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1
Foundations ofBiochemistry
1 The Molecular Logic of Life2 Cells3 Biomolecules4 Water
Fifteen to twenty billion years ago, the universe arose as a cataclysmiceruption of hot, energy-rich subatomic particles. Within seconds, the sim-plest elements (hydrogen and helium) were formed. As the universe ex-panded and cooled, material condensed under the influence of gravity toform stars. Some stars became enormous and then exploded as supernovae,releasing the energy needed to fuse simpler atomic nuclei into the morecomplex elements. Thus were produced, over billions of years, the earth it-self and the chemical elements found on the earth today. About four billionyears ago, life arose—simple microorganisms with the ability to extract en-ergy from organic compounds or from sunlight, which they used to make avast array of more complex biomolecules from the simple elements andcompounds on the earth’s surface. Biochemistry asks how the thousands ofdifferent biomolecules interact with each other to confer the remarkableproperties of living organisms.
In Part I, we will summarize the biological and chemical background tobiochemistry. Living organisms obey the same physical laws that apply to allnatural processes, and we begin by discussing those laws and several ax-ioms that flow from them (Chapter 1). These axioms make up the molecu-lar logic of life. They define the means by which cells transform energy toaccomplish work, catalyze chemical transformations, assemble complexmolecules from simpler subunits, form supramolecular structures that arethe machinery of life, and store and pass on the instructions for the assem-bly of all future generations of organisms from simple, nonliving precursors.
Cells, the units of all living organisms, share certain features; but thecells of different organisms, and the various cell types within a single or-ganism, are remarkably diverse in structure and function. Chapter 2 is abrief description of the common features and the diverse specializations ofcells, and of the evolutionary processes that have led to such diversity.
Nearly all of the organic compounds from which living organisms areconstructed are products of biological activity. These molecules were se-lected during the course of biological evolution for their fitness in perform-ing specific biochemical and cellular functions. Biomolecules can be char-acterized and understood in the same terms that apply to molecules ofinanimate matter: the types of bonds between atoms, the factors that con-tribute to bond formation and bond strength, the three-dimensional
facing pageThe Orion Nebula, a tremendous cloud of gas in whichmany hot, young stars are evolving rapidly toward cata-clysmic cosmic explosions called supernovae. Energyreleased by nuclear explosions in such supernovaebrought about the fusion of simple atomic nuclei, forming the more complex elements of which the earth,its atmosphere, and all living things are composed.
part
I
2 Part I Foundations of Biochemistry
structures of molecules, and chemical reactivities. Three-dimensionalstructure is especially important in biochemistry. Biological interactions,such as those between enzyme and substrate, antibody and antigen, hor-mone and receptor, are highly specific, and this specificity is achieved bysteric and electrostatic complementarity between molecules. Prominentamong the forces that stabilize three-dimensional structure are noncovalentinteractions, individually weak but with significant cumulative effects.Chapter 3 provides the chemical basis for later discussions of the structure,catalysis, and metabolic interconversions of individual classes of biomole-cules.
Water is the medium in which the first cells arose, and it is the solventin which most biochemical transformations occur. The properties of waterhave shaped the course of evolution, and the structure and interactions ofbiomolecules are profoundly influenced by the aqueous solution in whichbiomolecules reside. The weak interactions within and between biomole-cules are strongly affected by the solvent properties of water. Even water-insoluble components of cells, such as membrane lipids, interact with eachother in ways dictated by the polar properties of water. In Chapter 4 weconsider the properties of water, the weak noncovalent interactions that oc-cur in aqueous solutions of biomolecules, and the ionization of water and ofsolutes in aqueous solution.
These initial chapters are intended to provide a chemical backdrop forthe later discussions of biochemical structures and reactions, so whateveryour background in chemistry or biology, you can immediately begin to fol-low, and to enjoy, the action.
3
The Molecular Logic of Life
(a)
(c)
(b)
figure 1–1Some characteristics of living matter. (a) Microscopiccomplexity and organization are apparent in this colorizedthin section of vertebrate muscle tissue, viewed with theelectron microscope. (b) A prairie falcon acquires nutri-ents by consuming a smaller bird. (c) Biological repro-duction occurs with near-perfect fidelity.
Living organisms are composed of lifeless molecules. When these moleculesare isolated and examined individually, they conform to all the physical andchemical laws that describe the behavior of inanimate matter. Yet living or-ganisms possess extraordinary attributes not exhibited by any random col-lection of molecules. In this chapter, we first consider the properties of liv-ing organisms that distinguish them from other collections of matter, andthen we describe a set of principles that characterize all living organisms.These principles underlie the organization of organisms and their cells, andthey provide the framework for this book. They will help you to keep thelarger picture in mind while exploring the illustrative examples presentedin the text.
The Chemical Unity of Diverse Living OrganismsWhat distinguishes living organisms from inanimate objects? First is theirdegree of chemical complexity and organization. Thousands of differentmolecules make up a cell’s intricate internal structures (Fig. 1–1a). By con-trast, inanimate matter—clay, sand, rocks, seawater—usually consists ofmixtures of relatively simple chemical compounds.
Second, living organisms extract, transform, and use energy from theirenvironment (Fig. 1–1b), usually in the form of chemical nutrients or sun-light. This energy enables organisms to build and maintain their intricatestructures and to do mechanical, chemical, osmotic, and other types ofwork. Inanimate matter does not use energy in a systematic, dynamic wayto maintain structure or to do work; rather, it tends to decay toward a moredisordered state, to come to equilibrium with its surroundings.
The third attribute of living organisms is the capacity for precise self-replication and self-assembly, a property that is the quintessence of the liv-ing state (Fig. 1–1c). A single bacterial cell placed in a sterile nutrientmedium can give rise to a billion identical “daughter” cells in 24 hours. Eachof the cells contains thousands of different molecules, some extremely com-plex; yet each bacterium is a faithful copy of the original, its constructiondirected entirely from information contained within the genetic material ofthe original cell.
Although the ability to self-replicate has no true analog in the nonlivingworld, there is an instructive analogy in the growth of crystals in saturatedsolutions. Crystallization produces more material identical in lattice struc-ture to the original “seed” crystal. Crystals are much less complex than thesimplest living organisms, and their structure is static, not dynamic as areliving cells. Nevertheless, the ability of crystals to “reproduce” themselves
chapter
1
4 Part I Foundations of Biochemistry
figure 1–2Diverse living organisms share common chemical fea-tures. Birds, beasts, plants, and soil microorganismsshare with humans the same basic structural units (cells)and the same kinds of macromolecules (DNA, RNA, pro-teins) made up of the same kinds of monomeric subunits(nucleotides, amino acids). They utilize the same path-ways for synthesis of cellular components, share thesame genetic code, and derive from the same evolu-tionary ancestors. (“The Garden of Eden” (detail), by Jan van Kessel, the Younger (1626–1679).)
led the physicist Erwin Schrödinger to propose in his famous essay “WhatIs Life?” that the genetic material of cells must have some of the propertiesof a crystal. Schrödinger’s 1944 notion (years before our modern under-standing of gene structure) describes rather accurately some of the prop-erties of deoxyribonucleic acid, the material of genes.
