plasma medicine chapter 3

3

Selected Concepts in Biology and Medicine

for Physical Scientists

As evident from the previous chapter,plasma is a complex medium having a variety of different properties that can potentially in?uence living systems.These in?uences can be purely physical,that is,directly related to temperature or electric?elds for example,or biochemical.They can be subtle and selective affecting some biological molecules and cells more than others and,through them,initiating various cascades of biological consequences.This chapter will provide some background necessary to appreciate the structure of the biological world and living systems as the?rst step in learning possible consequences of applying plasma to such systems.Given the complexity of living systems and their molecular basis,the reader should be aware that the description below is a broad overview that relies on some oversimpli?cation and may not contain the precision and detail expected of more specialized texts.This overview does not presume detailed prior knowledge of organic chemistry,biology or medicine and is intended as an introduction to the above topics.An important goal of such an introduction is not only to describe the key concepts,but to familiarize the reader with the relevant terminology.

3.1Molecular basis of life:Organic molecules primer

3.1.1Essential primer on bonds and organic molecules

Living systems,as we know them on our planet,consist primarily of organic molecules and 91c28163c77da26925c5b0e7anic molecules,in turn,can be formed through activity of living systems(they may also be formed in other ways)and have a carbon backbone.Methane(CH4)is an example of a simple organic molecule.Removing a hydrogen atom(H)from a methane molecule and linking several such units together can form a more complex organic molecule.When two methane molecules are so combined,the resultant molecule is ethane which has the chemical formula C2H6.Molecules made up of only H and C are known as hydrocarbons.The formulae and structural representations of several hydrocarbon molecules are provided in Figure3.1.

In general,a number of smaller organic molecules acting as monomers can be joined together to form larger biopolymers(macromolecules).When two monomers join,a hydroxyl(OH)group is typically removed from one monomer and a hydrogen atom(H)is removed from the other,resulting in release of a water molecule. In this way,biopolymers are constructed by covalently bonding monomers in condensation reactions,where Plasma Medicine,First Edition.Alexander Fridman and Gary Friedman.

?2013John Wiley&Sons,Ltd.Published2013by John Wiley&Sons,Ltd.

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Figure3.1Formulae and structural representations of some hydrocarbon molecules.

water is released from the monomers.In living systems,certain organic molecules called enzymes(these are mostly proteins)sometimes help carry out this condensation as well as the reverse reaction of biopoly-mer hydrolysis(that disassembles macromolecules into smaller organic subunits).This reverse reaction of hydrolysis(hydration)consumes water when it breaks down polymers,taking a hydroxyl(OH)group from water and attaching it to one of the organic subunits while attaching the remaining hydrogen(H)to another organic subunit.

Human societies as well as all living forms extract most of the energy required for all their activity from organic molecules primarily through oxidation processes.This energy can be viewed as being stored in various bonds within organic molecules.Table3.1below lists some of the bond energies.Energy of any given Table3.1Typical bond energies in organic molecules.

Bond Bond energy(kJ mole–1)Bond Bond energy(kJ mole–1) H–H432C=O799

O–H460C–C347

C–H410C=C611

C–O360N=O623

O=O494O–O142

S–S250S–H360

Selected Concepts in Biology and Medicine for Physical Scientists83

bond can be affected by the presence of another bond to some extent,but energy that can be extracted from many organic molecules can be calculated with reasonable accuracy using energy per bond approximation. For example,in the reaction of methane with molecular oxygen:

CH4+2O2→CO2+2H2O(3.1) based on the information given in Table3.1,the initial reactants on the left-hand side have total bonding energy U i=–(4×410)–(2×494)=–2628kJ mole–1,while the right-hand side has U f=–(2×799)–(2×460)=–2518kJ mole–1of the total bonding energy.The right-hand side has lower‘bonding’energy;the reaction would therefore proceed under appropriate conditions(such as suf?ciently high temperature needed to overcome an energy barrier)to lower this potential energy.About800kJ mole–1of energy is produced in the process,usually in the form of heat.

While most of the bonds forming organic molecules are covalent(where,roughly speaking,atomic nuclei are attracted to the shared electron distribution that forms an electron pair),these bonds often have associated electric dipole moments.Different electronegativity of the bonding atoms is responsible for this dipole moment.Electronegativity,a concept originally introduced by Linus Pauling in the context of valence bond theory,describes the tendency of an atom to pull electrons in a covalent bond toward itself(although in reality is more complex because neighboring bonds can also affect each other and cannot always be considered independently).The most electronegative atom is?uorine,having an electronegativity value of4on the Pauling scale.The second-most electronegative atom is oxygen with a value of3.44on the Pauling scale, followed by chlorine and nitrogen with electronegativities of3.16and3.04,respectively.Carbon has an electronegativity of2.55on the Pauling scale,which is slighter lower than sulfur(2.58)and somewhat larger than hydrogen(2.20)and phosphorus(2.19).

In de?ning his electronegativity scale,Linus Pauling proposed the following phenomenological relationship between electronegativity and bond energies(in kJ mole–1):

U AB≈(U AA U BB)0.5+180( χAB)2(3.2) where U AB is the heteronuclear(having nuclei of different atoms)covalent bond energy of the atoms A and B,U AA and U BB are the corresponding homonuclear bond energies and χAB is the electronegativity difference.This relationship clearly reveals a correlation between energy release from bonds and change of bond polarities in a reaction.According to the above relationship,a bond becomes purely ionic when one of the atoms A or B does not form a stable covalent bond with itself,which is the case for metals such as sodium(Na),potassium(K)and others.Indeed,compounds such as NaCl and KCl are ionic and bond weakly compared to covalent bonds.

