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OUTLINE
SPIDER SILK: A BIOSTEEL PROTEIN
5.1 AMINO ACIDS Amino Acid Classes Biologically Active Amino Acids Modified Amino Acids in Proteins Amino Acid Stereoisomers Titration of Amino Acids Amino Acid Reactions 5.2 PEPTIDES 5.3 PROTEINS Protein Structure The Folding Problem Fibrous Proteins Globular Proteins 5.4 MOLECULAR MACHINES BIOCHEMISTRY IN PERSPECTIVE Spider Silk and Biomimetics
BIOCHEMISTRY IN THE LAB Protein Technology
Available Online BIOCHEMISTRY IN PERSPECTIVE Protein Poisons BIOCHEMISTRY IN PERSPECTIVE Lead Poisoning BIOCHEMISTRY IN PERSPECTIVE Protein Folding and Human Disease BIOCHEMISTRY IN PERSPECTIVE Myosin: A Molecular Machine BIOCHEMISTRY IN THE LAB Protein Sequence Analysis: The Edman Degradation
C^^5
H
A^
P
T^
E^
R
Amino Acids, Peptides,
and Proteins
A Spider’s Web Constructed with Silk Fiber The amino acid sequence of spider silk protein and the spider’s silk fiber spinning process combine to made spider silk, one of the strongest materials on earth.
Overview
PROTEINS ARE MOLECULAR TOOLS THAT PERFORM AN ASTONISHING VARI- ETY OF FUNCTIONS. IN ADDITION TO SERVING AS STRUCTURAL MATERIALS in all living organisms (e.g., actin and myosin in animal muscle cells), proteins are involved in such diverse functions as catalysis, metabolic regulation, transport, and defense. Proteins are composed of one or more polypeptides, unbranched polymers of 20 different amino acids. The genomes of most organisms specify the amino acid sequences of thousands or tens of thousands of proteins.
Spider Silk: A Biosteel Protein
S
piders have evolved over 400 million years into exceptionally successful predators. These invertebrate animals are a class of arthropods, called the arachnids. They have an exoskeleton, a segmented body, and jointed appendages. Although spiders possess an efficient venom in jection system, their most impressive feature is the production of silk, a multiuse protein fiber. Silk, which is spun through spinnerets at the end of the spider’s abdomen, is used in locomotion, mating, and offspring protection. The most promi- nent use of spider silk, however, is prey capture. The most sophisticated method of prey capture is the spiral, wheel-shape orb web, which is ori- ented vertically to intercept fast-moving flying prey. Spider silk’s mechanical properties ensure that the web readily absorbs impact energy so that prey is retained until the spider can subdue it. Orb webs (and the species that produce them) have fascinated humans for many thousands of years because of their dramatic visual impact. Ancient Greeks and Romans, for example, explained the occurrence of spiders and orb webs with the myth of Arachne, in which the mortal woman Arachne, an extraordinarily gifted weaver, offended Minerva (Athena in the Greek version), the goddess of weaving and other crafts, with her arrogant acceptance of a challenge to a weaving contest with the goddess. When confronted with Arachne’s flawless work, an enraged Minerva transformed her into a spider, doomed to forever weave webs. Humans have also long appreciated spider webs for their physical properties. Examples range from the ancient Greeks, who used spider webs to treat wounds, to the Australian aborigines who
used spider silk to make fishing lines. In modern times spider silk has served as crosshairs in sci- entific equipment and gun sights. In the past sev- eral decades, spider silk and orb webs have attracted the attention of life scientists, bioengi- neers, and material scientists as they began to appreciate the unique mechanical properties of this remarkable protein. There are eight different types of spider silk, although no spider makes all of them. Dragline silk, a very strong fiber, is used for frame and radial lines in orb webs and as a safety line (to break a fall or escape other predators). Capture silk, an elas- tic and sticky fiber, is used in the spiral of webs. Spider silk is a lightweight fiber with impressive mechanical properties.Toughness, a combination of stiffness and strength, is a measure of how much energy is needed to rupture a fiber. Spider silk is about five times as tough as high-grade steel wire of the same weight and about twice as tough as synthetic fibers such as Kevlar (used in body armor). Spider silk’stensile strength, the resis- tance of a material to breaking when stretched, is as great as that of Kevlar and greater than that of high-grade steel wire.Torsional resistance, the capacity of a fiber to resist twisting (an absolute requirement for draglines used as safety lines), is higher for spider silk than for all textile fibers, including Kevlar. It also has superiorelasticity and resilience, the capacity of a material when it is deformed elastically to absorb and then release energy. Scientists estimate that a 2.54 cm (1 in)–thick rope made of spider silk could be sub- stituted for the flexible steel arresting wires used on aircraft carriers to rapidly stop a jet plane as it lands.
