogen bonds. Maximal formation of multiple
hydrogen bonds, which maximizes enthalpy, can be maintained only by
increasing the order of the adjacent water molecules, with an
accompanying decrease in entropy.
It follows from the second law of thermodynamics that the optimal free
energy of a hydrocarbon-water mixture is a function of both maximal
enthalpy (from hydrogen bonding) and highest entropy (maximum degrees
of freedom). Thus, nonpolar molecules tend to form droplets that minimize
exposed surface area and reduce the number of water molecules whose
motional freedom becomes restricted. Similarly, in the aqueous
environment of the living cell the hydrophobic portions of biopolymers
tend to be buried inside the structure of the molecule, or within a lipid
bilayer, minimizing contact with water.
Electrostatic Interactions
Interactions between charged groups help shape biomolecular structure.
Electrostatic interactions between oppositely charged groups within or
between biomolecules are termed salt bridges. Salt bridges are
comparable in strength to hydrogen bonds but act over larger distances.
36
They therefore often facilitate the binding of charged molecules and ions
to proteins and nucleic acids.
van der Waals Forces

van der Waals forces arise from attractions between transient dipoles
generated by the rapid movement of electrons of all neutral atoms.
Significantly weaker than hydrogen bonds but potentially extremely
numerous, van der Waals forces decrease as the sixth power of the
distance separating atoms (Figure 2–4). Thus, they act over very short
distances, typically 2 to 4 Å.
FIGURE 2–4 The strength of van der Waals interactions varies with
the distance, R, between interacting species. The force of interaction
between interacting species increases with decreasing distance between
them until they are separated by the van der Waals contact distance (see
arrow marked A). Repulsion due to interaction between the electron clouds
of each atom or molecule then supervenes. While individual van der Waals
interactions are extremely weak, their cumulative effect is nevertheless
substantial for macromolecules such as DNA and proteins which have
many atoms in close contact.
Multiple Forces Stabilize Biomolecules

The DNA double helix illustrates the contribution of multiple forces to the
structure of biomolecules. While each individual DNA strand is held
together by covalent bonds, the two strands of the helix are held together
exclusively by noncovalent interactions such as hydrogen bonds between
37
nucleotide bases (Watson-Crick base pairing) and van der Waals
interactions between the stacked purine and pyrimidine bases. The double
helix presents the charged phosphate groups and polar hydroxyl groups
from the ribose sugars of the DNA backbone to water while burying the
relatively hydrophobic nucleotide bases inside. The extended backbone
maximizes the distance between negatively charged phosphates,
minimizing unfavorable electrostatic interactions (see Figure 34–2).
WATER IS AN EXCELLENT NUCLEOPHILE

Metabolic reactions often involve the attack by lone pairs of electrons
residing on electron-rich molecules termed nucleophiles upon electron-
poor atoms called electrophiles. Nucleophiles and electrophiles do not
necessarily possess a formal negative or positive charge. Water, whose two
lone pairs of sp3 electrons bear a partial negative charge (see Figure 2–1),
is an excellent nucleophile. Other nucleophiles of biologic importance
include the oxygen atoms of phosphates, alcohols, and carboxylic acids;
the sulfur of thiols; and the nitrogen atom of amines and of the imidazole
ring of histidine. Common electrophiles include the carbonyl carbons in
amides, esters, aldehydes, and ketones and the phosphorus atoms of
phosphoesters.
Nucleophilic attack by water typically results in the cleavage of the
amide, glycoside, or ester bonds that hold biopolymers together. This
process is termed hydrolysis. Conversely, when monomer units are joined
together to form biopolymers, such as proteins or glycogen, water is a
product, for example, during the formation of a peptide bond between two
amino acids.
While hydrolysis is a thermodynamically favored reaction, the amide
and phosphoester bonds of polypeptides and oligonucleotides are stable in
the aqueous environment of the cell. This seemingly paradoxical behavior
reflects the fact that the thermodynamics that govern the equilibrium point
of a reaction do not determine the rate at which it will proceed toward its
equilibrium point. In the cell, protein catalysts called enzymes accelerate
the rate of hydrolytic reactions when needed. Proteases catalyze the
hydrolysis of proteins into their component amino acids, while nucleases
catalyze the hydrolysis of the phosphoester bonds in DNA and RNA.
Careful control of the activities of these enzymes is required to ensure that
they act only at appropriate times.
38
Many Metabolic Reactions Involve Group Transfer
Many of the enzymic reactions responsible for synthesis and breakdown of
biomolecules involve the transfer of a chemical group G from a donor D to
an acceptor A to form an acceptor group complex, A—G:
The hydrolysis and phosphorolysis of glycogen, for example, involve the

