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K E Y C O N C E P T S
5.1 Macromolecules are polymers, built from
monomers
5.2 Carbohydrates serve as fuel and building material
5.3 Lipids are a diverse group of hydrophobic
molecules
5.4 Proteins include a diversity of structures,
resulting in a wide range of functions
5.5 Nucleic acids store, transmit, and help express
hereditary information
O V E R V I E W
The Molecules of Life
Given the rich complexity of life on Earth, we might expect organisms to have an enormous diversity of molecules. Re- markably, however, the critically important large molecules of all living things—from bacteria to elephants—fall into just four main classes: carbohydrates, lipids, proteins, and nucleic
acids. On the molecular scale, members of three of these classes—carbohydrates, proteins, and nucleic acids—are huge and are therefore called macromolecules. For example, a protein may consist of thousands of atoms that form a mo- lecular colossus with a mass well over 100,000 daltons. Con- sidering the size and complexity of macromolecules, it is noteworthy that biochemists have determined the detailed structure of so many of them. The scientist in the foreground of Figure 5.1 is using 3-D glasses to help her visualize the structure of the protein displayed on her screen. The architecture of a large biological molecule helps ex- plain how that molecule works. Like water and simple or- ganic molecules, large biological molecules exhibit unique emergent properties arising from the orderly arrangement of their atoms. In this chapter, we’ll first consider how macro- molecules are built. Then we’ll examine the structure and function of all four classes of large biological molecules: car- bohydrates, lipids, proteins, and nucleic acids.
C O N C E P T (^) 5.
Macromolecules are polymers, built from monomers
The macromolecules in three of the four classes of life’s or- ganic compounds—carbohydrates, proteins, and nucleic acids—are chain-like molecules called polymers (from the Greek polys , many, and meros , part). A polymer is a long molecule consisting of many similar or identical building blocks linked by covalent bonds, much as a train consists of a chain of cars. The repeating units that serve as the building blocks of a polymer are smaller molecules called monomers (from the Greek monos , single). Some of the molecules that serve as monomers also have other functions of their own.
The Synthesis and Breakdown of Polymers
Although each class of polymer is made up of a different type of monomer, the chemical mechanisms by which cells make and break down polymers are basically the same in all cases. In cells, these processes are facilitated by enzymes , special- ized macromolecules that speed up chemical reactions. Monomers are connected by a reaction in which two mol- ecules are covalently bonded to each other, with the loss of a water molecule; this is known as a dehydration reaction (Figure 5.2a). When a bond forms between two monomers, each monomer contributes part of the water molecule that is released during the reaction: One monomer provides a hydroxyl group (—OH), while the other provides a hydrogen (—H). This reaction is repeated as monomers are added to the chain one by one, making a polymer. Polymers are disassembled to monomers by hydrolysis , a process that is essentially the reverse of the dehydration reac-
Figure 5.1 Why do scientists study the structures of macromolecules?
The Structure and
Function of Large
Biological Molecules
68 U N I T O N E The Chemistry of Life
C H A P T E R 5 The Structure and Function of Large Biological Molecules 69
H
HO H
Short polymer
Dehydration removes a water molecule, forming a new bond.
Hydrolysis adds a water molecule, breaking a bond.
Longer polymer
Unlinked monomer
HO
H 2 O
H 2 O
HO 1 2 3 4 H
HO 1 2 3 H HO H
HO 1 2 3 H
(a) Dehydration reaction: synthesizing a polymer
(b) Hydrolysis: breaking down a polymer
Figure 5.2 The synthesis and breakdown of polymers.
tion (Figure 5.2b). Hydrolysis means to break using water (from the Greek hydro , water, and lysis , break). The bond be- tween the monomers is broken by the addition of a water mol- ecule, with the hydrogen from the water attaching to one monomer and the hydroxyl group attaching to the adjacent monomer. An example of hydrolysis working within our bod- ies is the process of digestion. The bulk of the organic material in our food is in the form of polymers that are much too large to enter our cells. Within the digestive tract, various enzymes attack the polymers, speeding up hydrolysis. The released monomers are then absorbed into the bloodstream for distri- bution to all body cells. Those cells can then use dehydration reactions to assemble the monomers into new, different poly- mers that can perform specific functions required by the cell.
The Diversity of Polymers
Each cell has thousands of different macromolecules; the col- lection varies from one type of cell to another even in the same organism. The inherent differences between human siblings reflect small variations in polymers, particularly DNA and proteins. Molecular differences between unrelated indi- viduals are more extensive and those between species greater still. The diversity of macromolecules in the living world is vast, and the possible variety is effectively limitless.
What is the basis for such diversity in life’s polymers? These molecules are constructed from only 40 to 50 common monomers and some others that occur rarely. Building a huge variety of polymers from such a limited number of monomers is analogous to constructing hundreds of thou- sands of words from only 26 letters of the alphabet. The key is arrangement—the particular linear sequence that the units follow. However, this analogy falls far short of describing the great diversity of macromolecules because most biological polymers have many more monomers than the number of letters in the longest word. Proteins, for example, are built from 20 kinds of amino acids arranged in chains that are typ- ically hundreds of amino acids long. The molecular logic of life is simple but elegant: Small molecules common to all or- ganisms are ordered into unique macromolecules. Despite this immense diversity, molecular structure and function can still be grouped roughly by class. Let’s examine each of the four major classes of large biological molecules. For each class, the large molecules have emergent properties not found in their individual building blocks.
C O N C E P T C H E C K 5.
1. What are the four main classes of large biological molecules? Which class does not consist of polymers? 2. How many molecules of water are needed to com- pletely hydrolyze a polymer that is ten monomers long? 3. Suppose you eat a serving of fish. What reactions must occur for the amino acid monomers in the protein of the fish to be converted to new pro- teins in your body? For suggested answers, see Appendix A.
C O N C E P T (^) 5.
Carbohydrates serve as fuel and building material
Carbohydrates include both sugars and polymers of sugars. The simplest carbohydrates are the monosaccharides, or simple sugars; these are the monomers from which more complex car- bohydrates are constructed. Disaccharides are double sugars, consisting of two monosaccharides joined by a covalent bond. Carbohydrates also include macromolecules called polysaccha- rides, polymers composed of many sugar building blocks.