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4 CHAPTER FIVE Amino Acids, Peptides, and Proteins
FIGURE 5. The Standard Amino Acids The ionization state of the amino acid molecules in this illustration represents the domi- nant species that occur at a pH of 7. The side chains are indicated by shaded boxes.
N
H 2 C (^) CH 2 CH (^2)
Glycine (Gly) Alanine (Ala) Valine (Val) Leucine (Leu) Isoleucine (Ile)
Phenylalanine (Pha) Tryptophan (Trp) Methionine (Met) Cysteine (Cys) Proline (Pro)
Serine (Ser) Threonine (Thr) Tyrosine (Tyr) Asparagine (Asp) Glutamine (Glm)
Aspartate (Asp) Glutamate (Glu) Lysine (Lys) Arginine (Arg) Histidine (His)
5.1 Amino Acids 5
FIGURE 5. General Structure of the -Amino Acids
C R
O O−
NH (^3)
H C
These amino acids are referred to as standard amino acids. Common abbreviations for the standard amino acids are listed in Table 5.1. Note that 19 of the standard amino acids have the same general structure (Figure 5.3). These molecules con- tain a central carbon atom (the -carbon) to which an amino group, a carboxy- late group, a hydrogen atom, and an R (side chain) group are attached. The exception, proline, differs from the other standard amino acids in that its amino group is secondary, formed by ring closure between the R group and the amino nitrogen. Proline confers rigidity to the peptide chain because rotation about the -carbon is not possible. This structural feature has significant implications in the structure and, therefore, the function of proteins with a high proline content. Nonstandard amino acids consist of amino acid residues that have been chem- ically modified after incorporation into a polypeptide or amino acids that occur in living organisms but are not found in proteins. Nonstandard amino acids found in proteins are usually the result of posttranslational modifications (chemical changes that follow protein synthesis). Selenocysteine, an exception to this rule, is discussed in Chapter 19. At a pH of 7, the carboxyl group of an amino acid is in its conjugate base form (—COO–), and the amino group is in its conjugate acid form (—NH 3 ). Thus each amino acid can behave as either an acid or a base. The term amphoteric is used to describe this property. Molecules that bear both positive and negative charges are called zwitterions. The R group gives each amino acid its unique properties.
Amino Acid Classes
Because the sequence of amino acids determines the final three-dimensional con- figuration of each protein, their structures are examined carefully in the next four subsections. Amino acids are classified according to their capacity to interact with water. By using this criterion, four classes may be distinguished: (1) nonpolar, (2) polar, (3) acidic, and (4) basic.
Three-Letter One-Letter Amino Acid Abbreviation Abbreviation Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys C Glutamic acid Glu E Glutamine Gln Q Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V
TABLE 5.1 Names and Abbreviations of the Standard Amino Acids
BASIC AMINO ACIDS Basic amino acids bear a positive charge at physiological pH. They can therefore form ionic bonds with acidic amino acids. Lysine, which has a side chain amino group, accepts a proton from water to form the conjugate acid (—NH 3 ). When lysine side chains in collagen fibrils, a vital structural component of ligaments and tendons, are oxidized and subsequently condensed, strong intramolecular and intermolecular cross-linkages are formed. Because the guanidino group of arginine has a p K a range of 11.5 to 12.5 in proteins, it is permanently protonated at physiological pH and, therefore, does not function in acid-base reactions. The imidazole side chain histidine, on the other hand, is a weak base because it is only partially ionized at pH 7 because its p K a is approximately 6. Its capacity under physiological conditions to accept or donate protons in response to small changes in pH plays an important role in the catalytic activity of numerous enzymes.
Biologically Active Amino Acids
In addition to their primary function as components of protein, amino acids have several other biological roles.
