the chemicals of biological systems

8/13/2019 The Chemicals of Biological Systems

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1 The chemicals ofb o og cal systems

1 1 IntroductionThis book is concerned with the chemistry taking place in the cells of livingorganisms. Cells consist of a semipermeable membrane enclosing anaqueous solution rich in a diverse range of chemicals (Fig. 1.1). To thechemist, cells are, in essence, sophisticated machines that undertake a widerange of chemistry in an organized fashion. Cells have the potential togrow, replicate and produce closely related daughter cells, therebyhanding down their controlled chemistry to the next generation. Theseremarkable characteristics all emerge from the chemical properties of theconstituent molecules of cells.

The chemicals present in cells appear to have been selected by theprocesses of evolution for their chemical utility. The aim of this text is toshow that many cellular processes can be understood in simple molecularterms. Although many biochemical molecules have complex structures,their biological properties can often be rationalized in terms of rathersimple chemistry. A comprehensive account of the chemistry of biologicalsystems is not the objective of this book; instead, a series of examples willbe used to exemplify many of the principles thatunderstanding the chemistry of cells.Cytosokan aqueous solution ofwater-soluble inorganic ions, e.g. K+and CI-; small water-soluble organiccompounds, e.g. sugars and aminoacids; and water-soluble organic -- \polymers, e.g. proteins and nucleic, aspects of life \acids I I I

Ribosome-an assemblyof polymers (proteins andRNA which catalysesthe production of proteins,essential to all

are important for

f/age//un+-molecular;machine to propel

bacteria, built from\,fibrous proteins\

organic compounds,lipids, of low solubilityin water, associatedwith water-insoluble

,-

organic polymer proteins, provide aof high mechanical I semipermeable barrierstrength DNA-an organic polymer, acts to the surroundings

Fig 1 1 A chemists schematic view of a bacterial cell.as the genetic information store

Figure 1.1 illustrates some grossfeatures of a typical prokaryoticcell-a cell lacking a nucleus. Allbacteria are prokaryotes,whereas all complex multicellularorganisms such as plants andanimals, as well as manyunicellular species, areeukaryotes-their cells have anucleus which houses DNA.Eukaryotic cells are rather morecomplex in structure and function;for mechanical strength they mayutilize an internal skeleton inaddition to, or instead of, anexternal cell wall; and theycontain a range of discreteinternal compartments. Althoughthe detailed workings ofprokaryotic and eukaryotic cellsare different, the types ofchemicals present, and thefactors affecting their location,are similar: lipids, and othermolecules with non-polar surfaces, are found inmembranes; and polar entitiessuch as sugars and amino acidsare retained in aqueous solution.


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2 The chemicals of biological systems1 2 The elemental composition of cellsThe contents of cells are related to, although different from, the chemicalcomposition of their external environment. It is possible to rationalizethe similarities and differences between cells and their environment inmolecular terms. The use of particular chemicals by biology is related totheir availability (now and in the past) and their chemical utility. Thechemistry of cells is dominated by compounds made up of a smallnumber of elements. For example, 99 per cent of the atoms are of fourelements: hydrogen 62.8 per cent); oxygen (25.4 per cent); carbon (9.4per cent) and nitrogen (1.4 per cent). This fact reflects the predominantrole of water in cells. Indeed, as can be seen from Fig. 1.2, the compo-sition of cells is related to the composition of sea water: in general,elements abundant in sea water are abundant in cells and vice versa. Thisis presumably because chemicals present in sea water were availableduring evolution. For example, as in sea water, many inorganic ions suchas sodium, potassium and chloride are present at high levels in cells. Thecomposition of sea water, in turn, reflects the chemicals available at thesurface of the earth, modified by their water solubility.

The way in which the composition of cells differs from that of sea watersheds light on the chemistry of life. All cells must concentrate and retainfoodstuffs and other essential chemicals. Cells must also discard unwantedchemicals into the environment. Some chemicals plentiful within cells areabsent, or present at lower Ievels, in the sea. These chemicals are enrichedin cells because of their chemical utility. In Fig. 1.2 the elements which areenriched in cells appear above the diagonal line, e.g. nitrogen, phosphorusand iron.