Although there are other methods of de?ning electronegativity in addition to Pauling’s,all the different forms of relative electronegativity of two atoms reliably determine which of the atoms attracts electrons toward itself in a covalent bond.If two atoms in a bond have a relatively small electronegativity difference, the bond is non-polar or weakly polar(has no or weak dipole moment).On the other hand,a relatively large electronegativity difference results in a more polar bond.For example,bonds between carbon and hydrogen (C–H)are weakly polar(and bonding of other hydrogen atoms to the same carbon often further reduces the polarity of each such bond)in contrast to strongly polar bonds between hydrogen and oxygen.

As a note of caution,it should be mentioned that dipole moments of bonds may or may not combine to contribute to dipole moments of molecules.In a water molecule,due to the angle of c.104?between the two O–H bonds,the dipole moments of the bonds contribute to a total dipole moment of the water molecule.This is the origin of a large dielectric constant of water.In an SF6molecule,despite strong polarity of the S–F bonds the molecule has no dipole moment because of the symmetry of the molecule.

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Dipole moments of bonds in functional groups(clusters of atoms with a characteristic structure and function) in organic molecules play an important role in determining molecular properties.For example,since living cells are70–90%water,the degree to which organic molecules interact with water strongly affects their function.Since electric dipoles can interact electrostatically,polar molecules with a suf?ciently large dipole moment tend to surround themselves with polar water molecules in order to reduce their electrostatic energy. As a result,strongly polar functional groups,such as those containing C–O and O–H bonds,are typically hydrophilic and help organic molecules dissolve in water with relative ease.On the other hand,weakly polar (or non-polar)functional groups,such as in hydrocarbons containing only C–H bonds,are hydrophobic. Bond polarity in some molecules is so pronounced that this bond is virtually ionic(bond energy due to electronegativity contribution dominates the right-hand side of Equation(3.2)).As already noted,ionic bonds are weaker than covalent bonds and atoms can separate(bonds can ionize)in the presence of nearby water molecules,offering effective electric?eld screening.This is typically the case with relatively easily ionized carboxyl(COOH)functional group,the presence of which will typically make molecules hydrophilic.More selected functional groups and a classi?cation of molecules are depicted in Figure3.2.

The change in bond polarities during chemical reactions is the essence of what is commonly referred to as the oxidation reaction.In the language of electrochemistry,these are oxidation/reduction or redox processes. Oxidants in such redox processes are those atoms that are reduced by‘taking’electrons in a reaction that oxidizes atoms that donate the electrons.Redox reactions associated with formation of more polar bonds also lead,according to Pauling’s relation(Equation(3.2)),to stronger and more stable bonds and therefore net energy release.

As an example,consider again the reaction of methane and oxygen described by Equation(3.1).As already discussed above,C–H bonds of methane are weakly polar.The bond in the oxygen molecule is completely non-polar.The products of the reaction are both highly polar molecules however because oxygen in carbon dioxide and in the water molecule is highly electronegative and‘takes’the electrons from carbon and hydrogen,respectively.The conversion of methane and oxygen molecules into carbon dioxide and water that produces excess energy therefore also produces net transfer of electrons from some atoms in the reactants to others.This electron transfer is often described as a change in the oxidation state of atoms(usually described by an integer indicating the number of electrons that shifted toward the more electronegative atom).Atoms that lose electrons(from which the electrons shift away as a result of the reaction)reach higher oxidation state or become more oxidized.In the above methane oxidation reaction for example,carbon‘had’all its electrons and an oxidation state of0in the methane molecule.It changed its oxidation state to+4in the carbon dioxide molecule by losing all of its electrons to the more electronegative oxygen.At the same time,each hydrogen atom(which had all its electrons and an oxidation state of0in the methane molecule)lost an electron and changed its oxidation state to+91c28163c77da26925c5b0e7 increase in the oxidation state of all carbons and hydrogen atoms is balanced by the net reduction in the oxidation state of oxygen,which gains the electrons lost by carbon and hydrogen atoms.

In contrast to releasing energy in the form of heat,living systems often convert the energy of the redox reaction into other forms including electrostatic;this is the case in cellular respiration when electrons are transported across membranes of intracellular organelles(mitochondria).In fact,it appears that plasma treatment interacts with cells and tissues at least in part by directly or indirectly in?uencing redox reactions in cells and cellular respiration.

3.1.2Main classes of organic molecules in living systems

In living systems there are four main classes of macromolecules that perform a variety of functions: (1)carbohydrates and sugars;(2)lipids(fats and oils);(3)polypeptides(proteins);and(4)nucleic acids.

Selected Concepts in Biology and Medicine for Physical Scientists85

Figure3.2Some classes of organic molecules and their relationship to speci?c functional groups.

3.1.2.1Carbohydrates

Carbohydrates(synonymous with saccharides in biochemistry)consist of carbon,oxygen and hydrogen where the number of hydrogen atoms is about twice as large as the number of oxygen atoms which,in turn, is about the same as the number of carbon atoms.Carbohydrates are used for a relatively short-term and intermediate-term energy storage(starch for plants and glycogen for animals).They are also employed as structural components in some cells(cellulose in the cell walls of plants and many protists and chitin in the exoskeleton of insects and other arthropods).