1. Several - amino acids or their derivatives act as chemical messengers (Figure 5.5). For example, glycine, glutamate, -amino butyric acid (GABA, a derivative of glutamate), and serotonin and melatonin (deriva- tives of try-ptophan) are neurotransmitters , substances released from one nerve cell that influence the function of a second nerve cell or a muscle cell. Thyroxine (a tyrosine derivative produced in the thyroid gland of animals) and indole acetic acid (a tryptophan derivative found in plants) are hor- mones —chemical signal mole-cules produced in one cell that regulate the function of othercells. 2. Amino acids are precursors of a variety of complex nitrogen-containing molecules. Examples include the nitrogenous base components of nucleotides and the nucleic acids, heme (the iron-containing organic group required for the biological activity of several important proteins), and chlorophyll (a pigment of critical importance in photosynthesis).
5.1 Amino Acids 7
KEY CONCEPT
Amino acids are classified according to their capacity to interact with water. This criterion may be used to distinguish four classes: nonpolar, polar, acidic, and basic.
FIGURE 5. Some Derivatives of Amino Acids
GABA
H 3 N CH 2 CH 2 CH 2 C O−
O
HO
N
CH 2 CH 2
NH (^3)
Serotonin
H
Thyroxine
HO O
I I
I I
CH 2 CH C O− +NH 3
O
Indole acetic acid
N H
CH 2 C OH
O
N H
H 3 C O
CH (^2)
CH (^2)
H 3 C C NH
Melatonin
O
FIGURE 5. Two Enantiomers
L-Alanine and D-alanine are mirror images of each other. (Nitrogen = large red ball; Hydrogen = small red ball; Carbon = black ball; Oxygen = blue balls)
3. Several standard and nonstandard amino acids act as metabolic interme- diates. For example, arginine (Figure 5.2), citrulline, and ornithine (Figure 5.6) are components of the urea cycle (Chapter 15). The synthe- sis of urea, a molecule formed in vertebrate livers, is the principal mech- anism for the disposal of nitrogenous waste.
Modified Amino Acids in Proteins
Several proteins contain amino acid derivatives that are formed after a polypep- tide chain has been synthesized. Among these modified amino acids is - carboxyglutamic acid (Figure 5.7), a calcium-binding amino acid residue found in the blood-clotting protein prothrombin. Both 4-hydroxyproline and 5-hydroxylysine are important structural components of collagen, the most abun- dant protein in connective tissue. Phosphorylation of the hydroxyl-containing amino acids serine, threonine, and tyrosine is often used to regulate the activity of proteins. For example, the synthesis of glycogen is significantly curtailed when the enzyme glycogen synthase is phosphorylated. Two other modified amino acids, selenocysteine and pyrolysine, are discussed in Chapter 19.
Amino Acid Stereoisomers
Because the - carbons of 19 of the 20 standard amino acids are attached to four different groups (i.e., a hydrogen, a carboxyl group, an amino group, and an R group), they are referred to as asymmetric , or chiral , carbons. Glycine is a sym- metrical molecule because its - carbon is attached to two hydrogens. Molecules with chiral carbons can exist as stereoisomers , molecules that differ only in the spatial arrangement of their atoms. Three-dimensional representations of amino acid stereoisomers are illustrated in Figure 5.8. Notice in the figure that the atoms of the two isomers are bonded together in the same pattern except for the position of the ammonium group and the hydrogen atom. These two isomers are mirror images of each other. Such mol- ecules, called enantiomers , can- not be superimposed on each other. Enantiomers have identical physical properties except that they rotate plane-polarized light in opposite directions. Plane- polarized light is produced by passing unpolarized light through a special filter; the light waves vibrate in only one plane. Mol- ecules that possess this property are called optical isomers. Glyceraldehyde is the reference compound for optical isomers (Figure 5.9). One glyceraldehyde isomer rotates the light beam in a clockwise direction and is said to be dextrorotatory (designated by ). The other glyceraldehyde isomer, referred to as levorotatory (designated by ), rotates the beam in the opposite direction to an equal degree. Optical isomers
8 CHAPTER FIVE Amino Acids, Peptides, and Proteins
C O−
O
CH CH (^2)
CH (^2)
CH (^2)
H 3 N CH
CH (^2)
CH 2
CH 2
NH
C
C O−
NH 2
O
O
+NH 3
Citrulline Ornithine
H 3 N
FIGURE 5. Citrulline and Ornithine
5-Hydroxylysine
NH CH
CH (^2)
CH (^2) CH
CH (^2)
C
O
OH
+NH 3
NH CH
CH 2 O
P
O−
o -Phosphoserine
C
O
−O C −O O
O CH
C
O−
O
NH CH
CH (^2)
C
O
γ -Carboxyglutamate
CH 2 CH (^2)
N CH
OH
C
O
4-Hydroxyproline
H
FIGURE 5. Some Modified Amino Acid Residues Found in Polypeptides
L-Alanine D -Alanine
10 CHAPTER FIVE Amino Acids, Peptides, and Proteins
Titration of Two Amino Acids
- Glycine 2.34 9. Amino Acid p K 1 (—COOH) p K 2 (—NH 3 ) p K R
- Alanine 2.34 9.