transfer of glucosyl groups to water or to orthophosphate. The equilibrium
constant for the hydrolysis of covalent bonds strongly favors the formation
of split products. Conversely, many group transfer reactions responsible
for the biosynthesis of macromolecules involve the thermodynamically
unfavored formation of covalent bonds. Enzyme catalysts play a critical
role in surmounting these barriers by virtue of their capacity to directly
link two normally separate reactions together. By linking an energetically
unfavorable group transfer reaction with a thermodynamically favorable
reaction, such as the hydrolysis of ATP, a new coupled reaction can be
generated whose net overall change in free energy favors biopolymer
synthesis.
Given the nucleophilic character of water and its high concentration in
cells, why are biopolymers such as proteins and DNA relatively stable?
And how can synthesis of biopolymers occur in an aqueous environment
that favors hydrolysis? Central to both questions are the properties of
enzymes. In the absence of enzymic catalysis, even reactions that are
highly favored thermodynamically do not necessarily take place rapidly.
Precise and differential control of enzyme activity and the sequestration of
enzymes in specific organelles determine the physiologic circumstances
under which a given biopolymer will be synthesized or degraded. The
ability of enzyme active sites to sequester substrates in an environment
from which water can be excluded facilitates biopolymer synthesis.
Water Molecules Exhibit a Slight but Important

Tendency to Dissociate
The ability of water to ionize, while slight, is of central importance for life.
Since water can act both as an acid and as a base, its ionization may be
represented as an intermolecular proton transfer that forms a hydronium
ion (H3O+) and a hydroxide ion (OH−):
39
The transferred proton is actually associated with a cluster of water
molecules. Protons exist in solution not only as H3O+, but also as
multimers such as H5O2+ and H7O3+. The proton is nevertheless routinely
represented as H+, even though it is in fact highly hydrated.
Since hydronium and hydroxide ions continuously recombine to form
water molecules, an individual hydrogen or oxygen cannot be stated to be
present as an ion or as part of a water molecule. At one instant it is an ion;
an instant later it is part of a water molecule. Individual ions or molecules
are therefore not considered. We refer instead to the probability that at any
instant in time a given hydrogen will be present as an ion or as part of a
water molecule. Since 1 g of water contains 3.46 × 1022 molecules, the
ionization of water can be described statistically. To state that the
probability that a hydrogen exists as an ion is 0.01 means that at any given
moment in time, a hydrogen atom has 1 chance in 100 of being an ion and
99 chances out of 100 of being part of a water molecule. The actual
probability of a hydrogen atom in pure water existing as a hydrogen ion is
approximately 1.8 × 10−9. The probability of its being part of a water
molecule thus is almost unity. Stated another way, for every hydrogen ion
or hydroxide ion in pure water, there are 0.56 billion or 0.56 × 109 water
molecules. Hydrogen ions and hydroxide ions nevertheless contribute
significantly to the properties of water.
For dissociation of water,
where the brackets represent molar concentrations (strictly speaking, molar

activities) and K is the dissociation constant. Since 1 mole (mol) of water
weighs 18 g, 1 liter (L) (1000 g) of water contains 1000 ÷ 18 = 55.56 mol.
Pure water thus is 55.56 molar. Since the probability that a hydrogen in
pure water will exist as a hydrogen ion is 1.8 × 10−9, the molar
concentration of H+ ions (or of OH− ions) in pure water is the product of
the probability, 1.8 × 10−9, times the molar concentration of water, 55.56
mol/L. The result is 1.0 × 10−7 mol/L.
We can now calculate the dissociation constant K for pure water:
40
The molar concentration of water, 55.56 mol/L, is too great to be
significantly affected by dissociation. It is therefore considered to be
essentially constant. This constant may therefore be incorporated into the
dissociation constant K to provide a useful new constant Kw termed the ion
product for water. The relationship between Kw and K is shown below:
Note that the dimensions of K are moles per liter and those of Kw are
moles2 per liter2. As its name suggests, the ion product Kw is numerically
equal to the product of the molar concentrations of H+ and OH−:
At 25°C, Kw = (10−7)2, or 10−14 (mol/L)2. At temperatures below 25°C,

Kw is somewhat less than 10−14, and at temperatures above 25°C it is
somewhat greater than 10−14. Within the stated limitations of temperature,
Kw equals 10−14 (mol/L)2 for all aqueous solutions, even solutions of
acids or bases. We use Kw to calculate the pH of acidic and basic
solutions.
pH IS THE NEGATIVE LOG OF THE HYDROGEN

ION CONCENTRATION
The term pH was introduced in 1909 by Sörensen, who defined it as the
negative log of the hydrogen ion concentration:
41
This definition, while not rigorous, suffices for many biochemical
purposes. To calculate the pH of a solution:
1. Calculate the hydrogen ion concentration [H+].
2. Calculate the base 10 logarithm of [H+].
3. pH is the negative of the value found in step 2.
For example, for pure water at 25°C,
This value is also known as the power (English), puissant (French), or