Sugars Monosaccharides (from the Greek monos , single, and sacchar , sugar) generally have molecular formulas that are some multiple of the unit CH 2 O. Glucose (C 6 H 12 O 6 ), the most com- mon monosaccharide, is of central importance in the chemistry
WHAT IF?
C H A P T E R 5 The Structure and Function of Large Biological Molecules 71
Figure 5.4 Linear and ring forms of glucose. Start with the linear form of fructose (see Figure 5.3) and draw the formation of the fructose ring in two steps. First, number the carbons starting at the top of the linear structure. Then attach carbon 5 via its oxygen to carbon 2. Compare the number of carbons in the fructose and glucose rings.
DRAW IT
H OH
C
H O
H
H OH
H OH
HO H
H OH
H
(a)
(b)
2 C
3 C
4 C^4 C
5 C
6 C
1
H OH
OH H
3 C
C
OH
H
4 C
H
OH
H 1
H
O
OH
OH H
OH 3 C^2 C 2 C
H
H 1
5 C 5 C
6 CH2OH 6 CH 2 OH
C
H
O
H OH
O H
H
CH 2 OH
OH H
H
HO 3 2 OH
1
5
6
4
O
Linear and ring forms. Chemical equilibrium between the linear and ring structures greatly favors the formation of rings. The carbons of the sugar are numbered 1 to 6, as shown. To form the glucose ring, carbon 1 bonds to the oxygen attached to carbon 5.
Abbreviated ring structure. Each corner represents a carbon. The ring’s thicker edge indicates that you are looking at the ring edge-on; the components attached to the ring lie above or below the plane of the ring.
protect the cell or the whole organism. The architecture and function of a polysaccharide are determined by its sugar monomers and by the positions of its glycosidic linkages.
Storage Polysaccharides
Both plants and animals store sugars for later use in the form of storage polysaccharides. Plants store starch , a polymer of glucose monomers, as granules within cellular structures known as plastids, which include chloroplasts. Synthesizing starch enables the plant to stockpile surplus glucose. Because glucose is a major cellular fuel, starch represents stored en-
ergy. The sugar can later be withdrawn from this carbohy- drate “bank” by hydrolysis, which breaks the bonds between the glucose monomers. Most animals, including humans, also have enzymes that can hydrolyze plant starch, making glucose available as a nutrient for cells. Potato tubers and grains—the fruits of wheat, maize (corn), rice, and other grasses—are the major sources of starch in the human diet. Most of the glucose monomers in starch are joined by 1–4 linkages (number 1 carbon to number 4 carbon), like the glucose units in maltose (see Figure 5.5a). The simplest form of starch, amylose, is unbranched. Amylopectin, a more complex
Figure 5.5 Examples of disaccharide synthesis. Referring to Figure 5.4, number the carbons in each sugar in this figure. Show how the numbering is consistent with the name of the glycosidic linkage in each disaccharide.
DRAW IT
O
Glucose Glucose Maltose
1 OH (^) H O OH
4 OH
glycosidic linkage
(a)
H 2 O
H OH
O H
H
CH 2 OH
OH H
H
HO
H OH
O H
H
CH 2 OH
OH H
H
HO
H OH
O H
H
CH 2 OH
OH H
H
H OH
O H
H
CH 2 OH
OH H
H
O
Sucrose
1 2
glycosidic linkage
H OH
O H
H
CH 2 OH
OH H
H
CH 2 OH HO
H
Glucose Fructose
OH H O
H 2 O
H OH
O H
H
CH 2 OH
OH H
H
HO
OH H
O
CH 2 OH
H HO
CH 2 OH
H
OH H
O
CH 2 OH
H HO
Dehydration reaction in the synthesis of maltose. The bonding of two glucose units forms maltose. The glycosidic linkage joins the number 1 carbon of one glucose to the number 4 carbon of the second glucose. Joining the glucose monomers in a different way would re- sult in a different disaccharide.
(b) Dehydration reaction in the synthesis of sucrose. Sucrose is a disaccharide formed from glucose and fructose. Notice that fructose, though a hexose like glucose, forms a five-sided ring.
72 U N I T O N E The Chemistry of Life
Figure 5.6 Storage polysaccharides of plants and animals. These examples, starch and glycogen, are composed entirely of glucose monomers, represented here by hexagons. Because of the angle of the 1–4 linkages, the polymer chains tend to form helices in unbranched regions.
Mitochondria Glycogen granules
Chloroplast
Amylose
Amylopectin
Glycogen
Starch granules
1 μm
0.5 μm
(a) Starch: a plant polysaccharide. This micrograph shows part of a plant cell with a chloroplast, the cellular organelle where glucose is made and then stored as starch granules. Amylose (unbranched) and amylopectin (branched) are two forms of starch.
(b) Glycogen: an animal polysaccharide. Animal cells stockpile glycogen as dense clusters of granules within liver and muscle cells, as shown in this micrograph of part of a liver cell. Mitochondria are cellular organelles that help break down glucose released from glycogen. Note that glycogen is more branched than amylopectin starch.
starch, is a branched polymer with 1–6 linkages at the branch points. Both of these starches are shown in Figure 5.6a. Animals store a polysaccharide called glycogen , a polymer of glucose that is like amylopectin but more extensively branched (Figure 5.6b). Humans and other vertebrates store glycogen mainly in liver and muscle cells. Hydrolysis of glyco- gen in these cells releases glucose when the demand for sugar increases. This stored fuel cannot sustain an animal for long, however. In humans, for example, glycogen stores are depleted in about a day unless they are replenished by consumption of food. This is an issue of concern in low-carbohydrate diets.
