Chemical Foundations

Biochemistry aims to explain biological form and function in chemical terms. As we noted earlier, one of the most fruitful approaches to understanding biological phenomena has been to purify an individual chemical component, such as a protein, from a living organism and to characterize its structural and chemical characteristics. By the late eighteenth century, chemists had concluded that the composition of living matter is strikingly different from that of the inanimate world. Antoine Lavoisier (1743–1794) noted the relative chemical simplicity of the “mineral world” and contrasted it with the complexity of the “plant and animal worlds”; the latter, he knew, were composed of compounds rich in the elements carbon, oxygen, nitrogen, and phosphorus. During the first half of the twentieth century, parallel biochemical investigations of glucose breakdown in yeast and in animal muscle cells revealed remarkable chemical similarities in these two apparently very different cell types; the breakdown of glucose in yeast and muscle cells involved the same ten chemical intermediates. Subsequent studies of many other biochemical processes in many different organisms have confirmed the generality of this observation, neatly summarized by Jacques Monod: “What is true of E. coli is true of the elephant.” The current understanding that all organisms share a common evolutionary origin is based in part on this observed universality of chemical intermediates and transformations. Only about 30 of the more than 90 naturally occur ring chemical elements are essential to organisms. Most of the elements in living matter have relatively low atomic numbers; only five have atomic numbers above that of selenium, 34 (Fig. 1–12). The four most abundant elements in living organisms, in terms of percentage of total number of atoms, are hydrogen, oxygen, nitrogen, and carbon, which together make up more than 99% of the mass of most cells. They are the lightest elements capable of forming one, two, three, and four bonds, respectively; in general, the lightest elements

FIGURE 1–12 Elements essential to animal life and health. Bulk elements (shaded orange) are structural components of cells and tissues and are required in the diet in gram quantities daily. For trace elements (shaded bright yellow), the requirements are much smaller: for humans, a few milligrams per day of Fe, Cu, and Zn, even less of the others. The elemental requirements for plants and microorganisms are similar to those shown here; the ways in which they acquire these elements vary.

form the strongest bonds. The trace elements (Fig. 1–12) represent a miniscule fraction of the weight of the hu man body, but all are essential to life, usually because they are essential to the function of specific proteins, including enzymes. The oxygen-transporting capacity of the hemoglobin molecule, for example, is absolutely dependent on four iron ions that make up only 0.3% of its mass.

Biomolecules Are Compounds of Carbon with a Variety of Functional Groups The chemistry of living organisms is organized around carbon, which accounts for more than half the dry weight of cells. Carbon can form single bonds with hydrogen atoms, and both single and double bonds with oxygen and nitrogen atoms (Fig. 1–13). Of greatest sig nificance in biology is the ability of carbon atoms to form very stable carbon–carbon single bonds. Each carbon atom can form single bonds with up to four other car bon atoms. Two carbon atoms also can share two (or three) electron pairs, thus forming double (or triple) bonds. The four single bonds that can be formed by a car bon atom are arranged tetrahedrally, with an angle of

FIGURE 1–13 Versatility of carbon bonding. Carbon can form covalent single, double, and triple bonds (in red), particularly with other carbon atoms. Triple bonds are rare in biomolecules.

FIGURE 1–14 Geometry of carbon bonding. (a)Carbon atoms have a characteristic tetrahedral arrangement of their four single bonds. (b)Carbon–carbon single bonds have freedom of rotation, as shown for the compound ethane (CH3OCH3). (c)Double bonds are shorter and do not allow free rotation. The two doubly bonded carbons and the atoms designated A, B, X, and Y all lie in the same rigid plane.

about 109.5 between any two bonds (Fig. 1–14) and an average length of 0.154 nm. There is free rotation around each single bond, unless very large or highly charged groups are attached to both carbon atoms, in which case rotation may be restricted. A double bond is shorter (about 0.134 nm) and rigid and allows little rotation about its axis. Covalently linked carbon atoms in biomolecules can form linear chains, branched chains, and cyclic structures. To these carbon skeletons are added groups of other atoms, called functional groups, which confer specific chemical properties on the molecule. It seems likely that the bonding versatility of carbon was a ma jor factor in the selection of carbon compounds for the molecular machinery of cells during the origin and evolution of living organisms. No other chemical element can form molecules of such widely different sizes and shapes or with such a variety of functional groups. Most biomolecules can be regarded as derivatives of hydrocarbons, with hydrogen atoms replaced by a variety of functional groups to yield different families of organic compounds. Typical of these are alcohols, which have one or more hydroxyl groups; amines, with amino groups; aldehydes and ketones, with carbonyl groups; and carboxylic acids, with carboxyl groups (Fig. 1–15). Many biomolecules are polyfunctional, containing two or more different kinds of functional groups (Fig. 1–16), each with its own chemical characteristics and reactions. The chemical “personality” of a compound is determined by the chemistry of its functional groups and their disposition in three-dimensional space.