After C, H N and 0 the otherelements important, or essential,to life are B, Ca, CI, Co, Cu, Fe, K,Mg, Mn, Mo, Na, Ni, P,S,Se, Siand Zn.The composition of sea water hasalso been modified during thecourse of life on earth. Theco-evolution of life and the earthform the basis of the Gaiahypothesis that has been putforward and discussed by JamesLovelock.Elements which are abundant inthe earths crust, e.g. Al 8.2 percent of the atoms) and Si (28 percent of the atoms), but which arenot readily soluble, are present atonly low levels in sea water andoften only present at low levels incells (Fig. 1.2 .For elements lying close to thediagonal line in Fig.1.2, theaverage concentration found inthe human body is comparablewith that found in sea water.Iron is an example of an elementmore plentiful within cells than inthe oceans. Iron carries out adiverse range of chemistry that isindispensable to cells. For overhalf of the 4.5 billion years of theearths existence, its surfaceenvironment is believed to havebeen more highly reducing than atpresent. In particular, oxygen isthought to have accumulated tosignificant levels only about 2billion years ago. Before theaccumulation of oxygen, much ofthe iron on the surface of theearth was present as moderatelysoluble iron 11) salts. Onceoxygen accumulated, however,more iron became trapped as iron111) hydroxide that is veryinsoluble. As the availability ofiron decreased, organismsevolved the ability to concentratethis element from theirenvironment.

O Na OP

1 2 3 4 5 6 7 8 9Log [element] in sea water (concentration n parts perlolo)

Fig 1 2 Comparison of the concentrations of elements in the human body and insea water.


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Foundations of chemical biology 3Tablel 1 Approximate chemical

compositionof a typical cell.3 The molecules present in cellsMany different organic compounds are found in cells. The interconver-sion of organic compounds is critical to the functioning of a cell-itprovides both the chemical energy required to fuel the cell s activities andthe materials needed by the cell to construct other molecular species. Thereactions of chemicals within cells are collectively known as metabolismand so these organic compounds are known as metabolites

Some of the small organic metabolites are used as building blocks ofpolymers synthesized and used by cells. These polymers include proteins,constructed from amino acids, and nucleic acids, which are derived fromsugars and phosphate ions in combination with another class of organiccompound, the heterocyclic bases. The properties of these polymers areone of the most distinctive chemical features of living cells.

Life is inextricably linked with water. The interior of a cell is an aqueoussolution, rich in a variety of chemicals including simple inorganic speciessuch as salts, small organic molecules, and a range of polymers derivedfrom these molecules. This solution of water-soluble chemicals is enclosedby membranes comprised of molecules not freely soluble in water. Theinteraction of cellular molecules with water is crucial in determining theirbiological properties and provides a focus for much of this book.

1.4 The importance of waterBecause of their non-polar nature, most organic compounds cannot formhydrogen bonds with water molecules and so do not dissolve in aqueoussolutions. Alkanes, for example, are immiscible with water and float on topof it. This arrangement minimizes the surface area of the organic com-pound in contact with water, leaving the water molecules free to hydrogenbond with each other. Molecules that have a very highly non-polar surfaceare relatively rare in biochemistry. Fats, e.g. triglycerides, are of this type(Fig. 1.3); they are immiscible with water and segregate themselves fromthe aqueous environment. Molecules, and portions of molecules, whichprefer to avoid contact with water are termed hydrophobic

The only organic compounds freely soluble in water bear polar groupson the carbon framework which can hydrogen bond with water. Hydroxylgroups fall into this category. Sugars, such as glucose, dissolve in water byvirtue of the hydroxyl groups attached to the carbon framework (Fig. 1.4).Functional groups that interact favourably with water are termedhydrophilic

0

HC O-~-CH2CH,CH2CH2CH2CH2CH2CH,CH,CH2CH2CH2CH2CH2CH3H2C( p

0 C-CH2CH2CH2CH2CH&H2CH2CH2CH2CH2CH,CH2CH2CH2CH3Fig 1 3 A triglyceride: a water-insoluble biochemical molecule.

Per cent of totalcell weight

Water 70inorganic ions 1Sugars 3Amino acids 0.5Nucleotides 0.5Lipids 2Macro- 22molecules

Hydrogen bonding results from anelectrostatic attraction betweenan electron-deficient hydrogenatom and an electron-rich centre.When hydrogen is attached to anelectronegative element, itbecomes relatively positive andcan interact favourably withrelatively negative centres.For example, in water:

0 is more electronegativethan H, resulting in a dipole

hydrogen bond due toelectrostatic attraction'Hydrophobic' is derived from theGreek words 'hydro' for water and'phobic' for fearing.

Hydroxyl groups canhydrogen bondeffectively with waterFig 1 4 Glucose: an example ofa water-solu ble biochemicalmolecule.'Hydrophilic' is derived from theGreek words 'hydro' for water and'philic' for loving.