Structural Polysaccharides
Organisms build strong materials from structural polysaccha- rides. For example, the polysaccharide called cellulose is a major component of the tough walls that enclose plant cells. On a global scale, plants produce almost 10^14 kg (100 billion tons) of cellulose per year; it is the most abundant organic compound on Earth. Like starch, cellulose is a polymer of glu- cose, but the glycosidic linkages in these two polymers differ. The difference is based on the fact that there are actually two slightly different ring structures for glucose (Figure 5.7a). When glucose forms a ring, the hydroxyl group attached to the number 1 carbon is positioned either below or above the plane of the ring. These two ring forms for glucose are called alpha (α) and beta (β), respectively. In starch, all the glucose monomers are in the α configuration (Figure 5.7b) , the arrangement we saw in Figures 5.4 and 5.5. In contrast, the
glucose monomers of cellulose are all in the β configuration, making every glucose monomer “upside down” with respect to its neighbors (Figure 5.7c). The differing glycosidic linkages in starch and cellulose give the two molecules distinct three-dimensional shapes. Whereas certain starch molecules are largely helical, a cellu- lose molecule is straight. Cellulose is never branched, and some hydroxyl groups on its glucose monomers are free to hydrogen-bond with the hydroxyls of other cellulose mol- ecules lying parallel to it. In plant cell walls, parallel cellulose molecules held together in this way are grouped into units called microfibrils (Figure 5.8). These cable-like microfibrils are a strong building material for plants and an important substance for humans because cellulose is the major con- stituent of paper and the only component of cotton. Enzymes that digest starch by hydrolyzing its α linkages are unable to hydrolyze the β linkages of cellulose because of the distinctly different shapes of these two molecules. In fact, few organisms possess enzymes that can digest cellulose. Ani- mals, including humans, do not; the cellulose in our food passes through the digestive tract and is eliminated with the feces. Along the way, the cellulose abrades the wall of the di- gestive tract and stimulates the lining to secrete mucus, which aids in the smooth passage of food through the tract. Thus, although cellulose is not a nutrient for humans, it is an important part of a healthful diet. Most fresh fruits, vegeta- bles, and whole grains are rich in cellulose. On food pack- ages, “insoluble fiber” refers mainly to cellulose.
74 U N I T O N E The Chemistry of Life
C O
CH 3
H NH
O OH
H
CH 2 OH
OH H
H
OH H
Chitin forms the exoskeleton of arthropods. This cicada is molting, shedding its old exoskeleton and emerging in adult form.
The structure of the chitin monomer
Chitin is used to make a strong and flexible surgical thread that decomposes after the wound or incision heals.
Figure 5.9 Chitin, a structural polysaccharide.
Some microorganisms can digest cellulose, breaking it down into glucose monomers. A cow harbors cellulose- digesting prokaryotes and protists in its stomach. These mi- crobes hydrolyze the cellulose of hay and grass and convert the glucose to other compounds that nourish the cow. Simi- larly, a termite, which is unable to digest cellulose by itself, has prokaryotes or protists living in its gut that can make a meal of wood. Some fungi can also digest cellulose, thereby helping recycle chemical elements within Earth’s ecosystems. Another important structural polysaccharide is chitin , the carbohydrate used by arthropods (insects, spiders, crus- taceans, and related animals) to build their exoskeletons (Figure 5.9). An exoskeleton is a hard case that surrounds the soft parts of an animal. Pure chitin is leathery and flexible, but it becomes hardened when encrusted with calcium car- bonate, a salt. Chitin is also found in many fungi, which use this polysaccharide rather than cellulose as the building ma- terial for their cell walls. Chitin is similar to cellulose, with β linkages, except that the glucose monomer of chitin has a nitrogen-containing appendage (see Figure 5.9, top right).
C O N C E P T C H E C K 5.
1. Write the formula for a monosaccharide that has three carbons. 2. A dehydration reaction joins two glucose molecules to form maltose. The formula for glucose is C 6 H 12 O 6. What is the formula for maltose? 3. After a cow is given antibiotics to treat an infection, a vet gives the animal a drink of “gut cul- ture” containing various prokaryotes. Why is this necessary? For suggested answers, see Appendix A.
C O N C E P T (^) 5.
Lipids are a diverse group of hydrophobic molecules
Lipids are the one class of large biological molecules that does not include true polymers, and they are generally not big enough to be considered macromolecules. The com- pounds called lipids are grouped together because they share one important trait: They mix poorly, if at all, with water. The hydrophobic behavior of lipids is based on their molecular structure. Although they may have some polar bonds associated with oxygen, lipids consist mostly of hydro- carbon regions. Lipids are varied in form and function. They include waxes and certain pigments, but we will focus on the most biologically important types of lipids: fats, phospho- lipids, and steroids.
Fats
Although fats are not polymers, they are large molecules assem- bled from smaller molecules by dehydration reactions. A fat is constructed from two kinds of smaller molecules: glycerol and fatty acids (Figure 5.10a). Glycerol is an alcohol; each of its three carbons bears a hydroxyl group. A fatty acid has a long carbon skeleton, usually 16 or 18 carbon atoms in length. The carbon at one end of the skeleton is part of a carboxyl group, the functional group that gives these molecules the name fatty acid. The rest of the skeleton consists of a hydrocarbon chain.
The relatively nonpolar C¬H bonds in the hydrocarbon
chains of fatty acids are the reason fats are hydrophobic. Fats separate from water because the water molecules hydrogen- bond to one another and exclude the fats. This is the reason that vegetable oil (a liquid fat) separates from the aqueous vine- gar solution in a bottle of salad dressing. In making a fat, three fatty acid molecules are each joined to glycerol by an ester linkage, a bond between a hydroxyl group and a carboxyl group. The resulting fat, also called a triacylglycerol , thus consists of three fatty acids linked to one glycerol molecule. (Still another name for a fat is
WHAT IF?