FIGURE 1–15 Some common functional groups of biomolecules. In this figure and throughout the book, we use R to represent “any substituent.” It may be as simple as a hydrogen atom, but typically it is a carbon-containing moiety. When two or more substituents are shown in a molecule, we designate them R1, R2, and so forth.

Cells Contain a Universal Set of Small Molecules Dissolved in the aqueous phase (cytosol) of all cells is a collection of 100 to 200 different small organic molecules (Mr ~100 to ~500), the central metabolites in the major pathways occurring in nearly every cell—the metabolites and pathways that have been conserved throughout the course of evolution. (See Box 1–1 for an explanation of the various ways of referring to molecular weight.) This collection of molecules includes the common amino acids, nucleotides, sugars and their phosphorylated derivatives, and a number of mono-, di-, and tricarboxylic acids. The molecules are polar or charged, water soluble, and present in micromolar to millimolar concentrations. They are trapped within the cell because the plasma membrane is impermeable to them—although specific membrane transporters can catalyze the movement of some molecules into and out

FIGURE 1–16 Several common functional groups in a single biomolecule. Acetyl-coenzyme A (often abbreviated as acetyl-CoA) is a carrier of acetyl groups in some enzymatic reactions.

of the cell or between compartments in eukaryotic cells. The universal occurrence of the same set of compounds in living cells is a manifestation of the universality of metabolic design, reflecting the evolutionary conserva tion of metabolic pathways that developed in the earli est cells. There are other small biomolecules, specific to cer tain types of cells or organisms. For example, vascular plants contain, in addition to the universal set, small molecules called secondary metabolites,which play a role specific to plant life. These metabolites include compounds that give plants their characteristic scents, and compounds such as morphine, quinine, nicotine, and caffeine that are valued for their physiological effects on humans but used for other purposes by plants. The entire collection of small molecules in a given cell has been called that cell’s metabolome, in parallel with the term “genome” (defined earlier and expanded on in Section 1.4). If we knew the composition of a cell’s metabolome, we could predict which enzymes and metabolic pathways were active in that cell.

Macromolecules Are the Major Constituents of Cells Many biological molecules are macromolecules, polymers of high molecular weight assembled from relatively simple precursors. Proteins, nucleic acids, and polysaccharides are produced by the polymerization of relatively small compounds with molecular weights of 500 or less. The number of polymerized units can range from tens to millions. Synthesis of macromolecules is a major energy-consuming activity of cells. Macromolecules themselves may be further assembled into supramolecular complexes, forming functional units such as ribosomes. Table 1–2 shows the major classes of biomolecules in the bacterium E.coli.

Proteins, long polymers of amino acids, constitute the largest fraction (besides water) of cells. Some pro teins have catalytic activity and function as enzymes; others serve as structural elements, signal receptors, or transporters that carry specific substances into or out of cells. Proteins are perhaps the most versatile of all biomolecules. The nucleic acids, DNA and RNA, are polymers of nucleotides. They store and transmit genetic information, and some RNA molecules have structural and catalytic roles in supramolecular complexes. The poly saccharides, polymers of simple sugars such as glucose, have two major functions: as energy-yielding fuel stores and as extracellular structural elements with specific binding sites for particular proteins. Shorter polymers of sugars (oligosaccharides) attached to proteins or lipids at the cell surface serve as specific cellular signals. The lipids, greasy or oily hydrocarbon derivatives, serve as structural components of membranes, energy-rich fuel stores, pigments, and intracellular signals. In proteins, nucleotides, polysaccharides, and lipids, the number of monomeric subunits is very large: molecular weights in the range of 5,000 to more than 1 million for proteins, up to several billion for nucleic acids, and in the millions for polysaccharides such as starch. Individual lipid mol ecules are much smaller (Mr 750 to 1,500) and are not classified as macromolecules. However, large num bers of lipid molecules can associate noncovalently into very large structures. Cellular membranes are built of enormous noncovalent aggregates of lipid and protein molecules. Proteins and nucleic acids are informational macromolecules: each protein and each nucleic acid has a characteristic information-rich subunit sequence. Some oligosaccharides, with six or more different sugars connected in branched chains, also carry information; on the outer surface of cells they serve as highly specific points of recognition in many cellular processes

Three-Dimensional Structure Is Described by Configuration and ConformationThe covalent bonds and functional groups of a biomol ecule are, of course, central to its function, but so also is the arrangement of the molecule’s constituent atoms in three-dimensional space—its stereochemistry. A carbon-containing compound commonly exists as stereoisomers, molecules with the same chemical bonds but different stereochemistry—that is, different configuration, the fixed spatial arrangement of atoms. Interactions between biomolecules are invariably stereo specific, requiring specific stereochemistry in the in teracting molecules. Figure 1–17 shows three ways to illustrate the stereo chemical structures of simple molecules. The perspective diagram specifies stereochemistry unambiguously, but bond angles and center-to-center bond lengths are better represented with ball-and-stick models. In space

FIGURE 1–17 Representations of molecules. Three ways to represent the structure of the amino acid alanine. (a) Structural formula in perspective form: a solid wedge (!) represents a bond in which the atom at the wide end projects out of the plane of the paper, toward the reader; a dashed wedge (^) represents a bond extending behind the plane of the paper. (b) Ball-and-stick model, showing relative bond lengths and the bond angles. (c) Space-filling model, in which each atom is shown with its correct relative van der Waals radius.