Each component of a living organism has a specific function. This istrue not only of macroscopic structures, such as leaves and stems or heartsand lungs, but also of microscopic intracellular structures such as the nu-cleus or chloroplast and of individual chemical compounds. The interplayamong the chemical components of a living organism is dynamic; changesin one component cause coordinating or compensating changes in another,with the whole ensemble displaying a character beyond that of its individ-ual constituents. The collection of molecules carries out a program, the endresult of which is reproduction of the program and self-perpetuation of thatcollection of molecules; in short, life.
Biochemistry Explains Diverse Forms of Life in Unifying Chemical TermsIf living organisms are composed of molecules that are intrinsically inani-mate, how do these molecules confer the remarkable combination of char-acteristics we call life? How can a living organism be more than the sum ofits inanimate parts? Philosophers once answered that living organisms areendowed with a mysterious and divine life force, but this doctrine, called vi-talism, has been firmly rejected by modern science. The study of biochem-istry shows how the collections of inanimate molecules that constitute liv-ing organisms interact to maintain and perpetuate life animated solely bythe chemical laws that govern the nonliving universe.
Living organisms are enormously diverse (Fig. 1–2). In appearance andfunction, birds and beasts, trees, grasses, and microscopic organisms differ
Erwin Schrödinger1887–1961
Chapter 1 The Molecular Logic of Life 5
M M P
E A A
S S S
S S S
A A A
G G G
E E E
S S S
Ordered linear sequences
Englishwords
ProteinDeoxyribonucleicacid (DNA)
For a segment of 8 subunits, the number ofdifferent sequences possible =
208 or2.56 � 1010
C
G
T
A
T
A
C
G
T
A
A
G
C
G
T
T
C
G
A
C
Monomeric subunits
Deoxyribo-nucleotides
(4 differentkinds)
Aminoacids
(20 differentkinds)
C
T
A
G
Letters ofEnglishalphabet
(26 differentkinds)
J TDH
NQIF
ZBU AP
E M
SOW
G XK L C
Phe
Lys
Gly
TyrThr
Asn Gln
AspMet
SerAla
Arg
His
Glu
Val
Leu
CysTrp
Ile
Pro
Gly
Val
Asp
Ser
Phe
Arg
Glu
Ala
Arg
Gly
Pro
Leu
Lys
Asn
Phe
Glu
Asp
Gly
Pro
Leu
Gly
Lys
Trp
Cys
268 or2.1 � 1011
48 or65,536
R
VY
T
A
T
C
figure 1–3Monomeric subunits in linear sequences can spell infi-nitely complex messages. The number of differentsequences possible (S) depends on the number of dif-ferent kinds of subunits (N ) and the length of the linearsequence (L): S � NL. For an average-sized protein (L � 400), S is 20400—an astronomical number.
1The terms used to indicate the size of a molecule are often confused. We use molecular weightor Mr , relative molecular mass, a dimensionless ratio of the mass of a molecule to one-twelfththe mass of 12C. The size of a molecule can also be correctly given in terms of molecular mass(m), which has units of daltons (Da) or atomic mass units (amu). A molecule should never bedescribed as having a molecular weight or Mr (a dimensionless property) expressed in daltonsor atomic mass units.
greatly. Yet, biochemical research has revealed that all organisms are re-markably alike at the cellular and chemical levels. Biochemistry describes in molecular terms the structures, mechanisms, and chemical processesshared by all organisms, and provides organizing principles that underlie lifein all of its diverse forms, principles we shall refer to collectively as the mol-
ecular logic of life. Although biochemistry provides important insights andpractical applications in medicine, agriculture, nutrition, and industry, itsultimate concern is with the wonder of life itself.
Despite the fundamental unity of life, very few generalizations aboutliving organisms are absolutely correct for every organism under every con-dition. The range of habitats in which organisms live, from hot springs toArctic tundra, from animal intestines to college dormitories, is matched bya correspondingly wide range of specific biochemical adaptations, achievedwithin a common chemical framework. For the sake of clarity, we will some-times risk certain generalizations, which, though not perfect, remain useful;we will also frequently point out the exceptions that illuminate scientificgeneralizations.
All Macromolecules Are Constructed from a Few Simple CompoundsMost of the molecular constituents of living systems are composed of car-bon atoms covalently joined with other carbon atoms and with hydrogen,oxygen, or nitrogen. The special bonding properties of carbon permit theformation of a great variety of molecules. Organic compounds of molecularweight (also called relative molecular mass, Mr)
1 less than about 500, suchas amino acids, nucleotides, and monosaccharides, serve as monomeric
subunits of macromolecules: proteins, nucleic acids, and polysaccha-rides. A single protein molecule may have 1,000 or more amino acids, anddeoxyribonucleic acid has millions of nucleotides.
Each cell of the bacterium Escherichia coli (E. coli) contains severalthousand kinds of organic compounds, including a thousand different pro-teins, a similar number of different nucleic acid molecules, and hundreds oftypes of carbohydrates and lipids. In humans there may be tens of thou-sands of different proteins, as well as many types of polysaccharides (chainsof simple sugars), a variety of lipids, and many other compounds of lowermolecular weight.
To purify and to characterize thoroughly all of these molecules wouldbe an insuperable task were it not for the fact that each class of macromol-ecules (proteins, nucleic acids, polysaccharides) is composed of a small,common set of monomeric subunits. These monomeric subunits can be co-valently linked in a virtually limitless variety of sequences (Fig. 1–3), justas the 26 letters of the English alphabet can be arranged into a limitlessnumber of words, sentences, and books.
Deoxyribonucleic acids (DNA) are constructed from only four dif-ferent kinds of simple monomeric subunits, the deoxyribonucleotides. Ribonucleic acids (RNA) are composed of just four types of ribonu-cleotides. Proteins are composed of 20 different kinds of amino acids. Theeight nucleotides from which all nucleic acids are built and the 20 differentamino acids from which all proteins are built are identical in all living
6 Part I Foundations of Biochemistry
[K�]fish[Na�]fish[Cl�]fish
[K�]lake[Na�]lake[Cl�]lake
���
[K�]body
K�
Na�
Cl�
[Na�]body[Cl�]body
CO2
NH3
Monomericsubunits
DNA, RNA,protein, lipids, etc.
2HPO4�
[K�]lake[Na�]lake[Cl�]lake
���Phyto-
plankton
figure 1–4Living organisms are not at equilibrium with their sur-roundings. Death and decay restore the equilibrium.During life, the fish uses energy from food to buildcomplex molecules and to concentrate ions from the sur-roundings. When it dies, it no longer derives energy fromfood and thus cannot maintain concentration gradients;ions leak out. Inexorably, macromolecular componentsdecay to simpler compounds. These simple compoundsserve as nutritional sources for microscopic plants andalgae (the phytoplankton), which are then eaten by largerorganisms. (By convention, square brackets denote con-centration—in this case, of ionic species.)
organisms. The specific sequence of monomeric subunits together withtheir arrangement in space shapes macromolecules for their particular bio-logical functions as genes, catalysts, hormones, and so on.