potennz (German) of the exponent, hence the use of the term “p.”
Low pH values correspond to high concentrations of H+ and high pH
values correspond to low concentrations of H+.
Acids are proton donors and bases are proton acceptors. Strong
acids (eg, HCl, H2SO4) completely dissociate into anions and protons
even in strongly acidic solutions (low pH). Weak acids dissociate only
partially in acidic solutions. Similarly, strong bases (eg, KOH, NaOH),
but not weak bases like Ca(OH)2, are completely dissociated even at high
pH. Many biochemicals are weak acids. Exceptions include
phosphorylated intermediates, whose phosphoryl group contains two
dissociable protons, the first of which is strongly acidic.
The following examples illustrate how to calculate the pH of acidic and
basic solutions.
Example 1: What is the pH of a solution whose hydrogen ion
concentration is 3.2 × 10−4 mol/L?
Example 2: What is the pH of a solution whose hydroxide ion

concentration is 4.0 × 10−4 mol/L? We first define a quantity pOH that is
equal to −log[OH−] and that may be derived from the definition of Kw:
42
To solve the problem by this approach:
The examples above illustrate how the logarithmic pH scale facilitates

recording and comparing hydrogen ion concentrations that differ by orders
of magnitude from one another, 0.00032 M (pH 3.5) and 0.000000000025
M (pH 10.6).
Example 3: What are the pH values of (a) 2.0 × 10−2 mol/L KOH and
of (b) 2.0 × 10−6 mol/L KOH? The OH− arises from two sources, KOH
and water. Since pH is determined by the total [H+] (and pOH by the total
[OH−]), both sources must be considered. In the first case (a), the
contribution of water to the total [OH−] is negligible. The same cannot be
said for the second case (b):
43
Once a decision has been reached about the significance of the
contribution of water, pH may be calculated as above.
The above examples assume that the strong base KOH is completely
dissociated in solution and that the concentration of OH− ions was thus
equal to that due to the KOH plus that present initially in the water. This
assumption is valid for dilute solutions of strong bases or acids, but not for
weak bases or acids. Since weak electrolytes dissociate only slightly in
solution, we must use the dissociation constant to calculate the
concentration of [H+] (or [OH−]) produced by a given molarity of a weak
acid (or base) before calculating total [H+] (or total [OH−]) and
subsequently pH.
Functional Groups That Are Weak Acids Have Great

Physiologic Significance
Many biochemicals possess functional groups that are weak acids or bases.
Carboxyl groups, amino groups, and phosphate esters, whose second
dissociation falls within the physiologic range, are present in proteins and
nucleic acids, most coenzymes, and most intermediary metabolites.
Knowledge of the dissociation of weak acids and bases thus is basic to
understanding the influence of intracellular pH on structure and biologic
activity. Charge-based separations such as electrophoresis and ion
exchange chromatography are also best understood in terms of the
dissociation behavior of functional groups.
We term the protonated species (HA or R—NH3+) the acid and the
unprotonated species (A− or R—NH2) its conjugate base. Similarly, we
may refer to a base (A− or R—NH2) and its conjugate acid (HA or R—
44
NH3+).
We express the relative strengths of weak acids and bases in terms of
their dissociation constants. Shown below are the expressions for the
dissociation constant (Ka) for two representative weak acids, R—COOH
and R—NH3+.
Since the numeric values of Ka for weak acids are negative exponential
numbers, we express Ka as pKa, where
Note that pKa is related to Ka as pH is to [H+]. The stronger the acid, the
lower is its pKa value.
Representative weak acids (left), their conjugate bases (center), and pKa
values (right) include the following:
pKa is used to express the relative strengths of both acids and bases. For
any weak acid, its conjugate is a strong base. Similarly, the conjugate of a
strong base is a weak acid. The relative strengths of bases are expressed
in terms of the pKa of their conjugate acids. For polyprotic compounds
containing more than one dissociable proton, a numerical subscript is
assigned to each dissociation, numbered starting from unity in decreasing
order of relative acidity. For a dissociation of the type
45
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life of David Rittenhouse, LLD. F.R.S., late
president of the American Philosophical Society,
&c
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eBook.
Title: Memoirs of the life of David Rittenhouse, LLD. F.R.S., late

president of the American Philosophical Society, &c
interspersed with various notices of many distinguished
men : with an appendix, containing sundry
philosophical and other papers, most of which have not
hitherto been published
Author: William Barton
Release date: December 2, 2023 [eBook #72283]
Language: English
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*** START OF THE PROJECT GUTENBERG EBOOK MEMOIRS

OF THE LIFE OF DAVID RITTENHOUSE, LLD. F.R.S., LATE
PRESIDENT OF THE AMERICAN PHILOSOPHICAL SOCIETY, &C
***
Transcriber’s Note:
Please consult the end notes for a discussion of the
handling of textual notes, and any other issues that arose
during the preparation of this transcription.
The front cover, which contained no text, has been
modified by adding a simplified version of the title page,
and, as so modified, is added to the public domain.
Any corrections are indicated as hyperlinks, which will
navigate the reader to the corresponding entry in the
corrections table in the note at the end of the text.
MEMOIRS
OF THE LIFE
OF
DAVID RITTENHOUSE, LLD. F.R.S.

