Because of the amino acid functional groups, proteins also possess charges in solution, which vary with pH. Like individual amino acids, proteins have an isoelectric point. These can range from less than 1.0 for pepsin, the digestion enzyme that must act under acidic conditions in the stomach, to 10.6 for cytochrome c, which is involved in cellular respiration.

Unlike polysaccharides, which can have random lengths and random branching, each peptide is a single chain with a precise sequence of amino acids. Changing even a single amino acid can destroy the ability of the resulting protein to perform its function. Furthermore, the peptide chain must arrange itself into a complex shape, which is determined by the exact amino acid sequence, and often by the method by which the cell machinery

Figure 3.10 Tertiary and quarternary protein structure as shown in bovine insulin. This protein consists of two polypeptide chains joined by two disulfide bonds. Another disulfide bond within the smaller chain contributes to the molecule's shape. (Based on Bailey and Ollis, 1986.)

constructs the protein. The structure of a protein has three or four levels of organization. The primary level is the actual amino acid sequence. The secondary level refers to relatively local arrangements such as coiling into a helix or folding into a pleated sheet. The helix is held together by hydrogen bonds between the peptide bonds of every fourth amino acid. The tertiary level of organization is larger-scale folding and coiling, to give the overall shape to the molecule. Some proteins will exhibit the quaternary level of structure, in which several polypeptides are linked together by a variety of attractions, including hydrogen bonds, ionic attraction, or covalent disulfide linkage between cysteine amino acids on the two peptides. Hemoglobin, for example, consists of four polypeptide units. Figure 3.10 shows an example of protein structure. If the protein forms a compact, water-soluble state, which the majority of proteins do, they are called globular proteins. Fibrous proteins are elongated and often function in structural applications in connective tissue, contractile tissue, or as part of the hair or skin in mammals.

Proteins molecules often have other chemical compounds, called prosthetic groups, included in their structure, usually through noncovalent bonding. Often, they include metal ions. Hemoglobin contains four organic prosthetic groups, each containing an iron atom. Other proteins may contain chromium, copper, or zinc, for example. This is one of the reasons that humans and other organisms have a nutritional requirement for some heavy metals.

Since the higher levels of protein structure depend on relatively weak bonds such as hydrogen bonds, they are easily disrupted by increasing temperature or by changing pH or ionic strength. Such changes may result in conversion of the protein to a nonfunctional form, which is said to be denatured. These changes are often reversible. For example, hair can be curled by wrapping it around a rod and heating. This breaks hydrogen bonds, which re-form upon cooling, "freezing" the protein in the new shape. However, there is tension in the hair fibers, and with time the hydrogen bonds gradually rearrange into their former relationship, losing the curl. A "permanent" rearrangement can be made by using chemical treatment, which breaks disulfide bonds between cysteine residues in hair proteins, then re-forms them in the curled shape. A common example of irreversibly denaturing proteins by heat is the cooking of eggs. Heat disrupts the globular albumin proteins, which do not return to their native state upon cooling.

Enzymes are protein catalysts that increase biochemical reaction rates by factors ranging from 106 to 1012 over the uncatalyzed reactions. They often include non-amino acid portions that may be organic or consist of metallic ions. These are called cofactors.

Most enzymes are named with the suffix -ase. For example, lipase is an enzyme that digests lipids. Another enzyme is lactase, which catalyzes the breakdown of milk sugar, the disaccharide lactose, into monosaccharides glucose and galactose. Many adults, and almost all non-Caucasian adults, lose their ability to produce lactase after early childhood. However, some bacteria, including Escherichia coli, produce a different lactose-digesting enzyme. Adults lacking lactase who eat milk products have abdominal disturbances when the bacteria in the gut begin to produce gas using the lactose.

Enzymes are very specific; each catalyzes one or only a few different reactions, which is sensitively controlled by its shape. It is remarkable that contrary to reactions in aqueous media in the laboratory, enzyme-catalyzed reactions produce few side reactions. Equally remarkable is the fact that, with enzymes, a wide variety of reactions are promoted at mild conditions of temperature, pressure, and pH.

Each enzyme has at least one active site, the location on the molecule that binds with the substrate(s) (the reactants in the catalyzed reaction). The active site attracts the substrate^) and holds it, usually by physicochemical forces. Two major mechanisms by which enzymes increase reaction rates are (1) by bringing the reactants close together, and (2) by holding them in an orientation that favors the reaction (Figure 3.11). It is also thought that enzymes can act by inducing strain in specific bonds of bound substrates, making certain reactions favorable.

Since the shape of a molecule is so sensitive to its environment, the cell can turn reactions on or off by changing conditions (e.g., pH) or by providing or withdrawing a cofac-tor or inhibitory compound. Figure 3.12 shows how a cofactor could promote binding of a single substrate with an enzyme. The cofactor binds first with the enzyme, changing the shape of the active site. This allows the substrate to bind, forming the complex. As with all proteins, denaturing stops the function of any enzyme.

Enzymes may also require coenzymes, which are molecules that function by accepting by-products of the main reaction, such as hydrogen. Coenzymes differ from cofactors and from enzymes themselves in that they are consumed by the reaction (although they may be regenerated in other reactions). Examples include NAD and FAD, discussed below. Some cofactors and coenzymes cannot be synthesized by mammals and must be included in their diet, making them what we call vitamins.

Figure 3.11 Enzyme control of proximity and orientation of substrates.

Another important protein function is their use as binding proteins. Hemoglobin is an example of a binding protein that transports oxygen in the blood. Other binding proteins are active in the immune system, which responds to foreign substances in animals. The cell membrane is studded with proteins that function in communicating substances

Figure 3.12

Hypothetical enzyme mechanism involving a cofactor.

Figure 3.12

Hypothetical enzyme mechanism involving a cofactor.

and signals into and out of the cell. Cell membrane proteins are also a point of attack for infectious agents such as viruses, or may bind with drugs, leading to reactions that produce their characteristic effects.

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