Most of the monomeric subunits from which all macromolecules areconstructed serve more than one function in living cells. Nucleotides servenot only as subunits of nucleic acids but also as energy-carrying mole-cules. Amino acids are subunits of protein molecules and are also precur-sors of hormones, neurotransmitters, pigments, and many other kinds ofbiomolecules.
We can now set out some of the principles in the molecular logic of life:
All living organisms build molecules from the same kinds ofmonomeric subunits.
The structure of a macromolecule determines its specific biologi-cal function.
Each genus and species is defined by its distinctive set of macro-molecules.
Energy Production and Consumption in MetabolismEnergy is a central theme in biochemistry: cells and organisms depend on aconstant supply of energy to oppose the inexorable tendency in nature fora system to decay to its lowest energy state. The storage and expression ofinformation costs energy, without which structures rich in information in-evitably become disordered and meaningless. The synthetic reactions thatoccur within cells, like the synthetic processes in any factory, require the in-put of energy. Energy is consumed in the motion of a bacterium or anOlympic sprinter, in the flashing of a firefly or the electrical discharge of aneel. Cells have evolved highly efficient mechanisms for coupling the energyobtained from sunlight or fuels to the many energy-consuming processesthey carry out.
Organisms Are Never at Equilibrium with Their SurroundingsOne of the first developments in biological evolution must have been an oilymembrane that enclosed the water-soluble molecules of the primitive cell,segregating them and allowing them to accumulate to relatively high con-centrations. The molecules and ions contained within a living organism dif-fer in kind and in concentration from those in the organism’s surroundings.For example, the cells of a freshwater fish contain certain inorganic ions atconcentrations far different from those in the surrounding water (Fig. 1–4).Proteins, nucleic acids, sugars, and fats are present in the fish but are essen-tially absent from the surrounding medium, which contains only simpler mol-ecules such as carbon dioxide, molecular oxygen, and water. Only by contin-uously expending energy can the fish establish and maintain its constituentsat concentrations distinct from those of the surroundings. When the fishdies, its components eventually come to equilibrium with its surroundings.
Molecular Composition Reflects a Dynamic Steady StateAlthough the chemical composition of an organism may be almost constantthrough time, the population of molecules within a cell or organism is farfrom static. Molecules are synthesized and then broken down by continuouschemical reactions, involving a constant flux of mass and energy throughthe system. The hemoglobin molecules carrying oxygen from your lungs to
Chapter 1 The Molecular Logic of Life 7
(a)
Precursorssynthesis
r1
Hemoglobindegradation
r2
Breakdown products(amino acids) (in erythrocyte) (amino acids)
When r1 � r2, the concentration of hemoglobin is constant.
(b)
Foodingestion
r1
Glucose(carbohydrates) (in blood)
utilizationr2
r3
r4
Waste CO2
Storage fats
Other products
When r1 � r2 � r3 � r4, the concentration of glucose in blood is constant.
figure 1–5The dynamic steady state. A dynamic steady stateresults when the rate of appearance of a cellular compo-nent is exactly matched by the rate of its disappearance.In this scheme, r1, r2, and so forth, represent the rates ofthe various processes. In (a), a protein (hemoglobin) issynthesized, then degraded. In (b), glucose derived fromfood (or from carbohydrate stores) enters the bloodstreamin some tissues (intestine, liver), then leaves the blood tobe consumed by metabolic processes in other tissues(heart, brain, skeletal muscle). The dynamic steady-stateconcentrations of hemoglobin and glucose are maintainedby complex mechanisms regulating the relative rates ofthe processes shown here.
your brain at this moment were synthesized within the past month; by nextmonth they will have been degraded and replaced by new molecules. Theglucose you ingested with your most recent meal is now circulating in yourbloodstream; before the day is over these particular glucose molecules willhave been converted into something else, such as carbon dioxide or fat, andwill have been replaced with a fresh supply of glucose. The amounts of he-moglobin and glucose in the blood remain nearly constant because the rateof synthesis or intake of each just balances the rate of its breakdown, con-sumption, or conversion into some other product (Fig. 1–5). The constancyof concentration is the result of a dynamic steady state.
Organisms Transform Energy and Matter from Their SurroundingsLiving cells and organisms must perform work to stay alive and to repro-duce themselves. The continual synthesis of cellular components requireschemical work; the accumulation and retention of salts and various organiccompounds against a concentration gradient involves osmotic work; and thecontraction of a muscle or the motion of a bacterial flagellum representsmechanical work. Biochemistry examines the processes by which energy isextracted, channeled, and consumed, so it is essential to develop an under-standing of the fundamental principles of bioenergetics—the energytransformations and exchanges on which all living organisms depend.
For chemical reactions occurring in solution, we can define a system asall of the reactants and products present, the solvent, and the immediate at-mosphere—in short, everything within a defined region of space. The sys-tem and its surroundings together constitute the universe. If the systemexchanges neither matter nor energy with its surroundings, it is said to beclosed. If the system exchanges energy but not matter with its surround-ings, it is an isolated system; if it exchanges both energy and material withits surroundings, it is an open system.
A living organism is an open system; it exchanges both matter and en-ergy with its surroundings. Living organisms use either of two strategies toderive energy from their surroundings: (1) they take up chemical fuels fromthe environment and extract energy by oxidizing them; or (2) they absorbenergy from sunlight.
Living organisms create and maintain their complex, orderly struc-tures using energy extracted from fuels or sunlight.
8 Part I Foundations of Biochemistry
figure 1–7Sunlight is the ultimate source of all biological energy.Thermonuclear reactions in the sun produce helium from hydrogen and release electromagnetic energy, which is transmitted to the earth as light and convertedinto chemical energy by plants and some algae and bacteria.
(a)
(b)
(c)
(d)
(e)
Energytransductions
accomplishwork
Potential energy
• Nutrients in environment (complex molecules such as sugars, fats)• Sunlight
Chemical transformationswithin cells
Cellular work:• chemical synthesis• mechanical work• osmotic and electrical gradients• light production• genetic information transfer
Heat
Increased randomness(entropy) in the surroundings
Metabolism produces compoundssimpler than the initialfuel molecules: CO2, NH3,H2O, HPO4
2�
Decreased randomness(entropy) in the system
Simple compounds polymerizeto form information-richmacromolecules: DNA, RNA,proteins
The first law of thermodynamics, developed from physics and chem-istry but fully valid for biological systems as well, describes the principle ofthe conservation of energy:
In any physical or chemical change, the total amount of energy inthe universe remains constant, although the form of the energymay change.
Cells are consummate transducers of energy, capable of interconvertingchemical, electromagnetic, mechanical, and osmotic energy with great effi-ciency (Fig. 1–6). Biological energy transducers differ from many familiarmachines that depend on temperature or pressure differences. The steamengine, for example, converts the chemical energy of fuel into heat, raisingthe temperature of water to its boiling point to produce steam pressure thatdrives a mechanical device. The internal combustion engine, similarly, de-pends upon changes in temperature and pressure. By contrast, all parts ofa living organism must operate at about the same temperature and pres-sure, and heat flow is therefore not a useful source of energy.
Living cells are chemical engines that function at constant temper-ature.