LATE PRESIDENT OF THE AMERICAN PHILOSOPHICAL SOCIETY, &c.
INTERSPERSED WITH
VARIOUS NOTICES OF MANY DISTINGUISHED MEN:
WITH
AN APPENDIX,
CONTAINING
SUNDRY PHILOSOPHICAL AND OTHER PAPERS,
MOST OF WHICH HAVE NOT HITHERTO BEEN PUBLISHED.
BY WILLIAM BARTON, M. A.
COUNSELLOR AT LAW;
Member of the American Philosophical Society, the Mass. Hist. Society, and the
Royal Economical Society of Valencia, in Spain.
PHILADELPHIA:
PUBLISHED BY EDWARD PARKER, NO. 178, MARKET-STREET.
W. Brown, Printer, Church-Alley.
1813.
DISTRICT OF PENNSYLVANIA, TO WIT:
BE IT REMEMBERED, That on the ninth day of October, in the
thirty-eighth year of the independence of the United States of
America, A. D. 1813, William Barton of the said district, hath
deposited in this office the Title of a book, the right whereof he
claims as Author, in the words following, to wit:
“Memoirs of the Life of David Rittenhouse, L. L. D. F.R.S, late
President of the American Philosophical Society, &c. Interspersed
with various notices of many distinguished men: with an Appendix,
containing sundry philosophical and other papers, most of which
have not hitherto been published. By William Barton, M. A.
Counsellor at Law; Member of the American Philosophical Society,
the Mass. Hist. Society, and the Royal Economical Society of
Valencia, in Spain.”
In conformity to the act of the Congress of the United States,
intituled, “An act for the encouragement of learning, by securing the
copies of maps, charts and books, to the authors and proprietors of
such copies during the times therein mentioned.”—And also to the
act entitled, “An act supplementary to an act, entitled, “An act for the
encouragement of learning, by securing the copies of maps, charts,
and books, to the authors and proprietors of such copies during the
times therein mentioned,” and extending the benefits thereof to the
arts of designing, engraving, and etching historical and other prints.”
D. CALDWELL,
Clerk of the District of Pennsylvania.
PREFACE.
Agreeably to the plan on which the following memoirs have been

conducted, it will be perceived, that they contain a great variety of
matter; of which, some particulars have a remote, others merely an
incidental connexion, with the chief object of the work. There may
perhaps be some readers, to whom the introduction of such matters
as the University of Pennsylvania and the Medical School connected
with it, the Pennsylvania Hospital, the Philadelphia Library, and the
like, into the Life of Rittenhouse, will, on a cursory view, seem to
have little or no affinity to that object. But when it is considered, that
this work is designed to comprehend Memoirs, not only of
Rittenhouse personally, but of several literary, scientific, and other
public institutions, as well as of many eminent men, with which his
individual history and the annals of his time were in various ways
associated, it is presumed, that the slight sketches which have been
taken of those matters, in passing along, will neither prove foreign to
the nature of the present undertaking, nor uninteresting in
themselves. As a citizen of Pennsylvania; as an inestimable public
and private character; as a distinguished son of science, of great
probity and extensive usefulness in society; in all these points of
view, the History of Dr. Rittenhouse may be contemplated, as holding
a relationship with almost every object connected with science and
the arts, in his day, that could in any wise contribute to the well being
of mankind in general, and his native country in particular.
Conspicuous and eminently meritorious as he was, yet an insulated
account of his talents, his virtues, and his personal services,—a bare
specification of such qualities and merits as he possessed,
abstracted from a due consideration of the state of society and
circumstances resulting from it, taken in connexion with them, during
the same period,—would not be equally intelligible and instructive;
and, consequently, must prove less useful. For these reasons, the
Memorialist has pursued that course which he conceives to be
perfectly congenial with the main design of his work; as best
calculated to promote its general usefulness, and most suitably
adapted to render it interesting, even to those who read for
amusement solely.
In the adoption of this plan, the writer has been chiefly influenced
by a desire to illustrate the history, genius and character of the times,
which his Memoirs embrace; together with the progress and
improvement of literature, science and the arts, within the same
compass, more especially in this country; and this consideration has
obviously led him to introduce, in conjunction with those objects, as
well as with the Life of the great American Philosopher, various
notices of many persons distinguished for their talents and merit, not
only in our own time, but at different periods in the annals of science.
He has thought it right to rescue from oblivion—to commemorate in
this way, if not to consecrate, the names of some men in this country,
more especially, who deserve to be ranked among the worthies of
America. All this the writer has done, too, in conformity to the mode
prosecuted by some of the most judicious biographers and
memorialists, together with other writers of the same class: It is
believed to be a manner of treating the interesting subjects, on which
the pens of such authors have been employed, which, while it
renders their works more pleasing, greatly increases their
usefulness.—If, therefore, some of the matter which has been
introduced into the present work should, at first sight, appear
irrelative, and even unimportant, the Memorialist nevertheless
flatters himself, that, on reflection, nothing will be deemed really so,
how remotely soever it may seem, on a transient view of the subject,
to be connected with the principal design of the undertaking;
provided it has a tendency to illustrate the great objects he was
desirous of accomplishing.[I1]
The diversity of the materials which are, by these means, blended

