Foundations of Chemical Biology

110 Pages·2001·7.96 MB·English

by  A. J., Dobson, C. M., Gerrard, J. A., Pratt

Foundations of
Chemical Biology
C. MI. Dobson
Departmento f Chemistry,U niversity of Cambridge
J. A. Gerrard
Department of Plant and Microbial Sciences,U niversityof Canterbury,
Christchurch, New Zealand
A. J. Pratt
Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
OXlFORD
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0 C. M. Dobson, J. A. Gerrard, and A. J. Pratt, 2001
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Series Editor’s Foreword
Huge progress towards the understanding of biological systems and
processes continues to be made through the application of the principles
and techniques of organic chemistry. As a result, chemical biology now
forms part of organic chemistry and biochemistry courses at University.
This Oxford Chemistry Primer provides a concise introduction to chem-
ical biology for chemistry and biochemistry students at the start of their
University apprenticeships, and will serve to stimulate and excite their
interest in this important area of science where chemistry overlaps with
biology. As with other ‘Foundation’ Chemistry Primers this primer will
also be of interest to young people studying chemistry or biology in their
final year at school or college and their teachers.
Professor Stephen G. Davies
The Dyson Perrins Laboratory
University of Oxford
Preface
Chemical biology is a subject born out of a desire to understand the Chemical biology is a subject in
molecular basis of life. What are the molecules found in cells? How do which the principles of chemistry
are applied to understand the
their intrinsic properties equip them to perform all the complex processes
function of biological
found in living systems? This book introduces the fundamental chemistry in their cellular environment.
of the molecules that are essential to all cells. The molecules we discuss
include amino acids and sugar phosphate derivatives, and the macro-
molecules derived from them (proteins and nucleic acids, respectively),
and the phospholipids and their derivatives that form the basis of bio-
The solution of research
logical membranes. In such a short text, it is not possible to provide a
problems in chemical biology is
comprehensive account Of the chemistry Of these mOleCUleS; instead, this the basis bv which the subiect
book attempts to introduce important concepts concerning their intrinsic develops. ?his type of research is
chemistry. The aim is to provide the fundamental ideas relating to the leading both to an increased
chemistry of life that can then be applied in due course to more advanced Of the
basis of life, and to exciting new
aspects of chemical biology. applications of chemistry in
This book developed from a course of lectures and classes that the three subjects such as medicine and
of us taught together for several years to undergraduate chemists and materials science.
Series Editor’s Foreword
Huge progress towards the understanding of biological systems and
processes continues to be made through the application of the principles
and techniques of organic chemistry. As a result, chemical biology now
forms part of organic chemistry and biochemistry courses at University.
This Oxford Chemistry Primer provides a concise introduction to chem-
ical biology for chemistry and biochemistry students at the start of their
University apprenticeships, and will serve to stimulate and excite their
interest in this important area of science where chemistry overlaps with
biology. As with other ‘Foundation’ Chemistry Primers this primer will
also be of interest to young people studying chemistry or biology in their
final year at school or college and their teachers.
Professor Stephen G. Davies
The Dyson Perrins Laboratory
University of Oxford
Preface
Chemical biology is a subject born out of a desire to understand the Chemical biology is a subject in
molecular basis of life. What are the molecules found in cells? How do which the principles of chemistry
are applied to understand the
their intrinsic properties equip them to perform all the complex processes
function of biological
found in living systems? This book introduces the fundamental chemistry in their cellular environment.
of the molecules that are essential to all cells. The molecules we discuss
include amino acids and sugar phosphate derivatives, and the macro-
molecules derived from them (proteins and nucleic acids, respectively),
and the phospholipids and their derivatives that form the basis of bio-
The solution of research
logical membranes. In such a short text, it is not possible to provide a
problems in chemical biology is
comprehensive account Of the chemistry Of these mOleCUleS; instead, this the basis bv which the subiect
book attempts to introduce important concepts concerning their intrinsic develops. ?his type of research is
chemistry. The aim is to provide the fundamental ideas relating to the leading both to an increased
chemistry of life that can then be applied in due course to more advanced Of the
basis of life, and to exciting new
aspects of chemical biology. applications of chemistry in
This book developed from a course of lectures and classes that the three subjects such as medicine and
of us taught together for several years to undergraduate chemists and materials science.
iv Preface
biochemists at the University of Oxford. It was our students on this
course, and a group of graduates and post-doctoral research assistants
who acted as their mentors, inspired this book. They, and many others
This book uses specific case
who have been exposed to parts of this material, have provided invaluable
studies to illustrate key features of
chemical biology. It is impossible feedback for which we are very grateful.