- Valine 2.32 9.
- Leucine 2.36 9.
- Isoleucine 2.36 9.
- Serine 2.21 9.
- Threonine 2.63 10.
- Methionine 2.28 9.
- Phenylalanine 1.83 9.
- Tryptophan 2.83 9.
- Asparagine 2.02 8.
- Glutamine 2.17 9.
- Proline 1.99 10.
- Cysteine 1.71 10.78 8.
- Histidine 1.82 9.17 6.
- Aspartic acid 2.09 9.82 3.
- Glutamic acid 2.19 9.67 4.
- Tyrosine 2.20 9.11 10.
- Lysine 2.18 8.95 10.
- Arginine 2.17 9.04 12.
- FIGURE 5. TABLE 5.2 pKa Values for the Ionizing Groups of the Amino Acids
As more base is added, the second carboxyl group loses a proton, and the molecule has a –1 charge. Adding additional base results in the ammonium ion losing its proton. At this point, glutamate has a net charge of –2. The pI value for glutamate is the pH halfway between the p K a values for the two carboxyl groups (i.e., the p K a values that bracket the zwitterion):
Problems 5.1 to 5.3 are sample titration problems. When amino acids are incorporated in polypeptides, the - amino and - carboxyl groups lose their charges. Consequently, except for the - amino and - carboxyl groups of the amino acid residues at the beginning and end, respec- tively, of a polypeptide chain all the ionizable groups of proteins are the side chain groups of seven amino acids: histidine, lysine, arginine, aspartate, glutamate, cysteine, and tyrosine. It should be noted that the p K a values of these groups can differ from those of free amino acids. The p K a values of individual R groups are affected by their positions within protein microenvironments. For example, when the side chain groups of two aspartate residues are in close proximity, the p K a of one of the carboxylate groups is raised. The significance of this phenom- enon will become apparent in the discussion of enzyme catalytic mechanisms (Section 6.4).
5.1 Amino Acids 11
Amino acids with ionizable side chains have more complex titration curves. Glutamic acid, for example, has a carboxyl side chain group (Figure 5.10b). At low pH, glutamic acid has net charge 1. As base is added, the - carboxyl group loses a proton to become a carboxylate group. Glutamate now has no net charge.
pI
Calculate the isoelectric point of the following tripeptide:
Assume that the p K a values listed for the amino acids in Table 5.2 are applica- ble to this problem.
QUESTION 5.
H 3 N CH
C NH
O CH CH (^2)
C
O NH CH SH
CH C
O O– CH (^2)
N H
H3C CH (^3)
5.1 Amino Acids 13
WORKED PROBLEM 5.
a. Sketch the titration curve for the amino acid lysine. Solution (a) Plateaus appear at the p K a and are centered about 0.5 equivalent (Eq), 1.5 Eq, and 2.5 Eq of base. There is a sharp rise at 1 Eq, 2 Eq, and 3 Eq. The isoelectric point is midway on the sharp rise between p K a1 and p K aR. b. In what direction does the amino acid move when placed in an electric field at the following pH values: 1, 3, 5, 7, 9, and 12? Choice 1 : does not move, Choice 2 toward the cathode (negative electrode), Choice 3 : toward the anode (positive electrode). Solution (b) At pH values below the p I (in this case 9.87), the amino acid is positively charged and moves to the cathode. Therefore, the amino acid in this problem will move, to the cathode at the pH values of 1, 3, 5, 7, and 9. The amino acid will be nega- tively charged at a pH value of 12. Under this condition, the amino acid will move to the anode.
WORKED PROBLEM 5.