The Flow of Electrons Provides Energy for OrganismsNearly all living organisms derive their energy, directly or indirectly, fromthe radiant energy of sunlight, which arises from thermonuclear fusion re-actions occurring in the sun (Fig. 1–7). Photosynthetic cells absorb lightenergy and use it to drive electrons from water to carbon dioxide, formingenergy-rich products such as starch and sucrose and releasing molecularoxygen into the atmosphere (Fig. 1–8). Nonphotosynthetic cells and or-ganisms obtain the energy they need by oxidizing the energy-rich productsof photosynthesis and then passing electrons to atmospheric oxygen toform water, carbon dioxide, and other end products, which are recycled inthe environment. Virtually all energy transductions in cells can be traced to
figure 1–6During metabolic transductions, the randomness of thesystem plus surroundings (expressed quantitatively asentropy) increases as the potential energy of complexnutrient molecules decreases. Living organisms (a) extractenergy from their environment; (b) convert some of it intouseful forms of energy to produce work; (c) return someenergy to the environment as heat; and (d) release end-product molecules that are less well organized than thestarting fuel, increasing the entropy of the universe. Oneeffect of all these transformations is (e) increased order(decreased randomness) in the form of complex macro-molecules. We shall return to a quantitative treatment ofentropy in Chapter 14.
Photons ofvisible light
4H
4He
Thermonuclearfusion
Chapter 1 The Molecular Logic of Life 9
Reduced fuelsand O2
CO2
Photosynthesis in plants,algae, bacteria
Cellular respiration inanimals, plants, algae, bacteria
figure 1–8Photosynthetic organisms (plants, some algae, and somebacteria) are the ultimate providers of fuels—reduced,energy-rich compounds—in the biosphere. The energy of sunlight drives the synthesis of fuels such as sucroseand starch, with O2 as a by-product. These fuels, or thephotosynthetic organisms themselves, are then a sourceof food for animals, which oxidize the sucrose and starch(using O2 and producing CO2) to supply energy. Thisprocess of fuel oxidation—cellular respiration—is theenergy source for metabolism in both photosynthetic andnonphotosynthetic organisms.
Workdoneraisingobject
Loss ofpotentialenergy of
position
∆G > 0 ∆G < 0
(b) Chemical example
(a) Mechanical example
ExergonicEndergonic
Fre
e en
ergy
, G Reaction 1:Glucose � Pi →
glucose 6-phosphate
Reaction 2:ATP → ADP � Pi Reaction 3:
Glucose � ATP →glucose 6-phosphate � ADP
∆G1
∆G2 ∆G3
∆G3 = ∆G1 � ∆G2
Reaction coordinate
this flow of electrons from one molecule to another, in a “downhill” flowfrom higher to lower electrochemical potential; as such, it is formally anal-ogous to the flow of electrons in a battery-driven electric circuit. All thesereactions involving electron flow are oxidation-reduction reactions;
some reactant is oxidized (loses electrons) as another is reduced (gainselectrons).
The energy needs of virtually all organisms are provided, directlyor indirectly, by solar energy.
The flow of electrons in oxidation-reduction reactions underliesenergy transductions in living cells.
Living organisms are interdependent, exchanging energy and mat-ter via the environment.
Energy Coupling Links Reactions in BiologyThe central issue in bioenergetics is the means by which energy from fuelmetabolism or light capture is coupled to energy-requiring reactions. It isinstructive to consider the simple mechanical example of energy couplingshown in Figure 1–9a. An object at the top of an inclined plane has a cer-tain amount of potential energy as a result of its elevation. It tends sponta-neously to slide down the plane, losing its potential energy of position as itapproaches the ground. When an appropriate string-and-pulley device cou-ples the falling object to another, smaller object, the spontaneous down-ward motion of the larger can lift the smaller, accomplishing a certainamount of work. The amount of energy actually available to do work, calledthe free energy, G, will always be somewhat less than the theoreticalamount of energy released, because some energy is dissipated as the heatof friction. The greater the elevation of the larger object relative to its finalposition, the greater is the release of energy as it slides downward, and thegreater the amount of work that can be accomplished.
Chemical reactions can also be coupled so that an energy-releasing re-action drives an energy-requiring one. Chemical reactions in closed systemsproceed spontaneously until equilibrium is reached. When a system is atequilibrium, the rate of product formation exactly equals the rate at which
figure 1–9Energy coupling in mechanical and chemical processes.(a) The downward motion of an object releases potentialenergy that can do mechanical work. The potential energymade available by spontaneous downward motion, anexergonic process (pink), can be coupled to the endergonicupward movement of another object (blue). (b) In reac-tion 1, the formation of glucose 6-phosphate from glucoseand inorganic phosphate, Pi, yields a product of higherenergy than the two reactants. For this endergonic reac-tion, �G is positive. In reaction 2, the exergonic break-down of adenosine triphosphate (ATP; see Fig. 1–10) candrive an endergonic reaction when the two reactions arecoupled. The exergonic reaction has a large, negativefree-energy change (�G2), and the endergonic reactionhas a smaller, positive free-energy change (�G1). Thethird reaction accomplishes the sum of reactions 1 and 2,and the free-energy change, �G3, is the arithmetic sum of�G1 and �G2. Because the value of �G3 is negative, theoverall reaction is exergonic and proceeds spontaneously.
10 Part I Foundations of Biochemistry
�O P
O�
O
O P
O�
O
O P
O�
OO CH2
OH
C
C
N
HC
C
NH2
N
O
H
OH
HHH
N NCH
figure 1–10Adenosine triphosphate (ATP). The removal of the ter-minal phosphoryl of ATP (shaded pink) is highly exergonic,and this reaction is coupled to many endergonic reactionsin the cell as in the example described in Figure 1–9b.
product is converted to reactant. Thus there is no net change in the con-centration of reactants and products; a “steady state” is achieved. The en-ergy change as the system moves from its initial state to equilibrium, withno changes in temperature or pressure, is given by the free-energy
change, �G. The magnitude of �G depends on the particular chemical re-action and on how far from equilibrium the system is initially. Each com-pound involved in a chemical reaction contains a certain amount of poten-tial energy, related to the kind and number of its bonds. In reactions thatoccur spontaneously, the products have less free energy than the reactants,thus the reaction releases free energy, which is then available to do work.Such reactions are exergonic; the decline in free energy from reactants toproducts is expressed as a negative value. Endergonic reactions require aninput of energy, and their �G values are therefore positive. As in mechani-cal processes, only part of the energy released in exergonic biochemical re-actions can be used to accomplish work. In living systems some energy isdissipated as heat or lost to increasing entropy, a measure of randomness,which we will define more rigorously in Chapter 14.
In living organisms, as in the mechanical example in Figure 1–9a, an ex-ergonic reaction can be coupled to an endergonic reaction or process todrive otherwise unfavorable reactions. Figure 1–9b illustrates this principlefor the case of glucose 6-phosphate synthesis, a reaction occurring in mus-cle cells. The simplest way to produce glucose 6-phosphate would be reac-tion 1, which is endergonic. (Pi is an abbreviation for inorganic phosphate,HPO4
2�. Don’t be concerned about the structure of these compounds now;we will describe them in detail later.)