FIGURE 1–18 Configurations of geometric isomers. (a) Isomers such as maleic acid and fumaric acid cannot be interconverted without breaking covalent bonds, which requires the input of much energy. (b) In the vertebrate retina, the initial event in light detection is the absorption of visible light by 11-cis-retinal. The energy of the absorbed light (about 250 kJ/mol) converts 11-cis-retinal to all-trans-retinal, triggering electrical changes in the retinal cell that lead to a nerve impulse. (Note that the hydrogen atoms are omitted from the ball-and stick models for the retinals.)

filling models, the radius of each atom is proportional to its van der Waals radius, and the contours of the model define the space occupied by the molecule (the volume of space from which atoms of other molecules are excluded). Configuration is conferred by the presence of either (1) double bonds, around which there is no freedom of rotation, or (2) chiral centers, around which substituent groups are arranged in a specific sequence. The identi fying characteristic of configurational isomers is that they cannot be interconverted without temporarily breaking one or more covalent bonds. Figure 1–18a shows the configurations of maleic acid and its isomer, fumaric acid. These compounds are geometric, or cis trans, isomers; they differ in the arrangement of their substituent groups with respect to the nonrotating double bond (Latin cis, “on this side”—groups on the same side of the double bond; trans, “across”—groups on opposite sides). Maleic acid is the cis isomer and fumaric acid the trans isomer; each is a well-defined compound that can be separated from the other, and each has its own unique chemical properties. A binding site (on an enzyme, for example) that is complementary to one of these molecules would not be a suitable binding site for the other, which explains why the two compounds have distinct biological roles despite their similar chemistry.

In the second type of configurational isomer, four different substituents bonded to a tetrahedral carbon atom may be arranged two different ways in space—that is, have two configurations (Fig. 1–19)—yielding two stereoisomers with similar or identical chemical proper ties but differing in certain physical and biological properties. A carbon atom with four different substituents is said to be asymmetric, and asymmetric carbons are called chiral centers (Greek chiros, “hand”; some stereoisomers are related structurally as the right hand is to the left). A molecule with only one chiral carbon can have two stereoisomers; when two or more (n) chi ral carbons are present, there can be 2n stereoisomers. Some stereoisomers are mirror images of each other; they are called enantiomers (Fig. 1–19). Pairs of stereoisomers that are not mirror images of each other are called diastereomers (Fig. 1–20). As Louis Pasteur first observed (Box 1–2), enantiomers have nearly identical chemical properties but differ in a characteristic physical property, their inter action with plane-polarized light. In separate solutions, two enantiomers rotate the plane of plane-polarized light in opposite directions, but an equimolar solution of the two enantiomers (a racemic mixture) shows no optical rotation. Compounds without chiral centers do not rotate the plane of plane-polarized light.

FIGURE 1–19 Molecular asymmetry: chiral and achiral molecules. (a) When a carbon atom has four different substituent groups (A, B, X, Y), they can be arranged in two ways that represent nonsuperim posable mirror images of each other (enantiomers). This asymmetric carbon atom is called a chiral atom or chiral center. (b) When a tetrahedral carbon has only three dissimilar groups (i.e., the same group occurs twice), only one configuration is possible and the molecule is symmetric, or achiral. In this case the molecule is superimposable on its mirror image: the molecule on the left can be rotated counter clockwise (when looking down the vertical bond from A to C) to create the molecule in the mirror.

Given the importance of stereochemistry in reac tions between biomolecules (see below), biochemists must name and represent the structure of each bio molecule so that its stereochemistry is unambiguous. For compounds with more than one chiral center, the most useful system of nomenclature is the RS system. In this system, each group attached to a chiral carbon is assigned a priority. The priorities of some common substituents are -OCH2>-OH>- NH2>-OCOOH>-CHO>-CH2OH >-CH3>- H For naming in the RS system, the chiral atom is viewed with the group of lowest priority (4 in the diagram on the next page) pointing away from the viewer. If the priority of the other three groups (1 to 3) decreases in clockwise order, the configuration is (R) (Latin rectus, “right”); if in counterclockwise order, the configuration

FIGURE 1–20 Two types of stereoisomers. There are four different 2,3-disubstituted butanes (n 2 asymmetric carbons, hence 2n 4 stereoisomers). Each is shown in a box as a perspective formula and a ball-and-stick model, which has been rotated to allow the reader to view all the groups. Some pairs of stereoisomers are mirror images of each other, or enantiomers. Other pairs are not mirror images; these are diastereomers.

is (S) (Latin sinister, "left”). In this way each chiral car bon is designated either (R) or (S), and the inclusion of these designations in the name of the compound pro vides an unambiguous description of the stereo chemistry at each chiral center.