to acknowledge all the scientists We should also like to take the opportunity to thank specifically our
who have contributed to these
colleagues who have provided detailed assistance in the production of the
studies, but they are the other
final version of book: Lorna Smith and Phillip Rendle were of great help
inspiration of this book. Special
in producing some of the diagrams involving macromolecular structures;
mention should, however, be
made of the pioneering research Jack Heinemann kindly helped us avoid errors of genetics in Chapter 9;
on globins by Max Perutz and and Peter Steel provided wise advice on organic chemistry. The input of
colleagues which forms the basis
Ashley Sparrow and Claire Vallance, who criticized earlier drafts of the
of much of Chapter 4; and of the
whole book from the perspective of non-specialists, was especially useful.
research onTlM by Jeremy
The errors that remain are, of course, solely our responsibility. A. J. P.
Knowles and colleagues which is
highlighted in Chapter 5. gratefully acknowledges funding from the University of Canterbury in the
The depictions of three-dimen- form of an Erskine Fellowship and study leave. Without such generous
sional protein structures were
support, this book would have had an even more prolonged gestation
produced using the program
period.
‘Molscript’ (P. J. Kraulis (1991)
Journal of Applied Crystal-
lography, 24, pp. 946-50). Cambridge C. M. D.
Christchzkrch J. A. G.
July 2001 A. J. P.
ontents
1 The chemicals of biological systems 1
2 Introduction to amino acids and proteins 7
3 The structures of proteins 19
4 From structure to metabolic function: the globins 29
5 Proteins as catalysts 39
6 Sugars and phosphates: an introduction 51
7 Metabolism and the biochemistry of glucose 59
8 Lipids: cells as compartments 69
9 Genetic information: nucleotides and nucleic acids 77
10 Epilogue: where to from here? 93
Index 95
1 The chemicals of
bi o Io g ic al systems
1.1 Introduction
This book is concerned with the chemistry taking place in the cells of living
organisms. Cells consist of a semipermeable membrane enclosing an
aqueous solution rich in a diverse range of chemicals (Fig. 1.1). To the
chemist, cells are, in essence, sophisticated machines that undertake a wide
range of chemistry in an organized fashion. Cells have the potential to
grow, replicate and produce closely related daughter cells, thereby
handing down their controlled chemistry to the next generation. These
remarkable characteristics all emerge from the chemical properties of the
constituent molecules of cells.
The chemicals present in cells appear to have been selected by the
Figure 1.1 illustrates some gross
processes of evolution for their chemical utility. The aim of this text is to
features of a typical prokaryotic
show that many cellular processes can be understood in simple molecular cell-a cell lacking a nucleus. All
terms. Although many biochemical molecules have complex structures, bacteria are prokaryotes,
their biological properties can often be rationalized in terms of rather whereas all complex multicellular
simple chemistry. A comprehensive account of the chemistry of biological organisms such as plants and
animals, as well as many
systems is not the objective of this book; instead, a series of examples will
unicellular species, are
be used to exemplify many of the principles that are important for eukaryotes-their cells have a
understanding the chemistry of cells. nucleus which houses DNA.
Eukaryotic cells are rather more
Cytosokan aqueous solution of Ribosome-an assembly complex in structure and function;
water-soluble inorganic ions, e.g. K+ of polymers (proteins and for mechanical strength they may
and CI-; small water-soluble organic RNA) which catalyses f/age//un+-molecular utilize an internal skeleton in
compounds, e.g. sugars and amino the production of proteins, ;machine to propel addition to, or instead of, an
acids; and water-soluble organic -- ‘\ essential to all bacteria, built from external cell wall; and they
apcoildyms ers, e.g. proteins and nucIl eI ic, ’’ aspects of life \I \,\f ibrous proteins contain a range of discrete
internal compartments. Although
the detailed workings of
prokaryotic and eukaryotic cells
,-
organic compounds, 1 are different, the types of
lipids, of low solubility# chemicals present, and the
in water, associated factors affecting their location,
with water-insoluble are similar: lipids, and other
organic polymer proteins, provide a
molecules with non-
of high mechanical I semipermeable barrier
strength DNA-an organic polymer, acts to the surroundings polar surfaces, are found in
as the genetic information store membranes; and polar entities
such as sugars and amino acids
Fig. 1.1 A chemist’s schematic view of a bacterial cell. are retained in aqueous solution.