Sugars are structurally the simplest carbohydrates.They are the key building materials that make up other types of carbohydrates.Monosaccharides(see examples in Figure3.3)are the simplest and smallest sugar

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Three-carbon sugar Glyceraldehyde H

1

5

41

3

2

23

O C C H OH O OH H

H

H

H

H 2OH

OH

OH

Ribose Deoxyribose

α-Glucose

β-Glucose

Five-carbon sugars C H

OH

H

C

C C C C

5

6

4

1

32O H OH

H or

OH H H 2OH HO OH H

H

C 5

41

3

2

O OH H

H

H

H

H 2OH

OH

H

C

C C C C Fructose

6

52

1

4

3

O OH H

H

HO

H 2OH

H 2OH

OH

H

C

C C C

C C C

C C

C C 5

6

4

1

32O H

OH H OH

H H 2OH HO

OH H

H C C

C C

C C Figure 3.3Examples of monosaccharides.

molecules with a formula [CH 2O]n ,where n is typically between 3and 6.Some important monosaccharides include ribose (C 5H 10O 5),glucose (C 6H 12O 6),and fructose.We classify monosaccharides by the number of carbon atoms,the arrangement of atoms (molecules that have the same chemical formula but different atomic arrangements are called isomers)and the types of functional groups present in them.For example,glucose and fructose (illustrated in Figure 3.3)have the same chemical formula (C 6H 12O 6),but a different structure.Glucose has an aldehyde (internal hydroxyl shown as –OH)and fructose has a keto group (internal double-bond O,shown as =O).This functional group difference,as small as it seems,accounts for the greater sweetness of fructose as compared to glucose.In an aqueous solution,glucose tends to have two isomer structures,α-and β-,with an intermediate straight-chain form (shown in Figure 3.3).

Disaccharides are formed when two monosaccharides are bound together releasing water and using an oxygen atom to connect carbon on originally different subunits,a bond known as the ester bond.Sucrose,a common plant disaccharide,is composed of the monosaccharides glucose and 91c28163c77da26925c5b0e7ctose,milk sugar,is a disaccharide composed of glucose and the monosaccharide galactose.The maltose that ?avors

Selected Concepts in Biology and Medicine for Physical Scientists

87

α

-Glucose 2

α-Glucose β-Fructose

β-Glucose

β-Maltose

β-Galactose

β-Lactose

Sucrose

Formation

of α-linkage

β-Glucose H 2O

α-Glucose β-Glucose

Figure 3.4Examples of disaccharides.

a malted milkshake is also a disaccharide made of two glucose molecules,bound together as shown in Figure 3.4.

Polysaccharides are larger molecules composed of several inpidual monosaccharide units.Starch,a common plant polysaccharide,is made up of many glucose units forming one of two types of structures:amylose and amylopectin.Glycogen is another polysaccharide used as an animal long-term energy storage product that accumulates in the vertebrate liver.Cellulose,a biopolymer that forms the ?brous part of the cell wall,is also a polysaccharide.Cellulose is an important and easily obtained part of dietary ?ber.As compared to starch and glycogen,which are each made up of mixtures of αand βglucose,cellulose (and the animal structural polysaccharide chitin)is made up of only βglucose.The three-dimensional structure of these polysaccharides is thus constrained into straight micro?brils by the uniform nature of its subunits,which resist the actions of enzymes (such as amylase)that breakdown energy-storing polysaccharides (such a starch).3.1.2.2

Lipids

Lipids form the second important class of macromolecules.They are involved in long-term energy storage as well as structural (phospholipids in cell membranes)and signaling (hormones)functions.In contrast to carbohydrates,which contain a roughly equal number of carbon and oxygen atoms,lipids consist primarily of carbon and hydrogen atoms with a relatively few oxygen and other atoms.Remarkably,there is no universally accepted de?nition of the term ‘lipid’.Some textbooks describe lipids as a group of naturally occurring

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OH

(b) Stearic acid

(c) Oleic acid

C O

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

CH 3

H 2C

OH C O

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

CH 2

H 2C

CH 3

H 2C

OH C O

CH 2

H 2C

CH 2

H 2C

CH 2

H 2C

CH 2

HC

HC

CH 2

H 2C

CH 2

H 2C

CH 2

CH 2

H 2C

H 3

C

Figure 3.5Fatty acid examples.

compounds which are not soluble in water (remember that C–H bonds and C–C bonds are weakly polar and non-polar),but are soluble in organic solvents such as hydrocarbons,chloroform,benzene,ethers and alcohols.Lipids include a perse range of compounds such as fatty acids and their derivatives,carotenoids,terpenes,steroids and bile acids.Many of these compounds have little by way of structure or function that unites them.In fact,the above de?nition can be misleading since some of the substances that are now widely regarded as lipids may be almost as soluble in water as in organic solvents.One alternative de?nition is that lipids are fatty acids and their derivatives,and substances related biosynthetically or functionally to these compounds.

Fatty acids have ‘tails’that are long hydrophobic hydrocarbon (consisting primarily of CH 2units)chains and a ‘head’that is a hydrophilic carboxyl (COOH)group.Some examples of fatty acids are shown in Figure 3.5.Fatty acids are the main component of soap for example,where their tails prefer to attach to oily dirt or bacterial particles and their heads are soluble in water to emulsify and wash away the oily dirt.When a fatty acid tail contains the maximum possible number of hydrogen molecules and no double bonds between carbon atoms,it is referred to as saturated (as in saturated by hydrogen).Palmitic and stearic acids in Figure 3.5are saturated,while oleic acid is unsaturated.