Reaction 1: Glucose � Pi 88n glucose 6-phosphate (endergonic, �G is positive)
In this reaction, the product contains more energy than the reactants.A second, very exergonic reaction can occur in living cells.
Reaction 2: ATP 88n ADP � Pi (exergonic, �G is negative)
In this reaction, the products contain less energy than the reactant—the re-action releases energy. The two chemical reactions share a common inter-mediate, Pi, which is consumed in reaction 1 and produced in reaction 2.The two reactions can be coupled in the form of a third reaction, which wecan write as the sum of reactions 1 and 2, with the common intermediate Pi
omitted from both sides of the equation:
Reaction 3: Glucose � ATP 88n glucose 6-phosphate � ADP
Because more energy is released in reaction 2 than is consumed in reaction1, reaction 3 is exergonic: some energy is released (�G3 in Fig. 1–9b). Livingcells thus make glucose 6-phosphate by catalyzing a direct reaction be-tween glucose and ATP, in effect coupling reaction 1 to reaction 2.
The coupling of exergonic reactions with endergonic ones is absolutelycentral to the energy exchanges in living systems. The mechanism by whichenergy coupling occurs in biological reactions is via a shared intermediate.We will see that reaction 2 in Figure 1–9b, the breakdown of adenosine
triphosphate (ATP), is the exergonic reaction that drives many ender-gonic processes in cells. In fact, ATP (Fig. 1–10) is the major carrier ofchemical energy in all cells, coupling endergonic processes to exergonicones. The terminal phosphoryl group of ATP, shaded pink in Figure 1–10, istransferred to a variety of acceptor molecules, which are thereby activatedfor further chemical transformation. The adenosine diphosphate (ADP)that remains is recycled (phosphorylated) to ATP, at the expense of eitherchemical energy (during oxidation of fuels) or solar energy (in photosyn-thetic cells).
Chapter 1 The Molecular Logic of Life 11
Activation barrier(transition state, ‡)
Fre
e en
ergy
, G
Reactants (A) �G‡cat
�G‡uncat
Products (B)�G
B)Reaction coordinate (A
figure 1–11Energy changes during a chemical reaction. An activa-tion barrier, representing the transition state, must beovercome in the conversion of reactants (A) into products(B), even though the products are more stable than thereactants, as indicated by a large, negative free-energychange (�G). The energy required to overcome the acti-vation barrier is the activation energy (�G‡). Enzymes cat-alyze reactions by lowering the activation barrier. Theybind the transition-state intermediates tightly, and thebinding energy of this interaction effectively reduces theactivation energy from �G‡
uncat to �G‡cat. (Note that the
activation energy is unrelated to the free-energy changeof the reaction, �G.)
Am
oun
t of
pro
duct
fo
rmed
(B)
Without enzyme (uncatalyzed)
Time
With enzyme
BReaction: A
figure 1–12An enzyme increases the rate of a specific chemical reaction. In the presence of an enzyme specific for theconversion of reactant A into product B, the rate of thereaction may increase by many orders of magnitude(powers of ten) over that of the uncatalyzed reaction. Likeall catalysts, the enzyme is not consumed in the process;one enzyme molecule can act repeatedly to convert manymolecules of A to B.
Endergonic cellular reactions are driven by coupling them to exer-gonic chemical or photochemical processes through shared chemi-cal intermediates.
Enzymes Promote Sequences of Chemical ReactionsAn exergonic reaction does not necessarily proceed rapidly. The path fromreactant(s) to product(s) almost invariably involves an energy barrier,called the activation barrier (Fig. 1–11), that must be surmounted for anyreaction to occur. The breaking of existing bonds and formation of new onesgenerally requires the distortion of the existing bonds, creating a transi-
tion state of higher free energy than either reactant or product. The high-est point in the reaction coordinate diagram represents the transition state.
Virtually every cellular chemical reaction occurs at a measurable rateonly because of the presence of enzymes—biocatalysts that, like all othercatalysts, greatly enhance the rate of specific chemical reactions withoutbeing consumed in the process. Enzymes lower the energy barrier betweenreactant and product. The activation energy (�G‡; Fig. 1–11) required toovercome this energy barrier could in principle be supplied by heating thereaction mixture, thereby increasing the kinetic energy of the molecules,the frequency with which they collide, and the likelihood that they will re-act. However, this option is not available in living cells, which generallymaintain a constant temperature. In fact, many cell components (proteins,membranes) are inactivated by temperatures only a few degrees above anorganism’s normal internal temperature. Instead, enzymes speed reactionsby taking advantage of binding effects. Two or more reactants bind to theenzyme’s surface close to each other and with stereospecific orientationsthat favor the reaction between them. Through this combination of prox-imity and orientation, the probability of productive collisions between reac-tants is increased by orders of magnitude relative to the uncatalyzedprocess, when reactants are randomly oriented and distributed throughoutan aqueous solution. Furthermore, the reactants themselves, in the processof binding to the enzyme, undergo changes in shape that distort them to-ward the transition state, thereby lowering the activation energy and enor-mously accelerating the rate of the reaction (Fig. 1–12). The relationshipbetween the activation energy and reaction rate is exponential; a small de-crease in �G‡ results in a very large increase in reaction rate. Enzyme-catalyzed reactions commonly proceed at rates up to 1010 to 1014 timesfaster than uncatalyzed reactions.
Metabolic catalysts are, with a few exceptions, proteins. (In a few cases,RNA molecules have catalytic roles, as discussed in Chapter 26.) Again witha few exceptions, each enzyme protein catalyzes a specific reaction, andeach reaction in a cell is catalyzed by a different enzyme. Thousands of dif-ferent enzymes are therefore required by each cell. The multiplicity of en-zymes, their specificity (the ability to discriminate between reactants), andtheir susceptibility to regulation give cells the capacity to lower activationbarriers selectively. This selectivity is crucial for the effective regulation ofcellular processes.
The thousands of enzyme-catalyzed chemical reactions in cells arefunctionally organized into many different sequences of consecutive reac-tions called pathways, in which the product of one reaction becomes thereactant in the next (Fig. 1–13). Some pathways degrade organic nutrients
A1
Benzyme 2
Cenzyme 3
Denzyme 4
Eenzyme 5
Fenzyme
figure 1–13A linear metabolic pathway. In this pathway, the reactantA is converted in five steps into the product F, with eachstep catalyzed by an enzyme specific for that reaction.
12 Part I Foundations of Biochemistry
into simple end products in order to extract chemical energy and convert itinto a form useful to the cell. Together these degradative, free-energy-yield-ing reactions are designated catabolism. Other pathways start with smallprecursor molecules and convert them to progressively larger and morecomplex molecules, including proteins and nucleic acids. Such syntheticpathways invariably require the input of energy and, taken together, repre-sent anabolism. The overall network of enzyme-catalyzed pathways con-stitutes cellular metabolism. ATP is the major connecting link (the sharedintermediate) between the catabolic and anabolic components of this net-work (Fig. 1–14). The linked systems of enzyme-catalyzed reactions thatact on the main constituents of cells—proteins, fats, sugars, and nucleicacids—are virtually identical in all living organisms.
ATP is the universal carrier of metabolic energy, linking catabolicand anabolic pathways.