2 The chemicals of biological systems
1.2 The elemental composition of cells
The contents of cells are related to, although different from, the chemical
composition of their external environment. It is possible to rationalize
After C, H,N and 0, the other the similarities and differences between cells and their environment in
elements important, or essential, molecular terms. The use of particular chemicals by biology is related to
to life are B, Ca, CI, Co, Cu, Fe, K,
their availability (now and in the past) and their chemical utility. The
Mg, Mn, Mo, Na, Ni, P, S, Se, Si
chemistry of cells is dominated by compounds made up of a small
and Zn.
number of elements. For example, 99 per cent of the atoms are of four
The composition of sea water has
elements: hydrogen (62.8 per cent); oxygen (25.4 per cent); carbon (9.4
also been modified during the
per cent) and nitrogen (1.4 per cent). This fact reflects the predominant
course of life on earth. The
role of water in cells. Indeed, as can be seen from Fig. 1.2, the compo-
co-evolution of life and the earth
form the basis of the ‘Gaia’ sition of cells is related to the composition of sea water: in general,
hypothesis that has been put elements abundant in sea water are abundant in cells and vice versa. This
forward and discussed by James
is presumably because chemicals present in sea water were available
Lovelock.
during evolution. For example, as in sea water, many inorganic ions such
Elements which are abundant in as sodium, potassium and chloride are present at high levels in cells. The
the earth’s crust, e.g. Al (8.2 per
composition of sea water, in turn, reflects the chemicals available at the
cent of the atoms) and Si (28 per
surface of the earth, modified by their water solubility.
cent of the atoms), but which are
The way in which the composition of cells differs from that of sea water
not readily soluble, are present at
only low levels in sea water and sheds light on the chemistry of life. All cells must concentrate and retain
often only present at low levels in foodstuffs and other essential chemicals. Cells must also discard unwanted
cells (Fig. 1.2).
chemicals into the environment. Some chemicals plentiful within cells are
For elements lying close to the absent, or present at lower Ievels, in the sea. These chemicals are enriched
diagonal line in Fig. 1.2, the in cells because of their chemical utility. In Fig. 1.2 the elements which are
average concentration found in
enriched in cells appear above the diagonal line, e.g. nitrogen, phosphorus
the human body is comparable
and iron.
with that found in sea water.
Iron is an example of an element
more plentiful within cells than in
the oceans. Iron carries out a
diverse range of chemistry that is
O N
indispensable to cells. For over a OP
half of the 4.5 billion years of the
earth’s existence, its surface
environment is believed to have
been more highly reducing than at
present. In particular, oxygen is
thought to have accumulated to
significant levels only about 2
billion years ago. Before the
accumulation of oxygen, much of
the iron on the surface of the
earth was present as moderately
soluble iron (11) salts. Once
oxygen accumulated, however,
more iron became trapped as iron
(111) hydroxide that is very
1 2 3 4 5 6 7 8 9
insoluble. As the availability of
iron decreased, organisms Log [element] in sea water (concentrationi n parts perlolo)
evolved the ability to concentrate
this element from their Fig. 1.2 Comparison of the concentrations of elements in the human body and in
environment. sea water.
Foundations of chemical biology 3
Tablel.1 Approximate chemical
1.3 The molecules present in cells
composition of a typical cell.
~
Many different organic compounds are found in cells. The interconver-
Per cent of total
sion of organic compounds is critical to the functioning of a cell-it
cell weight
provides both the chemical energy required to fuel the cell's activities and
the materials needed by the cell to construct other molecular species. The Water 70
inorganic ions 1
reactions of chemicals within cells are collectively known as metabolism
Sugars 3
and so these organic compounds are known as metabolites.
Amino acids 0.5
Some of the small organic metabolites are used as building blocks of Nucleotides 0.5
polymers synthesized and used by cells. These polymers include proteins, Lipids 2
constructed from amino acids, and nucleic acids, which are derived from Macro- 22
molecules
sugars and phosphate ions in combination with another class of organic
compound, the heterocyclic bases. The properties of these polymers are
one of the most distinctive chemical features of living cells.
Life is inextricably linked with water. The interior of a cell is an aqueous
Hydrogen bonding results from an
solution, rich in a variety of chemicals including simple inorganic species electrostatic attraction between
such as salts, small organic molecules, and a range of polymers derived an electron-deficient hydrogen
from these molecules. This solution of water-soluble chemicals is enclosed atom and an electron-rich centre.
by membranes comprised of molecules not freely soluble in water. The When hydrogen is attached to an
electronegative element, it
interaction of cellular molecules with water is crucial in determining their
becomes relatively positive and
biological properties and provides a focus for much of this book. can interact favourably with
relatively negative centres.