Triglycerides,which are commonly known as fats and oils,are made from two kinds of molecules:glycerol (a type of alcohol with a hydroxyl group on each of its three carbons)and three fatty acids joined by dehydration synthesis as illustrated in Figure 3.6.Fats,having more of the saturated fatty acids,tend to remain solid around room temperature due to the fact that saturated fatty acids have relatively straight tails and can pack closer together in making a solid.Oils,on the other hand,are more liquid at around room temperature because they contain more unsaturated fatty acids,making close packing more dif?cult.

Fats and oils function as long-term energy storage materials.Animals convert excess sugars (beyond their glycogen storage capacities)into fats.Fats yield c.9.3kcal g –1,while glycogens yield roughly 3.8kcal g –1.Most plants store excess sugars as starch,although some seeds and fruits have energy stored as oils (e.g.corn

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89

Glycerol Triglyceride

H H C

C O O

H H C H O C H

H O C H H

H O C H

H

H H C H H C H H C H H C H H C H H C H H C H H H C

C O

O

H H C H H C H H C H H C H H C H H

C

C O

O

H H C H H C H H C H H

C H H

C H H

C

H

H C H

C H H C H H C H H C H C

H

H C

H C

H H Figure 3.6Glycerol and formation of triglycerides from glycerol and fatty acids.

oil,peanut oil,palm oil,canola oil and sun?ower oil).Another use of fats is as insulators and cushions.The human body naturally accumulates some fats in the ‘posterior’area.Sub-dermal (’under the skin’)fat plays the role of insulation.

Phospholipids and glycolipids are also important examples of lipids.They are the key structural components of cell membranes.Phospholipids,shown in Figure 3.7,are made from glycerol,two fatty acids and,in place

Figure 3.7Phospholipids have a phosphate group replacing a fatty acid in a triglyceride molecule.

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H3C

H3C H3C

H3C H3C

H3C

H3C

H3C

H3C

H3C OH

O

C

O

OH

O

O CH2OH

HO CH3

CH3CH3

CH3 CH3

HO

(a) Testosterone (c) Vitamin D (b) Cortisone (d) Cholesterol

Figure3.8Examples of(a)steroids;(b)vitamins;(c)hormones;and(d)cholesterol.

of the third fatty acid,a phosphate group(PO4?)with some other molecule attached to its other end.The hydrocarbon tails of the fatty acids are still hydrophobic,but the phosphate group end of the molecule is hydrophilic because of the oxygen atoms with all of their pairs of unshared electrons.This means that phospholipids are soluble in both water and oil.Mammalian cell membranes are constructed as a double layer(bilayer)of phospholipids whose tails face each other in the interior of the membrane;phosphate group heads face water,which is on the outside as well as the inside of the cells.

Cholesterol,steroids and vitamins are another important type of lipids,which generally have a variety of biological roles ranging from structural to signaling.Cholesterol has the general structure consisting of three six-sided carbon rings side by side and a?ve-sided carbon ring,as illustrated in Figure3.8.The central core of this molecule,consisting of four fused rings,is shared by all steroids including estrogen(estradiol), progesterone,corticosteroids such as cortisol(cortisone),aldosterone,testosterone and Vitamin D.In the various types of steroids,various other groups/molecules are attached around the edges of the carbon rings.

3.1.2.3Proteins

Proteins play the primary role in control of all known biological systems.They also act as important structural elements in cell membranes and in extracellular tissues.Enzymes are proteins that act as organic catalysts (a catalyst is a chemical that promotes but is not changed by a chemical reaction).The building block of any protein is the amino acid,which has an amine group(NH2)and a carboxyl group(COOH).The general structures of all amino acids,as well as the speci?c structures of the20biological amino acids,are illustrated in Figure3.9.It is the side group(represented in the?gure as R)that is unique to every amino acid.All known living things(including viruses,if they can be considered living)use various combinations of the same 20amino acids.

Amino acids are linked together by joining the amino end of one molecule to the carboxyl end of another, as illustrated in Figure3.10,forming a macromolecule referred to as polypeptide.Removal of water allows formation of a type of covalent bond known as a peptide bond.Polypeptide can be roughly viewed as a stretched-out protein.However,a protein is more than a polypeptide sequence.Its function is largely related to a three-dimensional(3D)structure into which a polypeptide folds.This folded structure of a polypeptide sequence is often not uniquely determined by the sequence alone and may depend on environmental conditions such as pH,temperature and presence of chaperone molecules as well as the history of these environmental conditions.

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Conventional depiction

Amino Carboxyl αFigure 3.9Structure of amino acids and 20biological amino acids organized by properties of their side chains.

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Medicine

Figure 3.10Polypeptide formation and the peptide bond (see color plate).

Several structuring levels are usually identi?ed in folded proteins.The secondary structure is the tendency of the polypeptide to coil or pleat due to hydrogen bonding between the amino acid side groups.The tertiary structure is controlled by attraction (or repulsion in some cases)between the side groups.Tertiary structures of an HIV protein and of the similar gamma interferon are shown in Figure 3.11,for example.Many proteins such as hemoglobin are formed from one or more polypeptides.Such structures are referred to as quaternary.Structural proteins,such as collagen,have regular repeated primary structures.Collagens have a variety of functions in living things.Keratin is another structural protein.It is found in ?ngernails,feathers,hair and rhinoceros horns.Microtubules,important in cell pision and structures of ?agella and cilia (among other things),are composed of globular structural

proteins.