Consider the following dipeptide:
a. What is its isoelectric point? Solution (a) The isoelectric point is the average of the p K as of the amino group of glycine and the carboxyl group of phenylalanine (obtained from Table 5.2). p I = (9.60 + 1.83)/2 = 5. b. In which direction will the dipeptide move at pH 1, 3, 5, 7, 9, and 12? Solution (b) At pH values below that of the p I the dipeptide will move to the cathode (i.e., 1, 3, and 5). At pH values above the p I the dipeptide will move to the anode. These are 7, 9, and 12.
Amino Acid Reactions
The functional groups of organic molecules determine which reactions they may undergo. Amino acids with their carboxyl groups, amino groups, and various R groups can undergo numerous chemical reactions. Peptide bond and disulfide bridge formation, however, are of special interest because of their effect on pro- tein structure. Schiff base formation is another important reaction.
PEPTIDE BOND FORMATION Polypeptides are linear polymers composed of amino acids linked together by peptide bonds. Peptide bonds (Figure 5.11) are amide linkages formed when the unshared electron pair of the - amino nitrogen atom of one amino acid attacks the - carboxyl carbon of another in a
H 3 N CH (^2)
C N
O H CH CH (^2)
C
O O–
14 CHAPTER FIVE Amino Acids, Peptides, and Proteins
nucleophilic acyl substitution reaction. A generalized acyl substitution reaction is shown:
The linked amino acids in a polypeptide are referred to as amino acid residues because peptide bond formation is a dehydration reaction (i.e., a water mole- cule is removed). When two amino acid molecules are linked, the product is called a dipeptide. For example, glycine and serine can form the dipeptides gly- cylserine or serylglycine. As amino acids are added and the chain lengthens, the prefix reflects the number of residues: a tripeptide contains three amino acid residues, a tetrapeptide four, and so on. By convention, the amino acid residue with the free amino group is called the N-terminal residue and is written to the left. The free carboxyl group on the C-terminal residue appears on the right. Peptides are named by using their amino acid sequences, beginning from their N-terminal residue. For example, H 3 N
—Tyr—Ala—Cys—Gly—COO– is a tetrapeptide named tyrosylalanylcysteinylglycine.
O
R C X + Y
O
FIGURE 5. Formation of a Dipeptide
(a) A peptide bond forms when the -carboxyl group of one amino acid reacts with the amino group of another. (b) A water molecule is formed in the reaction.
O N
Cα
O
−
O Cα
−
O
N
O
− O
O
(a)
(b)
N
C α
–C α
N
O
N
16 CHAPTER FIVE Amino Acids, Peptides, and Proteins
KEY CONCEPTS
- Polypeptides are polymers composed of amino acids linked by peptide bonds. The order of the amino acids in a polypeptide is called the amino acid sequence.
- Disulfide bridges, formed by the oxidation of cysteine residues, are an important structural element in polypeptides and pro- teins.
- Schiff bases are imines that form when amine groups react reversibly with carbonyl groups.
In extracellular fluids such as blood (pH 7.2–7.4) and urine (pH 6.5), the sulfhydryl groups of cysteine (p K a 8.1) are subject to oxidation to form cystine. In peptides and proteins thiol groups are used to advantage in stabilizing protein structure and in thiol transfer reactions, but the free amino acid in tissue fluids can be prob- lematic because of the low solubility of cystine. In a genetic disorder known as cystinuria , defective membrane transport of cystine results in excessive excre- tion of cystine into the urine. Crystallization of the amino acid results in formation of calculi (stones) in the kidney, ureter, or urinary bladder. The stones may cause pain, infection, and blood in the urine. Cystine concentration in the kidney is reduced by massively increasing fluid intake and administering D-penicillamine. It is believed that penicillamine (Figure 5.14) is effective because penicil- lamine–cysteine disulfide, which is substantially more soluble than cystine, is formed. What is the structure of the penicillamine–cysteine disulfide?
QUESTION 5.
H 3 C C CH C OH
NH 2
CH 3 O
SH
FIGURE 5. Structure of Penicillamine
FIGURE 5. Oxidation of Two Cysteine Molecules to Form Cystine The disulfide bond in a polypeptide is called a disulfide bridge.