Metabolism Is Regulated to Achieve Balance and EconomyNot only do living cells simultaneously synthesize thousands of differentkinds of carbohydrate, fat, protein, and nucleic acid molecules and theirsimpler subunits, they do so in the precise proportions required by the cell.For example, during rapid cell growth, the precursors of proteins and nu-cleic acids must be made in large quantities, whereas in nongrowing cellsthe requirement for these precursors is much reduced. Key enzymes ineach metabolic pathway are regulated so that each type of precursor mole-cule is produced in a quantity appropriate to the current requirements ofthe cell. Consider the pathway that leads to the synthesis of isoleucine, oneof the amino acids, the monomeric subunits of proteins (Fig. 1–15). If a cellbegins to produce more isoleucine than is needed for protein synthesis, theunused isoleucine accumulates. High concentrations of isoleucine inhibitthe catalytic activity of the first enzyme in the pathway, immediately slow-ing the production of the amino acid. Such feedback inhibition keeps theproduction and utilization of each metabolic intermediate in balance.
�
Osmoticwork
Storednutrients
Ingestedfoods
Solarphotons
Othercellular work
Complexbiomolecules
Mechanicalwork
H2O
NH3
CO2
ADP
ATP
HPO42�
Simple products, precursors
Catabolicreaction
pathways(exergonic)
Anabolicreaction
pathways(endergonic)
A1
B C D E FThreonine Isoleucine
enzyme
figure 1–15Feedback inhibition. Regulation by feedback inhibitionin a typical synthetic (anabolic) pathway. In the bacteriumE. coli, the amino acid threonine is converted to anotheramino acid, isoleucine, in five steps, each catalyzed by aseparate enzyme. (The letters A through F represent thecompounds, or intermediates, in this pathway.) The accu-mulation of the product isoleucine (F) causes inhibition ofthe first reaction in the pathway by binding to the enzymecatalyzing this reaction and reducing its activity.
figure 1–14ATP is the shared chemical intermediate linking energy-releasing to energy-requiring cell processes. Its role in the cell is analogous to that of money in an economy: it is “earned/produced” in exergonic reactions and“spent/consumed” in endergonic ones.
Living cells also regulate the synthesis of their own catalysts, the en-zymes. Thus a cell can switch off the synthesis of an enzyme required to makea given product whenever that product is adequately supplied. These self-adjusting and self-regulating properties allow cells to maintain themselves ina dynamic steady state, despite fluctuations in the external environment.
Living cells are self-regulating chemical engines, continually ad-justing for maximum economy.
Chapter 1 The Molecular Logic of Life 13
(a) (b)
figure 1–16Two ancient scripts. (a) The Prism of Sennacherib,inscribed in about 700 B.C., describes in characters of the Assyrian language some historical events during thereign of King Sennacherib. The Prism contains about20,000 characters, weighs about 50 kg, and has survived almost intact for about 2,700 years. (b) Thesingle DNA molecule of the bacterium E. coli, seenleaking out of a disrupted cell, is hundreds of timeslonger than the cell itself and contains all of the encodedinformation necessary to specify the cell’s structure andfunctions. The bacterial DNA contains about 10 millioncharacters (nucleotides), weighs less than 10�10 g, andhas undergone only relatively minor changes during thepast several million years. The yellow spots and darkspecks in this colorized electron micrograph are artifactsof the preparation.
Biological Information TransferThe continued existence of a biological species requires that its genetic in-formation be maintained in a stable form and, at the same time, be ex-pressed with very few errors. Effective storage and accurate expression ofthe genetic message defines individual species, distinguishes them from oneanother, and assures their continuity over successive generations.
Among the seminal discoveries of twentieth-century biology are thechemical nature and the three-dimensional structure of the genetic mater-ial, deoxyribonucleic acid, or DNA. The sequence of deoxyribonucleotidesin this linear polymer encodes the instructions for forming all other cellularcomponents and provides a template for the production of identical DNAmolecules to be distributed to progeny when a cell divides.
Genetic Continuity Is Vested in DNA MoleculesPerhaps the most remarkable of all the properties of living cells and organ-isms is their ability to reproduce themselves with nearly perfect fidelity forcountless generations. This continuity of inherited traits implies constancy,over thousands or millions of years, in the structure of the molecules thatcontain the genetic information. Very few historical records of civilization,even those etched in copper or carved in stone, have survived for a thou-sand years. But there is good evidence that the genetic instructions in liv-ing organisms have remained nearly unchanged over very much longer pe-riods; many bacteria have nearly the same size, shape, and internalstructure and contain the same kinds of precursor molecules and enzymesas those that lived a billion years ago (Fig. 1–16).
14 Part I Foundations of Biochemistry
figure 1–17The complementary structure of DNA. Complementaritybetween the two strands accounts for the accurate repli-cation essential for genetic continuity. DNA is a linearpolymer of covalently joined subunits, the four deoxyribo-nucleotides: deoxyadenylate (A), deoxyguanylate (G),deoxycytidylate (C), and deoxythymidylate (T). Eachnucleotide has the intrinsic ability, due to its precisethree-dimensional structure, to associate very specificallybut noncovalently with one other nucleotide in the comple-mentary chain: A always associates with its complementT, and G with its complement C. Thus, in the double-stranded DNA molecule, the entire sequence ofnucleotides in one strand is complementary to the
sequence in the other; wherever G occurs in strand 1, C occurs in strand 2; wherever A occurs in strand 1, Toccurs in strand 2. The two strands of the DNA, heldtogether by a large number of hydrogen bonds (repre-sented here by vertical blue lines) between the pairs ofcomplementary nucleotides, twist about each other toform the DNA double helix. In DNA replication, prior tocell division, the two strands of the original DNA separateand two new strands are synthesized, each with asequence complementary to one of the original strands.The result is two double-helical DNA molecules, eachidentical to the original DNA.
Newstrand 1
Oldstrand 2
Newstrand 2
Oldstrand 1
CT
T
T
T T
T
T
T
T T
G
GG
G G
G
G
G
G
G G
GG
C
C
C C
C
C
C
C
C
C C
C
C
A
A
A A
A
A
G
Strand 2
Strand 1
Hereditary information is preserved in DNA, a long, thin organic poly-mer so fragile that it will fragment from the shear forces arising in a solutionthat is stirred or pipetted. A human sperm or egg, carrying the accumulatedhereditary information of millions of years of evolution, transmits these in-structions in the form of DNA molecules, in which the linear sequence of co-valently linked nucleotide subunits encodes the genetic message.
The Structure of DNA Allows for Its Repair and Replication with Near-Perfect FidelityThe capacity of living cells to preserve their genetic material and to dupli-cate it for the next generation results from the structural complementaritybetween the two halves of the DNA molecule (Fig. 1–17). The basic unit ofDNA is a linear polymer of four different monomeric subunits, deoxyri-
bonucleotides (Fig. 1–3), arranged in a precise linear sequence. It is thislinear sequence that encodes the genetic information. Two of these poly-meric strands are twisted about each other to form the DNA double helix,in which each monomeric subunit in one strand pairs specifically with acomplementary subunit in the opposite strand. Before a cell divides, thetwo DNA strands separate and each serves as a template for the synthesisof a new complementary strand, generating two identical double-helicalmolecules, one for each daughter cell. If one strand is damaged, continuityof information is assured by the information present in the other strand,which acts as a template for repair of the damage.