Figure 3.11Tertiary structures of HIV proteins and of similar gamma interferon.

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Sugar–phosphate

(a) Nucleotide (b) Nucleotide

Figure 3.12Structure of nucleotides and the four nucleotides used as the basis for the DNA molecule structure:adenine (A),guanine (G),cytosine (C)and thymine (T).Only the nitrogenous base is shown for thymine.

3.1.2.4Nucleic acids

Nucleic acids are polymers composed of monomer units known as nucleotides.There are very few different types of nucleotides.The main functions of nucleotide-based molecules are information storage (deoxyribonu-cleic acid or DNA),protein synthesis (ribonucleic acid or RNA)and energy transfers (adenosine triphosphate or ATP and nicotinamide adenine dinucleotide or NAD +).Nucleotides,as shown in Figure 3.12,consist of a sugar,a nitrogenous base and a phosphate.There are several common nitrogenous bases.Purines (adenine,guanine,xanthine and hypoxanthine)are double-ring structures,while pyrimidines (cytosine,thymine and uracil)are single-ringed.

DNA is probably the most well-known molecule based on nucleotides.It was ?rst isolated by Friedrich Meischer in 1869from ?sh sperm and the pus of open wounds.Since it came from nuclei,Meischer named this new chemical nuclein.Subsequently the name was changed to nucleic acid and lastly to deoxyribonucleic acid (DNA).In 1914,Robert Feulgen discovered that fuchsin dye-stained DNA,which was then found in the nucleus of all eukaryotic cells.During the 1920s,biochemist P.A.Levene analyzed the components of

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the DNA molecule.He found that,in addition to deoxyribose sugar and a phosphate group,it contained four out of?ve nitrogenous bases:cytosine,thymine,adenine and guanine(see Figure3.12).Until about the 1940s,it was widely thought that protein(not DNA)was the carrier of hereditary information.DNA was not shown to be the carrier of genetic inheritance until the experiments of Alfred D.Hershey and Martha Chase 91c28163c77da26925c5b0e7ing bacteriophage(virus which infects bacteria),a methodology pioneered by Max Delbruck and Salvador Luria in1940s,Hershey and Chase showed that radioactively labeled DNA and not protein is passed to progeny during bacterial replication.

The actual structure of DNA polymer and the basic idea behind its replication(but not really a detailed mechanism of DNA replication)was speci?ed by James Watson and Francis Crick in1954with the help of X-ray diffraction data from Rosalind Franklin and Maurice Wilkens.We now know that DNA consists of two strands,each containing sequences of complementary nucleotide bases(thymine/adenine or T/A and cytosine/guanine or C/G)bound to each other across the strands by hydrogen bonds(T/A requires two hydrogen bonds,while C/G requires three)and forming a double-helix coil structure as shown in Figure3.13. Within a strand,different nucleotides are covalently bound through phosphate group(the5 end of the strand) oxygen on deoxyribose(the3 end)by releasing water molecule and two of the three phosphate groups on the original nucleotide.

RNA(Figure3.14)was discovered after DNA.RNA,which is constructed using ribose sugar and can incorporate uracil as one of its nitrogenous bases,was found to be the molecule responsible for transcribing genetic information.It transports this information to the sites of protein construction and then actually helps to construct proteins according to this information.There are several different types of RNA including messenger

Figure3.13Double helix structure of a DNA molecule.The so-called5 end is the phosphate group,while the

3 end is the OH group on the deoxyribose.Double hydrogen bond holds the T and A nucleotides together,while

a triple hydrogen bond holds the C and G nucleotides in adjacent strands of single-stranded DNA.

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RNA (single-stranded)sugar

5′

Figure 3.14

Structure of single-stranded RNA.RNA molecules employ nucleotide Uracil,which is not employed

by DNA.RNA (mRNA),which serves as the blueprint for construction of a protein copied from DNA,ribosomal RNA (rRNA)used for protein construction and transfer RNA (tRNA),which can be viewed as a vehicle for the proper amino acid delivery to the protein construction site at the right time.

Adenosine triphosphate,better known as ATP,is probably the most important energy-exchange vehicle in cells.It is known as a coenzyme because it is a non-protein molecule that often binds to proteins to create a functional enzyme.Structurally,ATP consists of the adenine nucleotide (ribose sugar,adenine base and phosphate group,PO 42?)plus two other phosphate groups.This molecule transfers energy in endergonic (energy-absorbing)reactions within the cell that create many other important molecules needed for living functions.The transferred energy is stored in the covalent bonds between phosphates,with the greatest amount of energy (approximately 30kJ mole –1)in the bond between the second and third phosphate groups.This covalent bond is known as a pyrophosphate bond.When ATP donates the energy of this bond,it is converted into adenosine diphosphate (ADP).The process of transfer of the phosphate group to a protein or another organic molecule is known as phosphorylation,while the removal of this group is called dephosphorylation.Enzymes that catalyze phosphorylation are often called kinases,while those that assist in dephosphorylation are known as phosphatases.