and fishes are generally unsaturated, meaning that they are built of one or more types of unsaturated fatty acids. Usually liquid at room temperature, plant and fish fats are referred to as oils—olive oil and cod liver oil are examples. The kinks where the cis double bonds are located prevent the molecules from packing together closely enough to solidify at room tem- perature. The phrase “hydrogenated vegetable oils” on food labels means that unsaturated fats have been synthetically
C H A P T E R 5 The Structure and Function of Large Biological Molecules 75
triglyceride , a word often found in the list of ingredients on packaged foods.) The fatty acids in a fat can be the same, or they can be of two or three different kinds, as in Figure 5.10b. The terms saturated fats and unsaturated fats are commonly used in the context of nutrition (Figure 5.11). These terms refer to the structure of the hydrocarbon chains of the fatty acids. If there are no double bonds between carbon atoms composing a chain, then as many hydrogen atoms as possi- ble are bonded to the carbon skeleton. Such a structure is said to be saturated with hydrogen, and the resulting fatty acid therefore called a saturated fatty acid (Figure 5.11a). An unsaturated fatty acid has one or more double bonds, with one fewer hydrogen atom on each double-bonded car- bon. Nearly all double bonds in naturally occurring fatty acids are cis double bonds, which cause a kink in the hydrocarbon chain wherever they occur (Figure 5.11b). (See Figure 4.7 to remind yourself about cis and trans double bonds.) A fat made from saturated fatty acids is called a saturated fat. Most animal fats are saturated: The hydrocarbon chains of their fatty acids—the “tails” of the fat molecules—lack double bonds, and their flexibility allows the fat molecules to pack to- gether tightly. Saturated animal fats—such as lard and butter— are solid at room temperature. In contrast, the fats of plants
Figure 5.10 The synthesis and structure of a fat, or triacylglycerol. The molecular building blocks of a fat are one molecule of glycerol and three molecules of fatty acids. (a) One water molecule is removed for each fatty acid joined to the glycerol. (b) A fat molecule with three fatty acid units, two of them identical. The carbons of the fatty acids are arranged zigzag to suggest the actual orientations of the four single bonds extending from each carbon (see Figure 4.3a).
(a) One of three dehydration reactions in the synthesis of a fat
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C H
O HO
C
H H
H C OH
C H
H OH
C
H H O
H C
C H
H
H 2 O Fatty acid (in this case, palmitic acid)
Glycerol
C
O C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
H
O C
O C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
H
O C
O C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
C
H
H
H
(b) Fat molecule (triacylglycerol)
Ester linkage
O H
Cis double bond causes bending.
C
H H
H C O
C H
H O
O
C
C
C
O
O
O
Structural formula of an unsaturated fat molecule
C
H H
H C O
C H
H O
O
C
C
C
O
O
O
Space-filling model of oleic acid, an unsaturated fatty acid
(a) Saturated fat At room temperature, the molecules of a saturated fat, such as the fat in butter, are packed closely together, forming a solid.
(b) Unsaturated fat
Structural formula of a saturated fat molecule (Each hydrocarbon chain is represented as a zigzag line, where each bend represents a carbon atom and hydrogens are not shown.)
Space-filling model of stearic acid, a saturated fatty acid (red = oxygen, black = carbon, gray = hydrogen)
At room temperature, the molecules of an unsaturated fat such as olive oil cannot pack together closely enough to solidify because of the kinks in some of their fatty acid hydrocarbon chains.
Figure 5.11 Saturated and unsaturated fats and fatty acids.
At the surface of a cell, phospholipids are arranged in a similar bilayer. The hydrophilic heads of the molecules are on the outside of the bilayer, in contact with the aqueous so- lutions inside and outside of the cell. The hydrophobic tails point toward the interior of the bilayer, away from the water. The phospholipid bilayer forms a boundary between the cell and its external environment; in fact, cells could not exist without phospholipids.
Steroids
Steroids are lipids characterized by a carbon skeleton con- sisting of four fused rings. Different steroids, such as choles- terol and the vertebrate sex hormones, are distinguished by the particular chemical groups attached to this ensemble of rings (Figure 5.14). Cholesterol is a crucial molecule in ani- mals. It is a common component of animal cell membranes and is also the precursor from which other steroids are syn- thesized. In vertebrates, cholesterol is synthesized in the liver
C H A P T E R 5 The Structure and Function of Large Biological Molecules 77
Figure 5.13 Bilayer structure formed by self-assembly of phospholipids in an aqueous environment. The phospholipid bilayer shown here is the main fabric of biological membranes. Note that the hydrophilic heads of the phospholipids are in contact with water in this structure, whereas the hydrophobic tails are in contact with each other and remote from water.
WATER
WATER
Hydrophilic head
Hydrophobic tail
Figure 5.14 Cholesterol, a steroid. Cholesterol is the molecule from which other steroids, including the sex hormones, are synthesized. Steroids vary in the chemical groups attached to their four interconnected rings (shown in gold). Compare cholesterol with the sex hor- mones shown in Concept 4.3 on p. 63. Circle the chemical groups that cholesterol has in common with estradiol; put a square around the chemical groups that cholesterol has in common with testosterone.
MAKE CONNECTIONS
CH 3
HO
CH 3
H 3 C CH 3
CH 3
and obtained from the diet. A high level of cholesterol in the blood may contribute to atherosclerosis. In fact, both satu- rated fats and trans fats exert their negative impact on health by affecting cholesterol levels.
C O N C E P T C H E C K 5.
1. Compare the structure of a fat (triglyceride) with that of a phospholipid. 2. Why are human sex hormones considered lipids? 3. Suppose a membrane surrounded an oil droplet, as it does in the cells of plant seeds. Describe and explain the form it might take. For suggested answers, see Appendix A.
C O N C E P T (^) 5.
Proteins include a diversity of structures, resulting in a wide range of functions
Nearly every dynamic function of a living being depends on proteins. In fact, the importance of proteins is underscored by their name, which comes from the Greek word proteios , meaning “first,” or “primary.” Proteins account for more than 50% of the dry mass of most cells, and they are instru- mental in almost everything organisms do. Some proteins speed up chemical reactions, while others play a role in de- fense, storage, transport, cellular communication, move- ment, or structural support. Figure 5.15 , on the next page, shows examples of proteins with these functions, which you’ll learn more about in later chapters. Life would not be possible without enzymes, most of which are proteins. Enzymatic proteins regulate metabolism by acting as catalysts , chemical agents that selectively speed up chemical reactions without being consumed by the reac- tion. Because an enzyme can perform its function over and over again, these molecules can be thought of as workhorses that keep cells running by carrying out the processes of life. A human has tens of thousands of different proteins, each with a specific structure and function; proteins, in fact, are the most structurally sophisticated molecules known. Consistent with their diverse functions, they vary extensively in structure, each type of protein having a unique three-dimensional shape.