2H +^ +2e –
SCHIFF BASE FORMATION Molecules such as amino acids that possess primary amine groups can reversibly react with carbonyl groups. The imine products of this reaction are often referred to as Schiff bases. In a nucleophilic addition reaction, an amine nitrogen attacks the electrophilic carbon of a carbonyl group to form an alkoxide product. The transfer of a proton from the amine group to the oxygen to form a carbinolamine, followed by the transfer of another proton from an acid catalyst, converts the oxygen into a good leaving group (OH 2 ). The subsequent elimination of a water molecule followed by loss of a proton from the nitrogen yields the imine product. The most important examples of Schiff base formation in biochemistry occur in amino acid metabolism. Schiff bases, referred to as aldimines , formed by the reversible reaction of an amino group with an aldehyde group, are intermediates (species formed during a reaction) in transamination reactions (pp. xxx–xxx).
Cystinuria
5.2 PEPTIDES
Although less structurally complex than the larger protein molecules, peptides have significant biological activities. The structure and function of several inter- esting examples, presented in Table 5.3, are now discussed. The tripeptide glutathione ( - glutamyl-L-cysteinylglycine) contains an unusual -amide bond. (Note that the -carboxyl group of the glutamic acid residue, not the - carboxyl group, contributes to the peptide bond.) Found in almost all organ- isms, glutathione (GSH) is involved in protein and DNA synthesis, drug and envi- ronmental toxin metabolism, amino acid transport, and other important biological processes. One group of glutathione’s functions exploits its effectiveness as a reducing agent. Glutathione protects cells from the destructive effects of oxida- tion by reacting with substances such as peroxides (R–O–O–R), by-products of O 2 metabolism. For example, in red blood cells, hydrogen peroxide (H 2 O 2 ) oxidizes the iron of hemoglobin to its ferric form (Fe 3 ). Methemoglobin, the product of this reaction, is incapable of binding O 2. Glutathione protects against the formation of methemoglobin by reducing H 2 O 2 in a reaction catalyzed by
5.2 Peptides 17
Amine Alkoxide
Carbinolamine
R N C
O O−
H+
R R R
H R +N
H
R N C
OH H^2 O
R
R C R H R H
R N
N
+OH
Aldimine (Schiff Base)
R N
H
C R
R R C R
R
C H HR
Name Amino Acid Sequence
TABLE 5.3 Selected Biologically Important Peptides
5.3 PROTEINS
Of all the molecules encountered in living organisms, proteins have the most diverse functions, as the following list suggests.
1. Catalysis. Catalytic proteins called the enzymes accelerate thousands of biochemical reactions in such processes as digestion, energy capture, and biosynthesis. These molecules have remarkable properties. For example, enzymes can increase reaction rates by factors of between 10^6 and 10 12. They can perform this feat under mild conditions of pH and temperature because they can induce or stabilize strained reaction intermediates. For example, ribulose bisphosphate carboxylase is an important enzyme in photosynthesis, and the protein complex nitrogenase is responsible for nitrogen fixation. 2. Structure. Structural proteins often have very specialized properties. For example, collagen (the major components of connective tissues) and fibroin (silkworm protein) have significant mechanical strength. Elastin, the rub- berlike protein found in elastic fibers, is found in blood vessels and skin that must be elastic to function properly. 3. Movement. Proteins are involved in all cell movements. Actin, tubulin, and other proteins comprise the cytoskeleton. Cytoskeletal proteins are active in cell division, endocytosis, exocytosis, and the ameboid movement of white blood cells. 4. Defense. A wide variety of proteins are protective. In vertebrates, keratin, a protein found in skin cells, aids in protecting the organism against mechanical and chemical injury. The blood-clotting proteins fibrinogen and thrombin prevent blood loss when blood vessels are damaged. The immunoglobulins (or antibodies) are produced by lymphocytes when for- eign organisms such as bacteria invade an organism. Binding antibodies to an invading organism is the first step in its destruction. 5. Regulation. Binding a hormone molecule or a growth factor to cognate receptors on its target cell changes cellular function. For example, insulin and glucagon are peptide hormones that regulate blood glucose levels. Growth hormone stimulates cell growth and division. Growth factors are polypeptides that control animal cell division and differentiation. Examples include platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). 6. Transport. Many proteins function as carriers of molecules or ions across membranes or between cells. Examples of membrane transport proteins include the enzyme Na-K^ ATPase and the glucose transporter. Other transport proteins include hemoglobin, which carries O 2 to the tissues from the lungs, and the lipoproteins LDL and HDL, which transport water- insoluble lipids in the blood from the liver. Transferrin and ceruloplas- min are serum proteins that transport iron and copper, respectively. 7. Storage. Certain proteins serve as a reservoir of essential nutrients. For example, ovalbumin in bird eggs and casein in mammalian milk are rich sources of organic nitrogen during development. Plant proteins such as zein perform a similar role in germinating seeds. 8. Stress response. The capacity of living organisms to survive a variety of abiotic stresses is mediated by certain proteins. Examples include cytochrome P 450 , a diverse group of enzymes found in animals and plants that usually convert a variety of toxic organic contaminants into less toxic derivatives, and metallothionein, a cysteine-rich intracellular protein found in virtually all mammalian cells that binds to and sequesters toxic metals such as cadmium, mercury, and silver. Excessively high temperatures and other stresses result in the synthesis of a class of proteins called the heat
5.3 Proteins 19
Visit the companion website at www.oup.com/us/mckee to read the Biochemistry in Perspective essay on protein poisons.