Nicotinamide adenine dinucleotide,abbreviated NAD +,is a coenzyme found in all living cells that also plays an important role in cellular energy-exchange reactions.In cellular metabolism,NAD +is involved in redox (reduction and oxidation)reactions,carrying electrons from one reaction to another.The compound is a dinucleotide.It consists of two nucleotides joined through their phosphate groups;one nucleotide contains adenine base and the other nicotinamide.The coenzyme is therefore found in two forms in cells:NAD +is an oxidizing agent that accepts electrons from other molecules and becomes reduced.This reaction forms NADH,which can then be used as a reducing agent to donate electrons.

Nicotinamide adenine dinucleotide phosphate,abbreviated NADP +is another important coenzyme used in anabolic reactions such as lipid and nucleic acid synthesis,which employ NADPH (the reduced form of NADP +)as a reducing agent.NADP +differs from NAD +in the presence of an additional phosphate group on the ribose ring that carries the adenine moiety.The NADPH system is also responsible for generating free radicals in immune cells.These radicals are used to destroy pathogens in a process called the respiratory burst.

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3.2Function and classi?cation of living forms

3.2.1What is life:Functionality of living forms

De?ning a notion of life that is both useful and suf?ciently general turns out to be notoriously dif?cult.In

many ways,a lack of de?nition that clearly distinguishes the living system from its environment has been one of the key problems in the theory of evolution by natural selection as the unifying formalism and the organizing principle of all biology.Instead of a formal de?nition,the following functional characteristics of life are often mentioned.

r Organization:Living systems exhibit a hierarchy of organization levels being subpided into communities of living organisms,with multicellular organisms being subpided into cells,cells into organelles and organelles into molecules.

r Homeostasis:Living forms,from single cells to their communities to multicellular organisms,tend to maintain their internal environment including temperature,acidity levels,water concentrations and others within certain limits,despite time variations of various environmental parameters(such as temperature,

acidity,etc.).Much metabolic energy goes toward this function.

r Reproduction and heredity:Living forms are produced by and from other existing living forms.The reproduction certainly involves the passing of some material,but may also involve some variation of this

material.As a result,any given living form is rarely identical to its ancestor.

r Growth and development:All living forms,even single-celled organisms,grow and develop from the time of their?rst appearance.When?rst formed,cells are small and increase in size as they develop until maturity.Multicellular organisms pass through more complicated processes of differentiation and

organogenesis.

r Energy and mass?ux:Living forms exist in a state different from thermodynamic equilibrium usually maintained by a?ux of energy and/or mass.

Organization and homeostatic properties of living systems are known among other types of self-organizing systems.The last three properties emphasize non-equilibrium nature of life.Speci?cally,it is on the basis of the last functional property that viruses are often excluded as living forms.Viruses,being relatively complex molecular assemblies that may include genetic and/or gene transcription molecules,are in or very near thermal equilibrium for most of their existence.However,the same argument can be made regarding some cells(particularly bacterial cells)that may remain dormant for a long time under some external conditions before coming alive in other conditions.

The dif?culty of deciding if viruses are non-living or alive is only one example associated with the problem of de?ning the living system.However,the lack of a clear de?nition has not stopped substantial progress in life sciences whose practitioners often employ the principle“I know it when I see it”,famously expressed by the US Supreme Court Justice Potter Stewart in connection with identifying obscenity.

3.2.2Major classi?cation of living forms

Organizing all living forms into categories is useful because it not only helps to recognize life in the absence of a uniformly accepted de?nition,but assists in systematic comparison of different manifestations of life. Using the system originally developed by Carl Linne(popularly known as Linneus),biologists often classify all living forms as one of?ve kingdoms:Monera,Protista,Fungi,Plantae and Animalia.Figure3.15illustrates what is now thought to be the relationship between the different kingdoms.

Selected Concepts in Biology and Medicine for Physical Scientists 97ANIMALIA

(multicellular,

eukaryotic) PLANTAE (multicellular, eukaryotic)

FUNGI (multicellular,

eukaryotic)

EUBACTERIA

(single cell,

prokaryotic) ARCHAEBACTERIA (single cell, prokaryotic)

MONERA

PROTISTA (single cells

and multicellular,

Eukaryotic) Figure 3.15Classi?cation of living forms into ?ve animal kingdoms.

The subpision of the kingdom of Monera into Eubacteria and Archaebacteria is somewhat dated.It is now clear that these two sub-kingdoms differ more than originally thought.To emphasize this,the names Bacteria and Archae are often employed today instead of Eubacteria and Archaebacteria.Both are single-cell microorganisms whose cells do not contain kernels (Greek ‘karyose’).As a result,inhabitants of the Monera kingdom are referred to as prokaryotes.By ‘kernel’,biologists most often mean cell nucleus,which contains genetic material (molecules carrying information regarding the possible form a given living organism may assume).In addition,prokaryotes typically do not have other organelles such as mitochondria.

Protista were probably the ?rst of the eukaryotic kingdoms to allow for compartmentalization and dedication of speci?c areas for speci?c functions.The chief importance of Protista is their role as a stem group for the remaining kingdoms:plants,animals,and fungi.Major groups within the Protista include the algae,euglenoids,ciliates,protozoa and ?agellates.

3.3Cells:Organization and functions

As mentioned above,life exhibits hierarchical organization.Atoms are organized into molecules,molecules into organelles,organelles into cells and so on.It seems,however,that all living things are composed of one or more cells as the most basic units of life,and the functions of a multicellular organism are a consequence of the types of cells it contains and how these cells are arranged and work together.Cells fall into two broad groups:prokaryotes and eukaryotes.Prokaryotic cells are smaller (as a general rule)and lack much of the internal compartmentalization and complexity of eukaryotic cells.No matter which type of cell we are considering,all known cells have certain features in common such as a cell membrane,DNA and RNA,cytoplasm and ribosomes.