Another naming system for stereoisomers, the Dand L system, is described in Chapter 3. A molecule with a single chiral center (glyceraldehydes, for example) can be named unambiguously by either system.

Distinct from configuration is molecular conformation, the spatial arrangement of substituent groups that, without breaking any bonds, are free to assume different positions in space because of the freedom of rotation about single bonds. In the simple hydrocarbon ethane, for example, there is nearly complete freedom of rotation around the COC bond. Many different, in terconvertible conformations of ethane are possible, depending on the degree of rotation (Fig. 1–21). Two conformations are of special interest: the staggered, which is more stable than all others and thus predomi nates, and the eclipsed, which is least stable. We cannot isolate either of these conformational forms, because

FIGURE 1–21 Conformations. Many conformations of ethane are pos sible because of freedom of rotation around the COC bond. In the ball-and-stick model, when the front carbon atom (as viewed by the reader) with its three attached hydrogens is rotated relative to the rear carbon atom, the potential energy of the molecule rises to a maximum in the fully eclipsed conformation (torsion angle 0, 120, etc.), then falls to a minimum in the fully staggered conformation (torsion angle 60, 180, etc.). Because the energy differences are small enough to allow rapid interconversion of the two forms (millions of times per second), the eclipsed and staggered forms cannot be separately isolated. they are freely interconvertible. However, when one or more of the hydrogen atoms on each carbon is replaced by a functional group that is either very large or electrically charged, freedom of rotation around the COC bond is hindered. This limits the number of stable con formations of the ethane derivative.

Interactions between Biomolecules Are Stereospecific Biological interactions between molecules are stereo specific: the “fit” in such interactions must be stereo chemically correct. The three-dimensional structure of biomolecules large and small—the combination of con figuration and conformation—is of the utmost impor tance in their biological interactions: reactant with enzyme, hormone with its receptor on a cell surface, antigen with its specific antibody, for example (Fig. 1–22). The study of biomolecular stereochemistry with precise physical methods is an important part of mod ern research on cell structure and biochemical function. In living organisms, chiral molecules are usually present in only one of their chiral forms. For example, the amino acids in proteins occur only as their L isomers; glucose occurs only as its D isomer. (The conventions for naming stereoisomers of the amino acids are described in Chapter 3; those for sugars, in Chapter 7; the RS system, described above, is the most useful for some biomolecules.) In contrast, when a com pound with an asymmetric carbon atom is chemically synthesized in the laboratory, the reaction usually pro

FIGURE 1–22 Complementary fit between a macromolecule and a small molecule. A segment of RNA from the regulatory region TAR of the human immunodeficiency virus genome (gray) with a bound argininamide molecule (colored), representing one residue of a protein that binds to this region. The argininamide fits into a pocket on the RNA surface and is held in this orientation by several noncovalent interactions with the RNA. This representation of the RNA molecule is produced with the computer program GRASP, which can calculate the shape of the outer surface of a macromolecule, defined either by the van der Waals radii of all the atoms in the molecule or by the “solvent exclusion volume,” into which a water molecule cannot penetrate. duces all possible chiral forms: a mixture of the D and L forms, for example. Living cells produce only one chiral form of biomolecules because the enzymes that syn the size them are also chiral. Stereospecificity, the ability to distinguish between stereoisomers, is a property of enzymes and other proteins and a characteristic feature of the molecular logic of living cells. If the binding site on a protein is com plementary to one isomer of a chiral compound, it will not be complementary to the other isomer, for the same reason that a left glove does not fit a right hand. Two striking examples of the ability of biological systems to distinguish stereoisomers are shown in Figure 1–23.

FIGURE 1–23 Stereoisomers distinguishable by smell and taste in humans. (a) Two stereoisomers of carvone: (R)-carvone (isolated from spearmint oil) has the characteristic fragrance of spearmint; (S)-carvone (from caraway seed oil) smells like caraway. (b) Aspartame, the artificial sweetener sold under the trade name NutraSweet, is easily distinguishable by taste receptors from its bitter-tasting stereoisomer, although the two differ only in the configuration at one of the two chiral carbon atoms.

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Physical Foundations:- The Flow of Electrons Provides Energy for Organisms

Physical Foundations:- Organisms Transform Energy and Matter from Their Surroundings

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