with the biographical account of Dr. Rittenhouse, in the Memoirs now
presented to the world, made it expedient, in the opinion of the
writer, to have recourse to the free use of notes, for the purposes of
illustration, reference, and explanation. In a work of such a
complexion—constituting a book composed of very various
materials, designed to elucidate and inform, as well as to please—it
became, in fact, necessary to throw a large portion of that matter into
the form of notes; in order to avoid, by numerous digressions on
subjects arising out of the primary object of the work, too much
disjointing of the text. There are persons, no doubt, by whom this
course will be disapproved. The able and learned author of the
Pursuits of Literature has been accused by some critics—while
others, who have no pretensions to those qualifications which entitle
a man to exercise the functions of a critic, have even affected to
laugh at him—for the multiplicity, the variety, and the length of the
notes, which he has appended to that poem. But its being a satirical
poem, is the circumstance to which may be fairly attributed the
censorious cavils which his work excited: his satire was felt; and it
roused the spleen of those who were its objects, and their partizans.
The present work, however, is far from being intended to satirise any
one; its author has no such object in view: for, although he has, in
some instances, expressed his disapprobation of certain principles,
theories, and even measures, which he believes to be not only
repugnant to true science, but destructive of both private and social
happiness—he has refrained as far as possible from personal
censure;—he would much rather be engaged in the functions of an
eulogist, than those of a censor. The numerous notes the
Memorialist has employed—many of them, too, pretty long—will not
therefore, he presumes, be objected to, on the ground of personality
or supposed ill-humour. He has introduced them into his Memoirs,
because he believed them to be not only useful, but peculiarly well
adapted to a work of this nature, and suited to answer the general
scope of its design. The author may then say, in the words of the
poetical writer just mentioned—as an apology for the frequency and
copiousness of the notes annexed to these Memoirs;—“I have made
no allusions which I did not mean to explain. But I had something
further in my intention. The notes are not always explanatory; they
are of a structure rather peculiar to themselves: many of them are of
a nature between an essay and an explanatory comment. There is
much in a little compass, suited to the exigency of the times. I
expatiated on the casual subject which presented itself; and when
ancient or modern writers expressed the thoughts better than I could
myself, I have given the original languages. No man has a greater
contempt for the parade of quotation (as such) than I have. My
design is not to quote words, but to enforce right sentiments in the
manner which I think best adapted to the purpose, after much
reflection.”
The method of disposing of the notes, in this work, may be thought

by some to impair the symmetry of the page: but so trivial a defect as
this may be, in the typographical appearance of the book, will, it is
supposed, be amply compensated by the convenience the reader
will experience, in having the annotations, almost always, on the
same pages with their respective references.
In the arrangement of the Memoirs, the author has placed the

incidents and circumstances relating to the Life of Dr. Rittenhouse, in
their chronological order, as nearly as could be conveniently done.
An Appendix,—containing sundry letters and other papers, which

could neither be incorporated with propriety into the text, nor inserted
in marginal notes,—is placed after the conclusion of the Memoirs. In
this part of the work the reader will find, among other interesting
documents, Dr. Rittenhouse’s Oration on the subject of Astronomy,
pronounced before the American Philosophical Society, in the year
1775. The addition of this treatise to the Life of our Philosopher, was
rendered the more proper,—independently of the intrinsic merit of
the performance,—by reason of the pamphlet having had, originally,
a very limited circulation, and its being now out of print. The Notes,
added to this little tract, as well as to some other papers in the
Appendix, by the Memorialist, are designated by the initials of his
name; in order to distinguish the annotations from either the notes
originally attached to them,—or from other matter, in the Text, not
written by himself.
The author has embellished his work with an elegantly engraved
likeness of Dr. Rittenhouse, executed by an able artist, from a
portrait painted by Mr. C. W. Peale, in-the year 1772,[I2] when our
Philosopher was forty years of age. At that time he wore a wig,—and
was so represented in the picture: but afterwards, when he resumed
the wearing of his own hair, (and which he continued to do during the
remainder of his life,) the portrait was altered accordingly, by Mr.
Peale. The original picture (now in the possession of Mrs. Sergeant,)
bore a strong resemblance to Dr. Rittenhouse, at that period of his
life in which it was taken; and the engraving, prefixed to these
Memoirs, is an excellent copy.
To a portion of the readers of this work, some of the matter it

contains may be thought superfluous,—because already familiar to
them: and, to men of extensive learning and research, much of the
information herein collected may really be so. But to persons of less
erudition and science, the knowledge thus communicated it may be
presumed, will prove in some degree useful; and the writer indulges
a confident belief, that the greater number of his readers will derive
both instruction and gratification, from a perusal of the Memoirs now
offered to their attention.
The favours which the Memorialist has received, in the

communication of sundry papers and some information for this work,
demand his thankful acknowledgments to the contributors. Among
these,—besides those gentlemen occasionally mentioned in the
Memoirs,—the writer returns his thanks to his worthy relatives, Mrs.
Sergeant, Mrs. Waters, and Dr. Benjamin Smith Barton; and also to
the Rt. Rev. Bishop White, Andrew Ellicott, Esq. John Vaughan, Esq.
the Rev. Dr. Samuel Stanhope Smith, Charles Smith, Esq. and the
Rev. Mr. Cathcart. To the friendship and politeness of these very
respectable characters, he holds himself indebted, on this occasion.
[I3]
It has been the earnest desire of the writer, to adhere strictly to

