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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 UNIVERSITY PRESS OXFORD WNIVERSITY PRESS Great Clarendon Street, Oxford 0x2 ~ D P Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide in Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Published in the United States by Oxford University Press Inc., New York 0 C. M. Dobson, J. A. Gerrard, and A. J. Pratt, 2001 The moral rights of the authors have been asserted Database right Oxford University Press (maker) First published 2001, reprinted 2003, 2004, 2006, 2007, 2008, 2009 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this book in any other binding or cover and you must impose this same condition on any acquirer Library of Congress Cataloging in Publication Data (data applied for) ISBN: 978-0-19-924899-5 11 Typeset by Newgen Imaging Systems (P) Ltd, Chennai, India Printed in Great Britain on acid free paper by CPI Antony Rowe, Chippenham, Wiltshire 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.

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