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4 he chemicals o biological systemsThe interaction of compoundswith water is an equilibriumphenomenon. It can be related toGibbs free energy changes AG);these, in turn, have enthalpy (AH)and entropy AS)omponents:

AG =AH TASwhere Tis the temperature. AH isa measure of changes in heatassociated with a process,whereas AS s a measure ofchanges of the degree ofdisorder of a system. Favourableprocesses involve an overalldecrease in free energyAG 0) because of either

the liberation of heat AH< )or an increase in disorder,AS 0) or both.

Dispersing a non-polar organiccompound in water would forcethe water to adopt a moreordered structure in an effort toretain as much hydrogen bondingas possible. Segregation of theorganic compounds from waterminimizes this unfavourableentropy effect.Phosphates are anotherimportant class of ionic functionalgroup found in many metabolites.These deprotonated forms ofphosphoric acids also hydrogenbond readily with water. They arediscussed extensively in the latterhalf of the book.

Figure 1.6 illustrates a singletetramer, ABCD, formed from fourdistinct monomer units. There area total of 24 possible tetramersderived from combining a set offour different monomerstetramers (i.e.4 x 4 x 4 x 4 = 256) are possibleif any combination of such afamily of monomers may beemployed, correspondingto choosing any of the fourmonomers at each position, e.g.ABAD.

4 x 2 x 1 =24). Up to 256

k-------HCH 0 w N H 2 \Ethanolamine IH+ k - - I

CH3CO \ ._ydrogen bondingH3CO2H f

Glycine wUnder physiological conditions these equilibrialie to th e right; charged form s predominate

Fig 1 5 Representative water-soluble organic ions.Many inorganic salts are soluble in water. Likewise, the introduction of

charge into organic molecules enhances hydrophilicity. Charge arises inorganic molecules primarily via acid-base chemistry, e.g. the protonationof amines to form ammonium salts. As examples (Fig. 1.5 , ethanolamine,a biochemically important amine, is protonated at neutral pH, while acetic(ethanoic) acid is deprotonated. Both are charged at normal physiologicapH. By analogy, amino acids, such as glycine, contain two oppositecharges under the conditions found in cells.

The interactions of molecules with water are crucial in determining theirbiological functions. These interactions, in turn, are determined by thetype, number and distribution of polar functional groups over the non-polar hydrocarbon backbone of a molecule.1 5 Ordered molecular structures in b io logyA key feature of many important biochemical molecules is that they adoptordered structures. This ordering is the basis of their biological function.Two classes of ordering are highlighted in this text: the organized linkingof monomers to form polymers, and the formation of ordered three-dimensional structures by some classes of biological molecule when theycome into contact with water.

In biological polymers derived from a family of monomer units (notablyproteins and nucleic acids) the monomers are covalently linked in a specificorder in the final polymer chain, as illustrated schematically in Fig. 1.6.

Organic molecules, whether small or large, which contain both hydro-phobic and hydrophilic portions, have the potential to adoptordered structures in water. There is a driving force for such molecules tomolymerizationontrolled

Polymer with we//-defin ed88g

A family of related m onom ers can belinked in different orders to form polymerssequence of monomers

Fig 1 6 A schematic representation of the ordering of monomers in biologicalpolymers.


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Foundations of chemical biology 5maximize the interaction of hydrophilic portions with water, whilstminimizing the exposure of hydrophobic regions. Proteins, nucleic acidsand lipids all owe their biological function to the emergence of well-defined structures on interaction with water.

There are two different ways by which ordered structures emerge whenbiological molecules are in contact with water. A polymer chain can foldinto a three-dimensional structure in which hydrophobic regions are buriedaway from the solvent, water (Fig. 1.7). This type of structure is found formost proteins and some nucleic acids (e.g. see Sections 3.6,4.4 and 9.6).

Alternatively, molecules can associate non-covalently to form organizedassemblies. This ordering is observed for both large and small molecules.Some biological polymers come together to form multimeric structures (Fig.1.8). This association is important for the biological functioning of manyproteins (e.g. see Sections 3.4 and 4.4). The DNA double helix (Section 9.9)also involves ths type of molecular interaction. Lipids are small moleculesrather than polymers. Their spontaneous association to form bilayer assem-blies (Fig. 1.9) is the basis of biological membrane formation (Chapter 8).

- Linear polymer with polarfolds into a conformationwhich minimizes contact ofand non-polar side chainsn non-polar groups with water\ - - - - - .polymerbackbone

H20 H20 H20 H2O

Monomer umts

Fig 1 7 Schematic view of a polymer folding into a well-defined shape in water.