Truth, in every part of his narrative: he has not, therefore, introduced
into his work any thing, as a matter of Fact, which he did not believe
to be well founded. Wherever he has ventured to express an Opinion
of his own, on any subject of importance, it must be left to the
judgment and candour of others to determine, what weight it may be
entitled to.—In the various quotations which appear in his Memoirs,
the writer has endeavoured to observe the utmost fidelity, with
respect to the originals; and all his translations into the English, from
other languages, have been made with a like scrupulous attention to
correctness.—Some errors and inaccuracies have nevertheless, it
may be readily supposed, found their way into the following work;
though the writer trusts they are neither numerous nor very
important: and, as they are wholly unintentional, of whatever
description they may be, he hopes it will not be deemed
presumptuous in him, to claim for them the indulgence of a candid,
liberal, and discerning public.
Lancaster, in Pennsylvania,
April 11, 1813.
I1. The biographer of Rittenhouse entirely coincides with the

compilers of the Encyclopædia Britannica, in opinion, respecting the
utility and propriety of giving an account, in such Memoirs as the
present, of things as well as persons, connected in various ways with
the main object of the work.
In the preface to that useful dictionary of arts, sciences and

miscellaneous literature, are the following observations: the
consideration they merit; is submitted to the good sense of the
reader.
“While one part of our readers,” say the encyclopedists, when

referring to the biographical department of their work, “will regret that
we have given no account of their favourite philosopher, hero, or
statesman, others may be disposed to remark, that we have dragged
from obscurity the names of many persons who were no proper
objects of such public regard. To these we can only reply, that, with
the greatest biographer of modern times, we have long thought that
there has rarely passed a life, of which a faithful narrative would not
be useful; and that in the lives of the most obscure persons, of whom
we have given any account, we saw something either connected
with recent discoveries and public affairs, or which we thought
capable of affording a lesson to great multitudes in similar
circumstances.”—“Between eminent achievements and the scenes
where they were performed, there is a natural and necessary
connexion. The character of the warrior is connected with the fields
of his battles; that of the legislator, with the countries which he
civilized; and that of the traveller and navigator, with the regions
which they explored. Even when we read of the persons by whom,
and the occasions on which, any particular branch of knowledge has
been improved, we naturally wish to know something of the places
where such improvements were made.”
I2. Mr. C. W. Peale painted at the same time another portrait of

him, for himself; which is likewise altered from the original painting. It
has a place in Mr. Peale’s Gallery of Portraits. There is a third, by the
same hand, in the possession of the American Philosophical Society.
Another good picture of Dr. Rittenhouse was also then made, by

Mr. James Peale, for the Rev. Mr. Barton. This (which represents him
with a wig) is now in the possession of John Moore White, Esq. of
New-Jersey, who married Mr. Barton’s youngest daughter.
A pretty good mezzotinto, in a large size,—done from Mr. C. W.

Peale’s painting of our Philosopher,—was executed by Mr. E.
Savage, in the winter of 1796: and since that time, some small
engravings have been made from different pictures of him; but these
do not so well preserve the likeness.
I3. Some interesting information was likewise communicated by

the late Professor Rush. The death of that gentleman having
occurred since the completion of the present work, the author has
inserted a concise biographical notice of him, in the Appendix, in
place of the mention originally made of his name in this preface.
INTRODUCTION.
The individuals in society, who present to the view of their

cotemporaries, and transmit to posterity, Memorials of illustrious
men,—more especially those of their own country,—discharge
thereby a debt of gratitude: because every man is, directly or
indirectly, interested in the benefits conferred on his species, by
those who enlarge the sphere of human knowledge, or otherwise
promote the happiness of mankind.
But the biographer of an highly meritorious character aims at more

than the mere performance of that duty, which a grateful sense of
obligation exacts from him, in common with every member of the
community, in commemorating the beneficence of the wise and the
good: he endeavours to excite in great and liberal minds, by the
example of such, an ambition to emulate their talents and their
virtues;—and it is these, that, by their union, constitute true
greatness of character.
The meed of applause which may be sometimes, and too often is,
bestowed on meretricious worth, is ever unsteady and fleeting. The
pseudo-patriot may happen to enjoy a transient popularity; false
philosophy may, for a while, delude, if not corrupt, the minds of an
unthinking multitude; and specious theories in every department of
science,—unsupported by experience and untenable on principles of
sound reason,—may give to their projectors a short-lived reputation:
But the celebrity which is coveted by the man of a noble and
generous spirit,—that estimable species of fame, which alone can
survive such ephemera of error as are often engendered by the
vanity of the individual and nurtured by the follies or vices of the
many,—must ever rest on the permanent foundation of truth,
knowledge and beneficence.
Virtue is essentially necessary to the constitution of a truly great