Polypeptides
Diverse as proteins are, they are all unbranched polymers constructed from the same set of 20 amino acids. Polymers of amino acids are called polypeptides. A protein is a biolog- ically functional molecule that consists of one or more polypeptides, each folded and coiled into a specific three- dimensional structure.
WHAT IF?
78 U N I T O N E The Chemistry of Life
Amino Acid Monomers
All amino acids share a common structure. An amino acid is an or- ganic molecule possessing both an amino group and a carboxyl group (see Figure 4.9). The illustration at the right shows the general formula for an amino acid. At the center of the amino acid is an asymmetric carbon atom called the alpha ( a ) carbon. Its four different partners are an amino group, a car-
Enzymatic proteins
Storage proteins
Contractile and motor proteins
Hormonal proteins
Defensive proteins
Transport proteins
Structural proteins
Receptor proteins
100 μm 60 μm
Function: Selective acceleration of chemical reactions Example: Digestive enzymes catalyze the hydrolysis of bonds in food molecules.
Function: Storage of amino acids Examples: Casein, the protein of milk, is the major source of amino acids for baby mammals. Plants have storage proteins in their seeds. Ovalbumin is the protein of egg white, used as an amino acid source for the developing embryo.
Function: Movement Examples: Motor proteins are responsible for the undulations of cilia and flagella. Actin and myosin proteins are responsible for the contrac- tion of muscles.
Function: Coordination of an organism‘s activities Example: Insulin, a hormone secreted by the pancreas, causes other tissues to take up glucose, thus regulating blood sugar concentration.
Function: Protection against disease Example: Antibodies inactivate and help destroy viruses and bacteria.
Function: Transport of substances Examples: Hemoglobin, the iron-containing protein of vertebrate blood, transports oxygen from the lungs to other parts of the body. Other proteins transport molecules across cell membranes.
Function: Support Examples: Keratin is the protein of hair, horns, feathers, and other skin appendages. Insects and spiders use silk fibers to make their cocoons and webs, respectively. Collagen and elastin proteins provide a fibrous framework in animal connective tissues.
Function: Response of cell to chemical stimuli Example: Receptors built into the membrane of a nerve cell detect signaling molecules released by other nerve cells.
Enzyme
Ovalbumin Amino acids for embryo
Transport protein
Signaling molecules
Collagen
Receptor protein
Virus Bacterium
Antibodies
Cell membrane
High blood sugar
Normal blood sugar
Actin
Muscle tissue Connective tissue
Myosin
Insulin secreted
Figure 5.15 An overview of protein functions.
OH
O
CC C
R
H
Side chain (R group)
N
carbon H
H
Amino group
Carboxyl group
boxyl group, a hydrogen atom, and a variable group symbol- ized by R. The R group, also called the side chain, differs with each amino acid. Figure 5.16 shows the 20 amino acids that cells use to build their thousands of proteins. Here the amino groups and carboxyl groups are all depicted in ionized form, the way they usually exist at the pH found in a cell. The side chain (R group) may be as simple as a hydrogen atom, as in the amino acid glycine, or it may be a carbon skeleton with vari- ous functional groups attached, as in glutamine.
80 U N I T O N E The Chemistry of Life
The physical and chemical properties of the side chain de- termine the unique characteristics of a particular amino acid, thus affecting its functional role in a polypeptide. In Figure 5.16, the amino acids are grouped according to the properties of their side chains. One group consists of amino acids with nonpolar side chains, which are hydrophobic. An- other group consists of amino acids with polar side chains, which are hydrophilic. Acidic amino acids are those with side chains that are generally negative in charge owing to the presence of a carboxyl group, which is usually dissociated (ionized) at cellular pH. Basic amino acids have amino groups in their side chains that are generally positive in charge. (No- tice that all amino acids have carboxyl groups and amino groups; the terms acidic and basic in this context refer only to groups on the side chains.) Because they are charged, acidic and basic side chains are also hydrophilic.
Amino Acid Polymers
Now that we have examined amino acids, let’s see how they are linked to form polymers (Figure 5.17). When two amino acids are positioned so that the carboxyl group of one is adja- cent to the amino group of the other, they can become joined by a dehydration reaction, with the removal of a water mole- cule. The resulting covalent bond is called a peptide bond. Repeated over and over, this process yields a polypeptide, a polymer of many amino acids linked by peptide bonds. The repeating sequence of atoms highlighted in purple in Figure 5.17 is called the polypeptide backbone. Extending from this backbone are the different side chains (R groups) of the amino acids. Polypeptides range in length from a few amino acids to a thousand or more. Each specific polypeptide has a unique linear sequence of amino acids. Note that one end of the polypeptide chain has a free amino group, while the opposite end has a free carboxyl group. Thus, a polypep- tide of any length has a single amino end (N-terminus) and a single carboxyl end (C-terminus). In a polypeptide of any sig- nificant size, the side chains far outnumber the terminal groups, so the chemical nature of the molecule as a whole is determined by the kind and sequence of the side chains. The immense variety of polypeptides in nature illustrates an im- portant concept introduced earlier—that cells can make many different polymers by linking a limited set of monomers into diverse sequences.
Protein Structure and Function
The specific activities of proteins result from their intricate three-dimensional architecture, the simplest level of which is the sequence of their amino acids. The pioneer in determin- ing the amino acid sequence of proteins was Frederick Sanger, who, with his colleagues at Cambridge University in England, worked on the hormone insulin in the late 1940s and early 1950s. He used agents that break polypeptides at
Figure 5.17 Making a polypeptide chain. Peptide bonds are formed by dehydration reactions, which link the carboxyl group of one amino acid to the amino group of the next. The peptide bonds are formed one at a time, starting with the amino acid at the amino end (N-terminus). The polypeptide has a repetitive backbone (purple) to which the amino acid side chains (yellow and green) are attached. Circle and label the carboxyl and amino groups that will form the new peptide bond.