Genetic information is encoded in the linear sequence of fourkinds of subunits of DNA.
The double-helical DNA molecule contains an internal templatefor its own replication and repair.
Changes in the Hereditary Instructions Allow EvolutionDespite the near-perfect fidelity of genetic replication, infrequent, unre-paired mistakes in the replication process produce changes in the nu-cleotide sequence of DNA, representing a genetic mutation (Fig. 1–18).Incorrectly repaired damage to one of the DNA strands has the same effect.Mutations can change the instructions for producing cellular components.Many mutations are harmful or even lethal to the organism; they may, forexample, cause the synthesis of a defective enzyme that is not able to cat-alyze an essential metabolic reaction. Occasionally, a mutation better equipsan organism or cell to survive in its environment. The mutant enzyme
Chapter 1 The Molecular Logic of Life 15
figure 1–18Role of mutation in evolution. The gradual accumulationof mutations over long periods of time results in new bio-logical species, each with a unique DNA sequence. At thetop is shown a short segment of a gene in a hypotheticalprogenitor organism. With the passage of time, changesin nucleotide sequence (mutations, indicated here bycolored boxes) occur, one nucleotide at a time, resultingin progeny with different DNA sequences. These mutantprogeny themselves undergo occasional mutations, yieldingtheir own progeny differing by two or more nucleotidesfrom the original sequence. When two lineages havechanged so much by this mechanism that they can nolonger interbreed, a new species has been created.
Time
A
Mutation2
GA
A A
A
Mutation1
Mutation5
Mutation3
Mutation4
Mutation6
T G A G C T A
T G A C T A T G A C T AG
T G A C
G G
G
A T G A C T A
T C
C C
A C T AG
T
G G A C T AG
T A C A T G A C A
T A C TG T A C T AG
might, for example, have acquired a slightly different specificity, so that itis now able to use as a reactant some compound that the cell was previouslyunable to metabolize. If a population of cells were to find itself in an envi-ronment where that compound was the only available source of fuel, themutant cell would have an advantage over the other, unmutated (wild-
type) cells in the population. The mutant cell and its progeny would sur-vive in the new environment, whereas wild-type cells would starve and beeliminated.
Chance genetic variations in individuals in a population, combined withnatural selection (survival and reproduction of the fittest individuals in achallenging or changing environment), have resulted in the evolution of anenormous variety of organisms, each adapted to life in a particular ecologi-cal niche.
Molecular Anatomy Reveals Evolutionary RelationshipsThe eighteenth-century naturalist Carolus Linnaeus recognized theanatomic similarities and differences among living organisms and provideda framework for assessing the relatedness of species. Charles Darwin, in thenineteenth century, gave us a unifying hypothesis to explain the phylogenyof modern organisms—the origin of different species from a common an-cestor. Now biochemical research in the twentieth century has revealed themolecular anatomy of cells of different species—the subunit sequences andthe three-dimensional structures of individual nucleic acids and proteins.Biochemists have an enormously rich and increasing treasury of evidencethat can be used to analyze evolutionary relationships and to refine evolu-tionary theory. The nucleotide sequences of entire genomes (the genome is
Charles Darwin1809–1882
Carolus Linnaeus1707–1778
16 Part I Foundations of Biochemistry
table 1–1Some Organisms Whose Genomes Have Been Completely Sequenced
Genome sizeOrganism (million bases) Biological interest
Mycoplasma pneumoniae 0.8 Causes pneumoniaTreponema pallidum 1.1 Causes syphilisBorrelia burgdorferi 1.3 Causes Lyme diseaseHelicobacter pylori 1.7 Causes gastric ulcersMethanococcus jannaschii 1.7 Grows at 85 �C!Haemophilus influenzae 1.8 Causes bacterial influenzaMethanobacterium thermo- 1.8 Member of the Archaea
autotrophicumArchaeoglobus fulgidus 2.2 High-temperature methanogenSynechocystis sp. 3.6 CyanobacteriumBacillus subtilis 4.2 Common soil bacteriumEscherichia coli 4.6 Some strains cause toxic
shock syndromeSaccharomyces cerevisiae 12.1 Unicellular eukaryoteCaenorhabditis elegans 97.1 Multicellular roundworm
the complete genetic endowment of an organism) have been determined(Table 1–1). The genomic sequences of a number of eubacteria and an archaebacterium, a eukaryotic microorganism (Saccharomyces cerevisiae),and a multicellular animal (Caenorhabditis elegans) have been deter-mined; those of a plant (Arabidopsis thaliana) and even of Homo sapiens
will soon be known. With such sequences in hand, highly detailed and quan-titative comparisons among species will provide deep insight into the evo-lutionary process. Thus far, the molecular phylogeny derived from gene se-quences is consistent with, but in many cases more precise than, theclassical phylogeny based on macroscopic structures. Molecular structuresand mechanisms have been conserved in evolution even though organismshave continuously diverged at the level of gross anatomy. At the molecularlevel, the basic unity of life is readily apparent; crucial molecular structuresand mechanisms are remarkably similar from the simplest to the most com-plex organisms. Biochemistry makes possible the discovery of the unifyingfeatures common to all life.
The Linear Sequence in DNA Encodes Proteins with Three-Dimensional StructuresThe information in DNA is encoded as a linear (one-dimensional) sequenceof the nucleotide subunits, but the expression of this information results ina three-dimensional cell. This change from one to three dimensions occursin two phases. A linear sequence of deoxyribonucleotides in DNA codes(through an intermediary, RNA) for the production of a protein with a cor-responding linear sequence of amino acids (Fig. 1–19). The protein foldsinto a particular three-dimensional shape, determined by its amino acid se-quence and stabilized primarily by noncovalent interactions. Although thefinal shape of the folded protein is dictated by its amino acid sequence, thefolding process is aided by proteins that act as “molecular chaperones,” dis-couraging incorrect folding. The precise three-dimensional structure, ornative conformation, is crucial to the protein’s function.
Chapter 1 The Molecular Logic of Life 17
The linear sequence of amino acids in a protein leads to the acqui-sition of a unique three-dimensional structure.
Once a protein has folded into its native conformation, it may associ-ate noncovalently with other proteins, or with nucleic acids or lipids, toform supramolecular complexes such as chromosomes, ribosomes, andmembranes. These complexes are in many cases self-assembling. The indi-vidual molecules of these complexes have specific, high-affinity bindingsites for each other, and within the cell they spontaneously form functionalcomplexes.
Individual macromolecules with specific affinity for other macro-molecules self-assemble into supramolecular complexes.
Noncovalent Interactions Stabilize Three-Dimensional StructuresThe forces that provide stability and specificity to the three-dimensionalstructures of macromolecules and supramolecular complexes are mostlynoncovalent interactions. These interactions, individually weak but collec-tively strong, include hydrogen bonds, ionic interactions among chargedgroups, van der Waals interactions, and hydrophobic interactions amongnonpolar groups. These weak interactions are transient; individually theyform and break in small fractions of a second. The transient nature of non-covalent interactions gives macromolecules a flexibility that is critical totheir function. Furthermore, the large number of noncovalent interactionsin a single macromolecule makes it unlikely that at any given moment all theinteractions will be broken; thus macromolecular structures are stable overtime.