character. For, although brilliant talents are sometimes found
combined with vicious propensities,[1]—the impulse given to men of
this description, often renders their great abilities baneful to society:
they can seldom, if ever, be productive of real public good. Should
eminent talents, possessed by a man destitute of virtue, even take a
right direction in their operation, by reason of some extraordinary
circumstance,—such an event ought never to be calculated on: It is
not the part of common sense,—much less of a cautious prudence,
acquired by a knowledge of mankind,—to expect praise-worthy
conduct from any one, whose predominating passions are bad,
however great may be his capability of doing good.
While, therefore, the mind may view, with a sort of admiration, the
achievements of a magnanimous soldier, it turns with indignation
from the atrocities of a military tyrant: and at the same time that it
may be induced to contemplate even with complacency, at the first
view, the plausible, yet groundless speculations of ingenious
theorists, in matters of science,—still the fallacy of their systems,
when developed by experience, strips them of all their tinseled glare
of merit. Thus, too, the applause which the world justly attaches to
the character of a patriot-hero, deserts the unprincipled ruffian-
warrior, however valiant and successful he may prove: In like
manner, reason and experience expose to the censure of the good
and the derision of the wise, the deleterious doctrines of
metaphysical statesmen and philosophers.[2] Such estimable
qualities as they may possess, in either character, are merged in the
mischievous or base ones, with which they are combined: thus,
infamy or contempt eventually become the merited portion of crime
or of folly, as either one or the other may prevail. A Cæsar,[3] a
Cromwell and a Robespierre, with other scourges of mankind, of like
character, will therefore be viewed as objects of execration by
posterity, while the memories of an Alfred, a Nassau, and a
Washington—a Chatham, a Burke, and an Ames,—will be
venerated, to the latest posterity.
Much of the glory of a nation results from the renown of illustrious

men, among its citizens: a country which has produced many great
men, may justly pride itself on the fame which those individuals had
acquired. The community to which we belong is entitled to such
services as we can render to it: these the patriot will cheerfully
bestow; and, in promoting the honour and prosperity of his country, a
large portion of the lustre which the exertion of his talents shall have
shed upon it, are again reflected on himself.[4]
The cultivator of those branches of natural science which

constitute practical and experimental philosophy;—equally with the
teacher of religion and morals,—extends the beneficial effects of his
researches and knowledge beyond the bounds of his particular
country. Truth is every where the same; and the promulgation of it
tends, at all times and in all places, to elevate to its proper station
the dignity of man. The more extensively, then, true science can be
diffused, the greater will be the means—the fairer will be the rational
prospect, of enlarging the sphere of human happiness. The
philosopher may, pre-eminently, be considered as a citizen of the
world; yet without detracting in any degree from that spirit of
patriotism, which ever stimulates a good man to contribute his
primary and most important services to his own country. There are,
indeed, some species of aids, which are exclusively due to a
community, by all its citizens; and, consequently, such as they are
bound to withhold from other national communities, in certain
contingencies and under peculiar circumstances. But a knowledge of
those truths which lead to the acquisition of wisdom and practice of
virtue, serves to meliorate the condition of mankind generally, at all
times, and under all circumstances;—inasmuch as they greatly
assist in banishing error, with its frequent concomitant, vice, not only
from the more civilized portions of the world, but also by their
inherent influence, from among nations less cultivated and refined.
The truths promulgated by means of a natural and sublime
philosophy—corresponding, as this does, with the dignity of an
enlightened spirit—must ever emanate from a virtuous heart as well
as an expanded intellect. Hence, the real philosopher,—he whose
principles are unpolluted by the sophisticated tenets of some modern
pretenders to the appellation,—can scarcely fail to be a good man.
Such was the immortal Newton; such were a Boyle, a Hale and a
Barrow,—a Boerhaave, a Stephen Hales and a Bradley; with many
worthies equally illustrious,—whose glories will, for ever, retain their
primitive splendour.
Even the most celebrated sages of antiquity, extremely imperfect

as we know the philosophy of the early ages to have been,
elucidated, by the purity of their lives and the morality of their
doctrines, the truth of the position,—that the cultivation of natural
wisdom, unaided as it then was by the lights of revelation, encreased
every propensity to moral virtue. Such were Socrates, Plato his
disciple, and Anaxagoras; who flourished between four and five
centuries before the Christian era.
The life of Socrates, who is styled by Cicero the Father of