In water, individual lipidmolecules with polar andnon-polar regions associateinto a bilayer structure thatminimizes contact ofnon-polar groups with water

ig 1 9 Schematic view of lipids associating to form a bilayer.

In water, some individualpolymer chains associateto give multirnericstructures which minimizecontact of non-polar groupsI with the solvent.H2 2 0 O H 2 '20 H2O

Fig 1 8 Schematic view of poly-mer chains associating to form amultirneric structure.

Individual lipid molecules are notcovalently linked together inmembranes; the bilayer structureinvolves non-covalentassemblies of molecules. Thesame chemical principles areresponsible for the adoption ofthese non-covalent assembliesas in the adoption of well-definedstructures by proteins and nucleicacids. Individual lipid moleculescontain both hydrophilic andhydrophobic regions. The bilayerstructure allows the hydrophobicregions of lipid molecules to beburied away from water, leavingonly the hydrophilic portionsexposed.


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6 The chemicals o biological systemsA great deal of contemporaryresearch in chemistry is asso-ciated with trying to understandand learn from biology. The studyof simple chemical systems whichmimic the chemistry found incomplex biological systems is animportant area of research knownas biomimetic chemistry (e.g. seeSection 4.5). It is useful in unra-velling some of the basic princi-ples underlying the chemistryfound in cells.

1 6 An overview of the book: the emergence ofbiolog ical functionMuch of this book discusses the way in which small molecules present incells combine to generate ordered structures with biological function (Fig.1.10). To this end, the small molecules, and their derivatives, are con-sidered in two groups. The first half of the book (Chapters 2-5) introducesone family of molecules: amino acids and proteins. The second half(Chapters 6-9) deals with molecules derived from sugars and phosphates,including the nucleic acids. In each half of the book, the individualcomponents are described and then the discussion is elaborated to illus-trate how biological function is facilitated as these individual units cometogether to form complex entities.

CH3H2N +C02HAlanine, a typicala-amino acid in Chapter 3

a-Amino acids are the buildingblocks of proteins. Their intrinsic

Proteins are key polymers responsible formany cellular functions They fold intowell-defined three-dimensional structureswhich are the basis of their biologicalfunctions. These structures are discussed

Proteins can bind small molecules on parts of their Isurfaces. This property is exploited as a meansof, for example, storing and transporting smallmolecules (discussed n Chapter 4) and catalysingff Myoglobm a pfotelnchemical reactions.The catalysis of a key [ which stores oxyg enbiochemical reaction of sugar phosphates, byan enzyme, is discussed in Chapter 5. H - P H

1 CH,OP03*-DNA double helix

Sugar phosphate derivatives are used as linking groups in keybiochemicals When non-polar groups are appended, they adoptordered structures in water Some such molecules, lipids, form thebasis of biological membranes (discussed n Chapter 8). A familyof polymeric derivatives, nucleic acids (DNA and RNA), arediscussed in Chapter 9 They are the carriers of genetic information

D-G/ycera/dehyde-3-pbosphatetypic l sugar phosphate

Sugar phosphates are discussed in Chapter 6.Chapter 7 illustrates their role in the chemicalreactions of cells (metabolism)

Fig 1 10 A schematic overview of the book.

The science of new materials isone area which benefits from theprinciples learned from biology.As an example, one goal ofcurrent chemistry is to makemolecular devices, whereindividual molecules undertake arole normally performed by alarge-scale machine. Molecularmachines' have been found toplay an important role in biology(e.g. see Chapter 8). Suchresearch into 'nanotechnology' ishoped to provide new levels ofminiaturization for futuretechnological applications.

Further readingAn overview of cell biology is given in: H Lodish, D. Baltimore, A. Berk, S LZipursky, P Matsudaira and J. Darnel1 1995) Molecular Biology of the Cell3rd edn, W H Freeman & Co Ltd, Oxford.Bioinorganic chemistry is discussed in: P. A Cox 1995) The Elements on Earth

Oxford University Press, Oxford; P. C. Wilkins and R. G. Wilkins 1997)Zizorgaizic Chemistry in Biologj , Oxford University Press, Oxford; and R. J. P.Williams and J J. R. Frausto da Silva 1997) The Natural Selection of theCheinical Elements Oxford University Press, Oxford.Good recent general biochemistry texts include: C K Mathews, K E. van Holdeand K. G. Ahern 2000) Biochemistry 3rd edn, Benjamin/Cummings, SanFrancisco; and R. H. Garrett and C. M. Grisham 1998)Biochemistry 2nd edn,Sanders College Publishers, Fort Worth.

the chemicals of biological systems

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