The natural shapes of cells vary.For example,neurons can grow parts called axons that are often many centimeters long.Skeletal muscle cells can also be several centimeters long.Others such as parenchyma (a common type of plant cell)and erythrocytes (red blood cells)are much more equi-dimensional.Cells often change their shape when they attach to ?rm substrates or other cells.Some cells are encased in a rigid wall which constrains their shape,while others have a ?exible cell membrane (and no rigid cell wall).The size of cells is also related to their functions.Eggs (or to use the Latin word,ova)are relatively large,often being the largest cells an organism produces.The large size of many eggs is related to the process of development

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Nucleus

Ribosomes

Golgi apparatus Endoplastic reticulum

Mitochrondrion

Chromosome

Anatomy of a cell

Figure 3.16Eukaryotic cell anatomy (see color plate).

that occurs after the egg is fertilized,when the contents of the egg (now termed a zygote)are used in a rapid series of cellular pisions,each requiring tremendous amounts of energy.In general,cells range in size from small bacteria (about 1micrometer)to unfertilized eggs produced by birds and ?sh.

3.3.1Primary cell components

Just as larger living organisms differ from each other in structure and function,so do many cells.There are also many similarities between different types of cells.Figure 3.16illustrates the typical structure of a eukaryotic cell,while Figure 3.17shows the anatomy of a typical prokaryotic (bacterial in this case)cell.

3.3.1.1The cell envelope:Membranes and walls

The cell membrane functions as a semi-permeable mechanically ?exible barrier,allowing very few molecules across it while fencing the majority of organically produced chemicals inside the cell.Electron microscopy examinations of cell membranes have led to the development of the lipid bilayer model (also referred to as the ?uid-mosaic model).

As illustrated in Figure 3.18,the most common molecule in the model is the phospholipid,which has a polar (hydrophilic)head and two non-polar (hydrophobic)tails.These phospholipids are aligned tail to tail so the non-polar areas form a hydrophobic region between the hydrophilic heads on the membrane surfaces,facing toward the inside and outside of the membrane.This membrane is termed a bilayer partly because freeze-fracture preparation for electron microscopy is able to split the membrane into two layers.The bilayer membrane is actually ?uid-like in that various molecular structures in it can move as if in a ?uid when these structures are not otherwise anchored in some way to other molecular structures within cells.In mammalian cells,these anchors and structural support are partly provided by the cytoskeleton ?laments.Cholesterol is often an important component of mammalian cell membranes embedded in the hydrophobic areas of the inner

Selected Concepts in Biology and Medicine for Physical Scientists 99

Prokaryotic cell structure

Crytoplasm

Nucleoid

Flagella

Capsule Cell wall Cytoplasmic membrane Ribosomes

Pili

Figure 3.17Anatomy of a bacterial cell (see color plate).

Glycolipid

Carbohydrate chain

Outside cell Membrane protein Membrane protein

Inside cell

Filaments of the cytoskeleton

Phospholipid bilayer

Hydrophilic heads

Hydro-phobic tails Hydrophilic heads Cholesterol

Glycoprotein

Figure 3.18Cell membrane and various associated molecular structures (see color plate).

100Plasma Medicine

region(tail-tail region of the phospholipid bilayer).Most bacterial cell membranes do not contain cholesterol. Cholesterol partly aids in the?exibility of a cell membrane.

Cell membrane proteins are typically suspended within the bilayer,as illustrated in Figure3.18,although the more hydrophilic areas of these proteins‘stick out’into the cell interior as well as outside the cell.These proteins function as gateways that allow certain molecules to cross into and out of the cell by moving through open areas of the protein channel.In fact,the proteins integrated into the membrane are sometimes known as gateway proteins.The outer surface of the membrane will tend to be rich in glycolipids,which have their hydrophobic tails embedded in the hydrophobic region of the membrane and their heads exposed outside the cell.These,along with carbohydrates attached to the integral proteins,are thought to function in the recognition of self,a sort of cellular identi?cation system.

Most animal and animal-like protisan cells are enveloped only by cell membranes.Fluidity and?exibility differentiates these cell membranes from cell walls around many non-mammalian cell types.Many bacteria, fungi and plant cells are enveloped by cell walls that are complex semi-rigid structures.In gram-positive bacteria,for example,the cell wall envelopes the inner cytoplasmic lipid membrane.In gram-negative bacteria, the cell wall and the inner membrane are surrounded by an outer lipid-based membrane.

The chemical composition of the cell wall differs among various bacteria,but is substantially based on peptidoglycans.Peptidoglycan is essentially a polymer formed by repeating disaccharides interconnected by polypeptides.Gram-negative bacteria also have a relatively large periplasmic space or periplasm between the peptidoglycan cell wall and inner membrane,which may constitute up to40%of the total cell volume. An equivalent but much smaller space outside the inner membrane also exists in Gram-positive species. Periplasm contains a loose network of peptidoglycan chains as well as a gel containing enzymes,nutrient binding and transport proteins,hydrolytic proteins and antibiotic resistance proteins.Some enzymes in the gel are involved in various biochemical pathways including peptidoglycan synthesis,electron transport (described in Section3.3.4)and alteration of substances toxic to the cell.In some species the gel also contains beta-lactamase,an enzyme responsible for degrading penicillin.