20 CHAPTER FIVE Amino Acids, Peptides, and Proteins
shock proteins (hsps) that promote the correct refolding of damaged proteins. If such proteins are severely damaged, hsps promote their degradation. (Certain hsps function in the normal process of protein fold- ing.) Cells are protected from radiation by DNA repair enzymes. Protein research efforts in recent years have revealed that numerous proteins have multiple and often unrelated functions. Once thought to be a rare phenom- enon, multifunction proteins (sometimes referred to as moonlighting proteins ) are a diverse class of molecules. Glyceraldehyde-3-phosphate dehydrogenase (GAPD) is a prominent example. As the name suggests, GAPD (p. 273) is an enzyme that catalyzes the oxidation of glyceraldehyde-3-phosphate, an inter- mediate in glucose catabolism. The GAPD protein is now known to have roles in such diverse processes as DNA replication and repair, endocytosis, and mem- brane fusion events. In addition to their functional classifications, proteins are categorized on the basis of amino acid sequence similarities and overall three-dimensional shape. Protein families are composed of protein molecules that are related by amino acid sequence similarity. Such proteins share an obvious common ancestry. Classic protein fam- ilies include the hemoglobins (blood oxygen transport proteins, pp. 168–171) and the immunoglobulins, the antibody proteins produced by the immune system in response to antigens (foreign substances). Proteins more distantly related are often classified into superfamilies. For example, the globin superfamily includes a vari- ety of heme-containing proteins that serve in the binding and/or transport of oxy- gen. In addition to the hemoglobins and myoglobins (oxygen-binding proteins in muscle cells), the globin superfamily includes neuroglobin and cytoglobin (oxygen- binding proteins in brain and other tissues, respectively) and the leghemoglobins (oxygen-sequestering proteins in the root nodules of leguminous plants). Because of their diversity, proteins are often classified in two additional ways: shape and composition. Proteins are classified into two major groups based on their shape. As the name suggests, fibrous proteins are long, rod-shaped molecules that are insoluble in water and physically tough. Fibrous proteins, such as the ker- atins found in skin, hair, and nails, have structural and protective functions. Globular proteins are compact spherical molecules that are usually water-soluble. Typically, globular proteins have dynamic functions. For example, nearly all enzymes have globular structures. Other examples include the immunoglobulins and the transport proteins hemoglobin and albumin (a carrier of fatty acids in blood). On the basis of composition, proteins are classified as simple or conjugated. Simple proteins, such as serum albumin and keratin, contain only amino acids. In contrast, each conjugated protein consists of a simple protein combined with a non- protein component. The nonprotein component is called a prosthetic group. (A pro- tein without its prosthetic group is called an apoprotein. A protein molecule combined with its prosthetic group is referred to as a holoprotein .) Prosthetic groups typically play an important, even crucial, role in the function of proteins. Conjugated proteins are classified according to the nature of their prosthetic groups. For exam- ple, glycoproteins contain a carbohydrate component, lipoproteins contain lipid molecules, and metalloproteins contain metal ions. Similarly, phosphoproteins contain phosphate groups, and hemoproteins possess heme groups (p. xx).
Protein Structure
Proteins are extraordinarily complex molecules. Complete models depicting even the smallest of the polypeptide chains are almost impossible to comprehend. Simpler images that highlight specific features of a molecule are useful. Two methods of conveying structural information about proteins are presented in Figure 5.15. Another structural representation, referred to as a ball-and-stick model, is presented later (Figures 5.37 and 5.39). Biochemists have distinguished several levels of the structural organization of proteins. Primary structure , the amino acid sequence, is specified by genetic