DRAW IT
H N
H
C
H
C
O
CH 2
CH 2
CH 3
S
N C
H
C
O
CH 2
OH
N
H H
C
H
C
O
OH
SH
Peptide bond
CH 2
OH H
H N
H
C
H
C
O
CH 2
CH 2
CH 3
Amino end (N-terminus)
Carboxyl end (C-terminus)
New peptide bond forming
S
N C
H
C
O
CH 2
OH
N
H H
C
H
C
O
OH
SH
Peptide bond
CH 2
Side chains
Back- bone
H 2 O
specific places, followed by chemical methods to determine the amino acid sequence in these small fragments. Sanger and his co-workers were able, after years of effort, to recon- struct the complete amino acid sequence of insulin. Since then, most of the steps involved in sequencing a polypeptide have been automated. Once we have learned the amino acid sequence of a polypeptide, what can it tell us about the three-dimensional structure (commonly referred to simply as the “structure”) of the protein and its function? The term polypeptide is not syn- onymous with the term protein. Even for a protein consisting of a single polypeptide, the relationship is somewhat analo- gous to that between a long strand of yarn and a sweater of particular size and shape that can be knit from the yarn. A functional protein is not just a polypeptide chain, but one or more polypeptides precisely twisted, folded, and coiled into a molecule of unique shape (Figure 5.18). And it is the amino acid sequence of each polypeptide that determines what
C H A P T E R 5 The Structure and Function of Large Biological Molecules 81
three-dimensional structure the protein will have under nor- mal cellular conditions. When a cell synthesizes a polypeptide, the chain generally folds spontaneously, assuming the functional structure for that protein. This folding is driven and reinforced by the for- mation of a variety of bonds between parts of the chain, which in turn depends on the sequence of amino acids. Many proteins are roughly spherical ( globular proteins ), while others are shaped like long fibers ( fibrous proteins ). Even within these broad categories, countless variations exist. A protein’s specific structure determines how it works. In almost every case, the function of a protein depends on its ability to recognize and bind to some other molecule. In an especially striking example of the marriage of form and func- tion, Figure 5.19 shows the exact match of shape between an antibody (a protein in the body) and the particular foreign substance on a flu virus that the antibody binds to and marks for destruction. In Chapter 43, you’ll learn more about how the immune system generates antibodies that match the shapes of specific foreign molecules so well. Also, you may re- call from Chapter 2 that natural signaling molecules called endorphins bind to specific receptor proteins on the surface of brain cells in humans, producing euphoria and relieving pain. Morphine, heroin, and other opiate drugs are able to mimic endorphins because they all share a similar shape with endorphins and can thus fit into and bind to endorphin re- ceptors in the brain. This fit is very specific, something like a lock and key (see Figure 2.18). Thus, the function of a protein—for instance, the ability of a receptor protein to bind to a particular pain-relieving signaling molecule—is an emer- gent property resulting from exquisite molecular order.
Figure 5.18 Structure of a protein, the enzyme lysozyme. Present in our sweat, tears, and saliva, lysozyme is an enzyme that helps prevent infection by binding to and destroying specific molecules on the surface of many kinds of bacteria. The groove is the part of the protein that recognizes and binds to the target molecules on bacterial walls.
(a) A ribbon model shows how the single polypeptide chain folds and coils to form the functional protein. (The yellow lines represent disul- fide bridges that stabilize the protein’s shape; see Figure 5.20.)
Groove
(b) A space-filling model shows more clearly the globular shape seen in many proteins, as well as the specific three-dimensional structure unique to lysozyme.
Groove
Figure 5.19 An antibody binding to a protein from a flu virus. A technique called X-ray crystallography was used to generate a computer model of an antibody protein (blue and orange, left) bound to a flu virus protein (green and yellow, right). Computer software was then used to back the images away from each other, revealing the exact complementarity of shape between the two protein surfaces.
Antibody protein Protein from flu virus
Four Levels of Protein Structure
With the goal of understanding the function of a protein, learning about its structure is often productive. In spite of their great diversity, all proteins share three superimposed levels of structure, known as primary, secondary, and tertiary structure. A fourth level, quaternary structure, arises when a protein con- sists of two or more polypeptide chains. Figure 5.20 , on the following two pages, describes these four levels of protein structure. Be sure to study this figure thoroughly before going on to the next section.
Quaternary Structure
Association of multiple polypeptides,
forming a functional protein
Some proteins consist of two or more polypeptide chains aggregated into one functional macromolecule. Quaternary structure is the overall protein structure that results from the aggregation of these polypeptide subunits. For example, shown above is the complete globular transthyretin protein, made up of its four polypeptides. Another example is collagen, shown below, which is a fibrous protein that has three identical helical polypeptides intertwined into a larger triple helix, giving the long fibers great strength. This suits collagen fibers to their function as the girders of connective tissue in skin, bone, tendons, ligaments, and other body parts. (Collagen accounts for 40% of the protein in a human body.)
Hemoglobin, the oxygen-binding protein of red blood cells shown below, is another example of a globular protein with quaternary structure. It consists of four polypeptide subunits, two of one kind (α) and two of another kind (β). Both α and β subunits consist primarily of α-helical secondary structure. Each subunit has a nonpolypeptide component, called heme, with an iron atom that binds oxygen.