Some species of bacteria have a third protective covering,a capsule made up of polysaccharides.Capsules play a number of roles,the most important of which is probably keeping the bacterium from drying out and protecting it from phagocytosis(engul?ng)by larger microorganisms.The capsule is a major virulence factor in the major disease-causing bacteria,such as Escherichia coli(E-Coli)and Streptococcus pneumoniae. Capsules are relatively impermeable structures that cannot be stained with dyes such as India ink.Capsules can be in the form of a slime layer involved in attachment of bacteria to other cells or inanimate surfaces to form bio?lms.Slime layers can also be used as a food reserve for the cell.

The cell wall has at least three major functions that include:(1)constraining the internal volume;

(2)de?ning the cell shape;and(3)anchoring extracellular projections such as?agella,by which some bacteria move.The three primary shapes in bacteria are coccus(spherical),bacillus(rod-shaped)and spiril-lum(spiral).Bacteria such as mycoplasma have no cell wall and therefore have no de?nite shape.Constraining cell volume and shape helps protect the cell against rupturing when exposed to low salt solutions such as distilled water.Plant cell walls are mostly polysaccharides such as cellulose.Fungi cell walls often rely on chitin.

3.3.1.2The nucleus,DNA and chromosomes

The nucleus is found only in eukaryotic cells,and is the location for most of the DNA and RNA.Danish biologist Joachim Hammerling carried out an important experiment in1943showing the role of the nucleus in controlling the shape and features of the cell.DNA is the molecular carrier of inheritance and,with the exception of plastid DNA(cp DNA and m DNA found in the chloroplasts and mitochondria,respectively),all DNA is restricted to the nucleus.RNA is formed in the nucleus using the DNA base sequence as a template,

Selected Concepts in Biology and Medicine for Physical Scientists101 and moves out into the cytoplasm where it functions in the assembly of proteins.The nucleolus is an area of the nucleus(usually two nucleoli per nucleus)where ribosomes are constructed.The nuclear envelope is a double-membrane structure.Numerous pores occur in the nuclear envelope allowing RNA and other molecules to pass,but not DNA.

Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell.The primary functions of chromatin are:to package DNA into a smaller volume to?t in the cell’s nucleus;to strengthen the DNA;to prevent its damage as much as possible;to control gene expression(a process that eventually leads to production of proteins the cell needs);and to control DNA replication and DNA repair, should damage occur.The primary protein components of chromatin are histones.Chromatin is found mostly in eukaryotic cells,while DNA-associated structure in prokaryotes is different and referred to as genophore. In eukaryotic cells chromatin is typically pided into separate chromosomes,which have linear strands of DNA containing anywhere from105to109nucleotides.In prokaryotic cells,the separate pieces of genetic material(which are also called chromosomes)are typically connected in a circle.Eukaryotic cells may also contain more than one type of chromosome.For example,mitochondria in most eukaryotes and chloroplasts in plants have their own small circular chromosomes.

The structure of chromatin depends on several factors,including the stage of the cell cycle.The majority of the time,the chromatin is structurally loose to allow DNA transcription and replication in preparation for cell pision.The chromatin structure also exhibits local variations with more loosely packed DNA portions being actively transcribed.Epigenetic modi?cations of the structural proteins in chromatin are partly responsible for the local chromatin structure variations.Such chemical modi?cations include methylation and acetylation. As the cell prepares to pide,the chromatin packs more tightly in preparation for chromosome segregation. During this stage of the cell cycle,tight packing of chromatin makes the inpidual chromosomes more easily visible with an optical microscope.

There are typically three levels of chromatin organization.At the?nest level,DNA wraps around histone proteins forming nucleosomes which might resemble a beads-on-a-string structure(euchromatin).Multiple histones wrap into their most compact form(heterochromatin),which is?ber of c.30nm diameter consisting of nucleosome arrays.These heterochromatin?bers pack into the chromosome during cell pision.Unduplicated chromosomes are single linear strands,whereas duplicated chromosomes contain two identical copies(called chromatids)joined in a chromosomal region called the centromere.

There are also cells which do not follow this organization,however.For example,spermatozoa and avian red blood cells have more tightly packed chromatin than most eukaryotic cells.Some cells do not condense their chromatin into visible chromosomes for cell pision.

Genetic information contained in chromosomes is often segregated between different chromosome sets, where some correspondence exists between certain chromosomes in different sets.This correspondence between chromosomes is often based on homology.Homologous chromosomes are those that carry alternate alleles.Allele is the term used to describe alternate forms of gene coding for alternate forms of functionally similar protein(for example genes that might code for some protein essential in the function of the heart or liver).Humans normally receive one set of homologous chromosomes from each parent.

Ploidy is the term referring to the number of chromosome sets.Diploid organisms have two(di)sets of chromosomes.Most human,animals and many plant cells are diploid.In humans,a single set consists of 23chromosomes and most cells have a total of46chromosomes.Haploid organisms/cells have only one set of 91c28163c77da26925c5b0e7anisms with more than two sets of chromosomes are termed polyploid.

3.3.1.3Cytoplasm and cytosol

The cytoplasm is the material between the plasma membrane(cell membrane)and the nuclear envelope.The part of the cytoplasm that is outside all the organelles is called the cytosol.The cytosol is a gel-like complex

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