Philosophers, afforded a laudable example of moderation, patience,
and other virtues; and his doctrines abound with wisdom.
Anaxagoras and Plato united with some of the nobler branches of
natural science, very rational conceptions of moral truth. Both of
them had much higher claims to the title of philosophers, than
Aristotle, who appeared about a century afterwards. This
philosopher, however,—for, as such, he continued for many ages to
be distinguished in the schools,—was, like Socrates, more a
metaphysician than an observer of the natural world. His morality is
the most estimable part of his works; though his conceptions of
moral truths were much less just than those of Anaxagoras and
Plato:[5] for his physics are replete with notions and terms alike
vague, unmeaning and obscure.[6] The intimate connexion that
subsists between the physical and moral fitness of things, in relation
to their respective objects, was more evidently known to Anaxagoras
and Plato, than to either Socrates or Aristotle: and the reason is
obvious;—both of the former cultivated the sublime science of
Astronomy.
To this cause, then, may be fairly attributed the half-enlightened

notions of the Deity,[7] and of a future state, entertained by these
pagan searchers after truth. To the same cause may be traced the
sentiment that dictated the reply made by Anaxagoras,—when, in
consequence of his incessant contemplation of the stars, he was
asked, “if he had no concern for his country?”—“I incessantly regard
my country,” said he, pointing to Heaven.
Plato’s attention to the same celestial science unquestionably

enlarged his notions of the Deity, and enabled him to think the more
justly of the moral attributes of human nature. According to Plato—
whose morality, on the whole, corresponds with the system
maintained by Socrates,[8]—the human soul is a ray from the Divinity.
He believed, that this minute portion of infinite Wisdom, Goodness
and Power, was omniscient, while united with the Parent stock from
which it emanated; but, when combined with the body, that it
contracted ignorance and impurity from that union. He did not, like
his master Socrates, neglect natural philosophy; but investigated
many principles which relate to that branch of knowledge:—and,
according to this philosopher, all things consisted of two principles,—
God and matter.
It is evident that Plato believed in the immortality of the soul of

man; but he had, at the same time, very inadequate conceptions of
the mode or state of its existence, when separated from the body. It
seems to have been reserved for the Christian dispensation, to
elucidate this great arcanum, hidden from the most sagacious of the
heathen philosophers.[9] It was the difficulty that arose on this
subject, the incapability of knowing how to dispose of the soul, or
intellectual principle in the constitution of our species, after its
disentanglement from the body; a difficulty by which all the
philosophers, antecedent to the promulgation of Christianity, were
subjected to unsurmountable perplexities;—it was this, that rendered
even the expansive genius of Anaxagoras utterly incompetent to

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Medicine is an ever-changing science. As new research and clinical

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THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION

Peter L. Gross, MD, MSc, FRCP(C)

Molly Jacob MD, PhD

Peter A. Mayes, PhD, DSc

Robert K. Murray, MD, PhD

Margaret L. Rand, PhD

Joe Varghese, PhD

1 Biochemistry & Medicine

3 Amino Acids & Peptides

4 Proteins: Determination of Primary Structure

5 Proteins: Higher Orders of Structure

7 Enzymes: Mechanism of Action

9 Enzymes: Regulation of Activities

10 The Biochemical Roles of Transition Metals

13 The Respiratory Chain & Oxidative Phosphorylation

15 Carbohydrates of Physiological Significance

16 The Citric Acid Cycle: The Central Pathway of Carbohydrate,

17 Glycolysis & the Oxidation of Pyruvate

19 Gluconeogenesis & the Control of Blood Glucose

20 The Pentose Phosphate Pathway & Other Pathways of Hexose

23 Biosynthesis of Fatty Acids & Eicosanoids

24 Metabolism of Acylglycerols & Sphingolipids

25 Lipid Transport & Storage

26 Cholesterol Synthesis, Transport, & Excretion

28 Catabolism of Proteins & of Amino Acid Nitrogen

29 Catabolism of the Carbon Skeletons of Amino Acids

30 Conversion of Amino Acids to Specialized Products

31 Porphyrins & Bile Pigments

33 Metabolism of Purine & Pyrimidine Nucleotides

34 Nucleic Acid Structure & Function

35 DNA Organization, Replication, & Repair

36 RNA Synthesis, Processing, & Modification

37 Protein Synthesis & the Genetic Code

38 Regulation of Gene Expression

39 Molecular Genetics, Recombinant DNA, & Genomic

41 The Diversity of the Endocrine System

42 Hormone Action & Signal Transduction

44 Micronutrients: Vitamins & Minerals

45 Free Radicals & Antioxidant Nutrients

50 The Extracellular Matrix

51 Muscle & the Cytoskeleton

52 Plasma Proteins & Immunoglobulins

53 Red Blood Cells

54 White Blood Cells

58 Biochemical Case Histories

The Answer Bank

Cover Illustration for the Thirty-first Edition

Changes in the Thirty-first Edition

Organization of the Book

After studying this chapter, you should be able to:

Understand the importance of the ability of cell-free extracts of

DISCOVERY THAT A CELL-FREE EXTRACT OF

BIOCHEMISTRY & MEDICINE HAVE

FIGURE 1–1 A two-way street connects biochemistry and medicine.

BIOCHEMICAL PROCESSES UNDERLIE

Most Diseases Have a Biochemical Basis

Impact of the Human Genome Project on