Collagen
Heme Iron
α subunit
β subunit
β subunit
α subunit
Hemoglobin
Hydrogen bond Hydrophobic interactions and van der Waals interactions
Ionic bond
Disulfide bridge
Polypeptide backbone
OH
CH 2
S
CH (^2)
S CH (^2)
O CH 2
C
NH 2 CH 3 CH 3
CH
CH 3 CH 3 CH
O –
CH (^2) O C
CH (^2) CH 2
CH (^2) CH (^2)
NH 3 +
Tertiary Structure
Three-dimensional shape stabilized by
interactions between side chains
Superimposed on the patterns of secondary structure is a protein’s tertiary structure, shown above in a ribbon model of the trans- thyretin polypeptide. While secondary structure involves interac- tions between backbone constituents, tertiary structure is the overall shape of a polypeptide resulting from interactions between the side chains (R groups) of the various amino acids. One type of interaction that contributes to tertiary structure is—somewhat mis- leadingly—called a hydrophobic interaction. As a polypeptide folds into its functional shape, amino acids with hydrophobic (nonpolar) side chains usually end up in clusters at the core of the protein, out of contact with water. Thus, a “hydrophobic interac- tion” is actually caused by the exclusion of nonpolar substances by water molecules. Once nonpolar amino acid side chains are close together, van der Waals interactions help hold them together. Meanwhile, hydrogen bonds between polar side chains and ionic bonds between positively and negatively charged side chains also help stabilize tertiary structure. These are all weak interactions in the aqueous cellular environment, but their cumulative effect helps give the protein a unique shape. Covalent bonds called disulfide bridges may further reinforce the shape of a protein. Disulfide bridges form where two cysteine monomers, which have sulfhydryl groups (¬SH) on their side chains (see Figure 4.9), are brought close together by the folding of the protein. The sulfur of one cysteine bonds to the sulfur of the second, and the disulfide bridge (¬S¬S¬) rivets parts of the pro- tein together (see yellow lines in Figure 5.18a). All of these different kinds of interactions can contribute to the tertiary structure of a protein, as shown here in a small part of a hypothetical protein:
Transthyretin polypeptide
Transthyretin protein (four identical polypeptides)
C H A P T E R 5 The Structure and Function of Large Biological Molecules 83
Sickle-Cell Disease: A Change in Primary Structure
Even a slight change in primary structure can affect a pro- tein’s shape and ability to function. For instance, sickle-cell disease , an inherited blood disorder, is caused by the substi- tution of one amino acid (valine) for the normal one (glu- tamic acid) at a particular position in the primary structure of hemoglobin, the protein that carries oxygen in red blood cells. Normal red blood cells are disk-shaped, but in sickle-cell dis- ease, the abnormal hemoglobin molecules tend to crystallize, deforming some of the cells into a sickle shape (Figure 5.21). A person with the disease has periodic “sickle-cell crises” when the angular cells clog tiny blood vessels, impeding blood flow. The toll taken on such patients is a dramatic ex- ample of how a simple change in protein structure can have devastating effects on protein function.
What Determines Protein Structure?
You’ve learned that a unique shape endows each protein with a specific function. But what are the key factors deter- mining protein structure? You already know most of the an- swer: A polypeptide chain of a given amino acid sequence can spontaneously arrange itself into a three-dimensional shape determined and maintained by the interactions re- sponsible for secondary and tertiary structure. This folding normally occurs as the protein is being synthesized in the
84 U N I T O N E The Chemistry of Life
Figure 5.21 A single amino acid substitution in a protein causes sickle-cell disease. Considering the chemical characteristics of the amino acids valine and glutamic acid (see Figure 5.16), propose a possible explanation for the dramatic effect on protein function that occurs when va- line is substituted for glutamic acid.
MAKE CONNECTIONS
1^ Val 2 His 3^ Leu 4 Thr 5^ Pro 6 Glu 7^ Glu
1 Val 2^ His 3 Leu 4^ Thr 5 Pro 6 Val 7 Glu
Normal hemoglobin
Sickle-cell hemoglobin
Exposed hydrophobic region
Molecules do not associate with one another; each carries oxygen.
subunit
subunit
Normal hemoglobin^10 μm
Sickle-cell hemoglobin
Primary Structure
Secondary and Tertiary Structures
Quaternary Structure Function^ Red Blood Cell Shape Normal red blood cells are full of individual hemoglobin molecules, each carrying oxygen.
Fibers of abnormal hemoglobin deform red blood cell into sickle shape.
Molecules interact with one another and crystallize into a fiber; capacity to carry oxygen is greatly reduced.
10 μm
Figure 5.22 Denaturation and renaturation of a protein. High temperatures or various chemical treatments will denature a protein, causing it to lose its shape and hence its ability to function. If the denatured protein remains dissolved, it can often renature when the chemical and physical aspects of its environment are restored to normal.
Normal protein Denatured protein
Dena
turation
Ren aturation
crowded environment within a cell, aided by other proteins. However, protein structure also depends on the physical and chemical conditions of the protein’s environment. If the pH, salt concentration, temperature, or other aspects of its envi- ronment are altered, the weak chemical bonds and interac- tions within a protein may be destroyed, causing the protein to unravel and lose its native shape, a change called denaturation (Figure 5.22). Because it is misshapen, the denatured protein is biologically inactive. Most proteins become denatured if they are transferred from an aqueous environment to a nonpolar solvent, such as
86 U N I T O N E The Chemistry of Life
C O N C E P T C H E C K 5.
1. Why does a denatured protein no longer function normally? 2. What parts of a polypeptide participate in the bonds that hold together secondary structure? Tertiary structure? 3. Where would you expect a polypeptide region that is rich in the amino acids valine, leucine, and isoleucine to be located in the folded polypep- tide? Explain. For suggested answers, see Appendix A.
WHAT IF?
Figure 5.24 INQUIRY
What can the 3-D shape of the enzyme RNA
polymerase II tell us about its function?
EXPERIMENT In 2006, Roger Kornberg was awarded the Nobel Prize in Chemistry for using X-ray crystallography to determine the 3-D shape of RNA polymerase II, which binds to the DNA double helix and synthesizes RNA. After crystallizing a complex of all three components, Kornberg and his colleagues aimed an X-ray beam through the crystal. The atoms of the crystal diffracted (bent) the X-rays into an orderly array that a digital detec- tor recorded as a pattern of spots called an X-ray diffraction pattern.
RESULTS Using data from X-ray diffraction patterns, as well as the amino acid sequence determined by chemical methods, Kornberg and colleagues built a 3-D model of the complex with the help of computer software.