For example, in water:
1.4 The importance of water
Because of their non-polar nature, most organic compounds cannot form 0 is more electronegative
than H, resulting in a dipole
hydrogen bonds with water molecules and so do not dissolve in aqueous
I
solutions. Alkanes, for example, are immiscible with water and float on top
of it. This arrangement minimizes the surface area of the organic com-
pound in contact with water, leaving the water molecules free to hydrogen
bond with each other. Molecules that have a very highly non-polar surface
are relatively rare in biochemistry. Fats, e.g. triglycerides, are of this type hydrogen bond due to
electrostatic attraction
(Fig. 1.3); they are immiscible with water and segregate themselves from
the aqueous environment. Molecules, and portions of molecules, which 'Hydrophobic' is derived from the
prefer to avoid contact with water are termed hydrophobic. Greek words 'hydro' for water and
The only organic compounds freely soluble in water bear polar groups 'phobic' for fearing.
on the carbon framework which can hydrogen bond with water. Hydroxyl
groups fall into this category. Sugars, such as glucose, dissolve in water by
virtue of the hydroxyl groups attached to the carbon framework (Fig. 1.4).
Functional groups that interact favourably with water are termed
hydrophilic.
Hydroxyl groups can
hydrogen bond
0 effectively with water
Fig.1.4 Glucose: an example of
a water-solu ble biochemical
H'C - O-~-CH2CH,CH2CH2CH2CH2CH2CH,CH,CH2CH2CH2CH2CH2CH3 molecule.
H2C( p
0- C-CH2CH2CH2CH2CH&H2CH2CH2CH2CH2CH,CH2CH2CH2CH3 'Hydrophilic' is derived from the
Greek words 'hydro' for water and
Fig. 1.3 A triglyceride: a water-insoluble biochemical molecule. 'philic' for loving.
4 The chemicals of biological systems
The interaction of compounds + HC
with water is an equilibrium H 0 w N H 2 f + k-------\
phenomenon. It can be related to
Gibbs free energy changes (AG); Ethanolamine I
t
ahneds e,n tinro tpuyrn (, hAaSv)ec oemntphoanlpeyn t(sA: H) CH3CO2H f- H+ b CH3COk; -- ,'\ ._H ydroI gen bonding
AG = AH - TAS
where Tis the temperature. AH is
a measure of changes in heat Glycine w
associated with a process, lUien tdoe trh peh ryisgihotl;o cghicaargl ceodn fdoirtmiosn sp rtehdeosem einqautieli bria
whereas AS is a measure of
changes of the degree of Fig. 1.5 Representative water-soluble organic ions.
disorder of a system. Favourable
processes involve an overall Many inorganic salts are soluble in water. Likewise, the introduction of
decrease in free energy
(AG< 0) because of either charge into organic molecules enhances hydrophilicity. Charge arises in
the liberation of heat (AH<0 ) organic molecules primarily via acid-base chemistry, e.g. the protonation
or an increase in disorder, of amines to form ammonium salts. As examples (Fig. 1.5), ethanolamine,
(AS> 0) or both. a biochemically important amine, is protonated at neutral pH, while acetic
(ethanoic) acid is deprotonated. Both are charged at normal physiological
Dispersing a non-polar organic pH. By analogy, amino acids, such as glycine, contain two opposite
compound in water would force charges under the conditions found in cells.
the water to adopt a more The interactions of molecules with water are crucial in determining their
ordered structure in an effort to biological functions. These interactions, in turn, are determined by the
retain as much hydrogen bonding type, number and distribution of polar functional groups over the non-
as possible. Segregation of the
organic compounds from water polar hydrocarbon backbone of a molecule.
minimizes this unfavourable
entropy effect. 1.5 Ordered molecular structures in biology
Phosphates are another A key feature of many important biochemical molecules is that they adopt
important class of ionic functional ordered structures. This ordering is the basis of their biological function.
group found in many metabolites. Two classes of ordering are highlighted in this text: the organized linking
These deprotonated forms of
phosphoric acids also hydrogen of monomers to form polymers, and the formation of ordered three-
bond readily with water. They are dimensional structures by some classes of biological molecule when they
discussed extensively in the latter come into contact with water.
half of the book. In biological polymers derived from a family of monomer units (notably
proteins and nucleic acids) the monomers are covalently linked in a specific
Figure 1.6 illustrates a single order in the final polymer chain, as illustrated schematically in Fig. 1.6.
tetramer, ABCD, formed from four Organic molecules, whether small or large, which contain both hydro-
distinct monomer units. There are phobic and hydrophilic portions, have the potential to adopt
a total of 24 possible tetramers
derived from combining a set of ordered structures in water. There is a driving force for such molecules to
four different monomers
(4 x 3 x 2 x 1 =24). Up to 256
tetramers (i.e.
4 x 4 x 4 x 4 = 256) are posible 88g -poClymonetrmoizlaletdio n
if any combination of such a Polymer with we//-defined
family of monomers may be A family of related monomers can be sequence of monomers
employed, corresponding linked in different orders to form polymers
to choosing any of the four
monomers at each position, e.g. Fig.1.6 A schematic representation of the ordering of monomers in biological
ABAD. polymers.