Three-dimensional biological structures combine the properties offlexibility and stability.
For example, the double-helical DNA molecule, with its complementarystrands held together by many weak interactions, has enough flexibility toallow strand separation during DNA replication (Fig. 1–17), yet enough sta-bility to ensure genetic continuity.
Noncovalent interactions are also central to the specificity and catalyticefficiency of enzymes. Enzymes bind transition-state intermediates throughnumerous weak but precisely oriented interactions. Because the weak in-teractions are flexible, the enzyme-substrate complex survives the struc-tural distortions that occur as the reactant is converted into product.
Gene 1
RNA 1 RNA 2 RNA 3
Gene 2
Transcription of DNA sequenceinto RNA sequence
Translation on the ribosome of RNA sequenceinto protein sequence and folding of protein
into native conformation
Formation of supramolecular complex
Gene 3
Protein 1 Protein 2 Protein 3
figure 1–19Linear sequences of deoxyribonucleotides in DNA,arranged into units known as genes, are transcribed intoribonucleic acid (RNA) molecules with complementaryribonucleotide sequences. The RNA sequences are thentranslated into linear protein chains, which fold into theirnative three-dimensional shapes, often aided by otherproteins called molecular chaperones. Individual proteinscommonly associate with other proteins to form supramol-ecular complexes, stabilized by numerous weak interactions.
18 Part I Foundations of Biochemistry
Noncovalent interactions provide the energy for self-assembly ofmacromolecules by stabilizing their native conformations relative to theirunfolded, random forms. A protein will assume this more stable shape, itsnative conformation, when the energetic advantages of forming weak inter-actions outweigh the tendency of the protein chain to assume randomforms.
The Physical Roots of the Biochemical WorldWe can now summarize the various principles of the molecular logic of life:
A living cell is a self-contained, self-assembling, self-adjusting, self-perpetuating constant-temperature system of molecules that ex-tracts free energy and raw materials from its environment.
The cell uses this energy to maintain itself in a dynamic steadystate, far from equilibrium with its surroundings.
The many chemical transformations within cells are organized intoa network of reaction pathways, promoted at each step by specificcatalysts, called enzymes, which the cell itself produces. A greateconomy of parts and processes is achieved by regulation of theactivity of key enzymes.
Self-replication through many generations is ensured by the self-repairing, linear information-coding system. Genetic informationencoded as sequences of nucleotide subunits in DNA and RNAspecifies the sequence of amino acids in each distinct protein,which ultimately determines the three-dimensional structure andfunction of each protein.
Many weak (noncovalent) interactions, acting cooperatively, stabi-lize the three-dimensional structures of biological macromoleculesand supramolecular complexes, while allowing sufficient flexibilityfor biological actions.
The chemical reactions and regulatory processes of cells have beenhighly refined over the course of billions of years of evolution. Nevertheless,no matter how complex it may seem, the organic machinery of living cellsfunctions within the same set of physical laws that governs the operation ofinanimate machines.
This set of principles has been most thoroughly validated in studies ofunicellular organisms (such as the bacterium E. coli), which are excep-tionally amenable to biochemical and genetic investigation. Multicellular or-ganisms must solve certain problems not encountered by unicellular organ-isms, such as the differentiation of the fertilized egg into specialized celltypes. Yet here, too, the same principles have been found to apply. Can suchsimple and mechanical statements apply to humans as well, with their ex-traordinary capacity for thought, language, and creativity? The pace of re-cent biochemical progress toward understanding such processes as generegulation, cellular differentiation, communication among cells, and neuralfunction has been extraordinarily fast and is accelerating. The success ofbiochemical methods in solving and redefining these problems justifies thehope that the most complex functions of the most highly developed organ-isms will eventually be explicable in molecular terms.
The relevant facts of biochemistry are many; the student approachingthis subject for the first time may occasionally feel overwhelmed. Perhaps
Chapter 1 The Molecular Logic of Life 19
further readingAsimov, I. (1962) Life and Energy: An Exploration
of the Physical and Chemical Basis of Modern
Biology, Doubleday & Co., Inc., New York.An engaging account of the role of energy transfor-mations in biology, written for the intelligent layper-son by a biochemist and superb writer.
Blum, H.F. (1968) Time’s Arrow and Evolution,
3rd edn, Princeton University Press, Princeton, NJ.An excellent discussion of the way the secondlaw of thermodynamics has influenced biologicalevolution.
Darwin, C. (1964) On the Origin of Species. A
Facsimile of the First Edition (published in
1859), Harvard University Press, Cambridge, MA.One of the most influential scientific works ever published.
Dulbecco, R. (1987) The Design of Life, Yale University Press, New Haven, CT.
An unusual and excellent introduction to biology.
Fruton, J.S. (1972) Molecules and Life: Historical
Essays on the Interplay of Chemistry and Biology,
Wiley-Interscience, New York.This series of essays describes the development ofbiochemistry from Pasteur’s studies of fermentationto the present studies of metabolism and informationtransfer. You may want to refer to these essays asyou progress through this textbook.
Fruton, J.S. (1992) A Skeptical Biochemist,
Harvard University Press, Cambridge, MA.
Jacob, F. (1973) The Logic of Life: A History of
Heredity, Pantheon Books, Inc., New York. Originallypublished (1970) as La logique du vivant: une his-
toire de l’hérédité, Editions Gallimard, Paris.A fascinating historical and philosophical account ofthe route by which we came to the present molecularunderstanding of life.
Judson, H.F. (1979) The Eighth Day of Creation:
The Makers of the Revolution in Biology, JonathanCape, London.
A highly readable and authoritative account of therise of biochemistry and molecular biology in thetwentieth century.
Kornberg, A. (1987) The two cultures: chemistryand biology. Biochemistry 26, 6888–6891.
The importance of applying chemical tools to biologi-cal problems, described by an eminent practitioner.
Mayr, E. (1997) This Is Biology: The Science of the
Living World, Belknap Press, Cambridge, MA.A history of the development of science, with specialemphasis on Darwinian evolution, by an eminent Darwin scholar.
Monod, J. (1971) Chance and Necessity, Alfred A.Knopf, Inc., New York. [Paperback version (1972)Vintage Books, New York.] Originally published(1970) as Le hasard et la nécessité, Editions duSeuil, Paris.
An exploration of the philosophical implications of biological knowledge.
Schrödinger, E. (1944) What Is Life? CambridgeUniversity Press, New York. [Reprinted (1956) inWhat Is Life? and Other Scientific Essays, Double-day Anchor Books, Garden City, NY.]
A thought-provoking look at life, written by a promi-nent physical chemist.
the most encouraging development in twentieth-century biology is the realization that, for all of the enormous diversity in the biological world,there is a fundamental unity and simplicity to life. The organizing principles,the biochemical unity, and the evolutionary perspective of diversity pro-vided at the molecular level will serve as helpful frames of reference for thestudy of biochemistry.