CONCLUSION By analyzing their model, the researchers developed a hy- pothesis about the functions of different regions of RNA polymerase II. For example, the region above the DNA may act as a clamp that holds the nu- cleic acids in place. (You’ll learn more about this enzyme in Chapter 17.)
SOURCE A. L. Gnatt et al., Structural basis of transcription: an RNA poly- merase II elongation complex at 3.3Å, Science 292:1876–1882 (2001).
If you were an author of the paper and were describing the model, what type of protein structure would you call the small polypeptide spirals in RNA polymerase II?
WHAT IF?
Diffracted X-rays
Digital detector X-ray diffraction pattern
Crystal
X-ray beam
X-ray source
Figure 5.25 DNA → RNA → protein. In a eukaryotic cell, DNA in the nucleus programs protein production in the cytoplasm by dictating synthesis of messenger RNA (mRNA). (The cell nucleus is actually much larger relative to the other elements of this figure.)
mRNA
Ribosome
Amino Polypeptide acids
CYTOPLASM
DNA
mRNA
NUCLEUS
Synthesis of mRNA in the nucleus
Movement of mRNA into cytoplasm via nuclear pore
Synthesis of protein using information carried on mRNA
C O N C E P T (^) 5.
Nucleic acids store, transmit, and help express hereditary information
If the primary structure of polypeptides determines a pro- tein’s shape, what determines primary structure? The amino acid sequence of a polypeptide is programmed by a discrete unit of inheritance known as a gene. Genes consist of DNA, which belongs to the class of compounds called nucleic acids. Nucleic acids are polymers made of monomers called nucleotides.
The Roles of Nucleic Acids The two types of nucleic acids, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) , enable living organisms to re- produce their complex components from one generation to the next. Unique among molecules, DNA provides directions for its own replication. DNA also directs RNA synthesis and, through RNA, controls protein synthesis (Figure 5.25). DNA is the genetic material that organisms inherit from their parents. Each chromosome contains one long DNA mol- ecule, usually carrying several hundred or more genes. When a cell reproduces itself by dividing, its DNA molecules are copied and passed along from one generation of cells to the next. Encoded in the structure of DNA is the information that
RNA
RNA
polymerase II
DNA
C H A P T E R 5 The Structure and Function of Large Biological Molecules 87
programs all the cell’s activities. The DNA, however, is not di- rectly involved in running the operations of the cell, any more than computer software by itself can print a bank state- ment or read the bar code on a box of cereal. Just as a printer is needed to print out a statement and a scanner is needed to read a bar code, proteins are required to implement genetic programs. The molecular hardware of the cell—the tools for biological functions—consists mostly of proteins. For exam- ple, the oxygen carrier in red blood cells is the protein hemo- globin, not the DNA that specifies its structure. How does RNA, the other type of nucleic acid, fit into gene expression, the flow of genetic information from DNA to pro- teins? Each gene along a DNA molecule directs synthesis of a type of RNA called messenger RNA ( mRNA ). The mRNA mol- ecule interacts with the cell’s protein-synthesizing machinery to direct production of a polypeptide, which folds into all or part of a protein. We can summarize the flow of genetic infor- mation as DNA S^ RNA S^ protein (see Figure 5.25). The sites of protein synthesis are tiny structures called ribosomes. In a eukaryotic cell, ribosomes are in the cytoplasm, but DNA re- sides in the nucleus. Messenger RNA conveys genetic instruc- tions for building proteins from the nucleus to the cytoplasm. Prokaryotic cells lack nuclei but still use mRNA to convey a
(a) Polynucleotide, or nucleic acid
(b) Nucleotide
(c) Nucleoside components
NH 2
NH 2
NH 2
C C
N
H
O
CH
CH
N
C
N
H
O
C
CH
HN
C
CH 3
O
C
N
H
O
CH
CH
HN
C
O
O
Cytosine (C)
Nitrogenous bases Pyrimidines
Sugars
Purines
Thymine (T, in DNA)
C
N
C
C
N
CH
C
Adenine (A)
Deoxyribose (in DNA) Ribose (in RNA)
N
N
H
C
N
C
NH
C
HC HC
N
N
H
Guanine (G)
Nitrogenous base
Nucleoside
5‘ end
3‘ end
5‘C
Sugar (pentose)
Phosphate group
Sugar-phosphate backbone (on blue background)
O
O–
– O P O
OH
CH 2 O
O
O
O
O
4 1
5
3 2
HOCH 2 OH HOCH 2
H H
H
OH
H
H
O
4 1
5
3 2
OH
H H
H
OH
H
OH
O
Uracil (U, in RNA)
3‘C
3‘C
1‘C
5‘C
5‘C
3‘C
Figure 5.26 Components of nucleic acids. (a) A polynucleotide has a sugar-phosphate backbone with variable appendages, the nitrogenous bases. (b) A nucleotide monomer includes a nitrogenous base, a sugar, and a phosphate group. Without the phosphate group, the structure is called a nucleoside. (c) A nucleoside includes a nitrogenous base (purine or pyrimidine) and a five-carbon sugar (deoxyribose or ribose).
message from the DNA to ribosomes and other cellular equip- ment that translate the coded information into amino acid se- quences. In recent years, the spotlight has been turned on other, previously unknown types of RNA that play many other roles in the cell. As is so often true in biology, the story is still being written! You’ll hear more about the newly discov- ered functions of RNA molecules in Chapter 18.
The Components of Nucleic Acids
Nucleic acids are macromolecules that exist as polymers called polynucleotides (Figure 5.26a). As indicated by the name, each polynucleotide consists of monomers called nucleotides. A nucleotide, in general, is composed of three parts: a nitrogen- containing (nitrogenous) base, a five-carbon sugar (a pentose), and one or more phosphate groups (Figure 5.26b). In a polynu- cleotide, each monomer has only one phosphate group. The portion of a nucleotide without any phosphate groups is called a nucleoside. To build a nucleotide, let’s first consider the nitrogenous bases (Figure 5.26c). Each nitrogenous base has one or two rings that include nitrogen atoms. (They are called nitroge- nous bases because the nitrogen atoms tend to take up H
