Enzymes Biological Catalysts

When we know the change in free energy (AG) of a reaction, we know where the equilibrium point of the reaction lies: The more negative AG is, the further the reaction proceeds toward completion. However, AG tells us nothing about the rate of a reaction—the speed at which it moves toward equilibrium. The reactions that occur in cells are so slow that they could not contribute to life unless the cells did something to speed them up. That is the role of catalysts: substances that speed up a reaction without being permanently altered by that reaction. A catalyst does not cause a reaction that would not take place eventually without it, but merely speeds up the rates of both forward and backward reactions, allowing equilibrium to be approached faster.

Most biological catalysts are proteins called enzymes. Although we will focus here on proteins, some catalysts—per-haps the earliest ones in the origin of life—are RNA molecules called ribozymes (see Chapter 3). A biological catalyst, whether protein or RNA, is a framework or scaffold in which chemical catalysis takes place. It does not matter whether the framework is RNAor protein—indeed, artificial catalysts can be made from DNA. Evolution has selected proteins as catalysts, probably because of their great diversity in three-dimensional structure and variety of chemical functions.

In the discussion that follows, we will identify the energy barrier that controls the rate of reactions. Then we'll focus on the role of enzymes: how they interact with reactants, how they lower the energy barrier, and how they permit reactions to proceed faster. After exploring the nature and significance of enzyme specificity, we'll look at how enzymes contribute to the coupling of reactions.

For a reaction to proceed, an energy barrier must be overcome

An exergonic reaction may release a great deal of free energy, but the reaction may take place very slowly. Some reactions are slow because there is an energy barrier between reactants and products. Think about a gas stove. The burning of the natural gas (methane + O2 ^ CO2 + H2O) is obviously an ex-ergonic reaction—heat and light are released. Once started, the reaction goes to completion: all of the methane reacts with oxygen to form carbon dioxide and water vapor.

Because burning methane liberates so much energy, you might expect this reaction to proceed rapidly whenever methane is exposed to oxygen. But this does not happen. Simply mixing methane with air produces no reaction. Methane will start burning only if a spark—an input of energy—is provided. (On the stove, this energy is supplied by electricity.) The need for this spark to start the reaction shows that there is an energy barrier between the reactants and the products.

In general, exergonic reactions proceed only after the re-actants are pushed over the energy barrier by a small amount of added energy. The energy barrier thus represents the amount of energy needed to start the reaction, known as the activation energy (Ea) (Figure 6.8a). Recall the ball rolling down the hill in Figure 6.3. The ball has a lot of potential energy at the top of the hill. However, if the ball is stuck in a small depression, it won't roll down the hill, even though that action is exergonic (Figure 6.8b). To start the ball rolling, a small amount of energy (activation energy) is needed to get the ball out of the depression (Figure 6.8c).

In a chemical reaction, the activation energy is the energy needed to change the reactants into unstable molecular forms called transition-state species. Transition-state species have higher free energies than either the reactants or the products. Their bonds may be stretched and hence unstable. Although the amount of activation energy needed for different reactions varies, it is often small compared with the change in free energy of the reaction. The activation energy that starts a reaction is recovered during the ensuing "downhill" phase of the reaction, so it is not a part of the net free energy change, AG (see Figure 6.8a).

Where does the activation energy come from? In any collection of reactants at room or body temperature, molecules are moving around and could use their kinetic energy of motion to overcome the energy barrier, enter the transition state, and react (Figure 6.9). However, at normal temperatures, only a few molecules have enough energy to do this; most have insufficient kinetic energy for activation, so the reaction takes place slowly. If the system were heated, all the reactant molecules would move faster and have more kinetic energy. Since more of them would have energy exceeding the required activation energy, the reaction would speed up.

However, adding enough heat to increase the average kinetic energy of the molecules won't work in living systems. Such a nonspecific approach would accelerate all reactions, including destructive ones, such as the denaturation of proteins (see Figure 3.11). A more effective way to speed up a

Exergonic Reaction Ball Rolling Model

Course of reaction

6.9 Over the Energy Barrier Some molecules have enough kinetic energy to surmount the energy barrier and react, forming products. At the temperatures of most organisms, however, only a small proportion of the molecules have that much kinetic energy.

Course of reaction

6.9 Over the Energy Barrier Some molecules have enough kinetic energy to surmount the energy barrier and react, forming products. At the temperatures of most organisms, however, only a small proportion of the molecules have that much kinetic energy.

Catalytic Enzymes Plasma Membrane

3) AG for the reaction is not affected by Ea.

energy required for a reaction to begin.

Products

3) AG for the reaction is not affected by Ea.

energy required for a reaction to begin.

Products

Course of reaction

Course of reaction

Exergonic Reaction Ball Rolling Model
6.8 Activation Energy Initiates Reactions (a) In any chemical reaction, an initial stable state must become less stable before change is possible. (b,c) A ball on a hillside provides a physical analogy to the biochemical principle graphed in (a).

reaction in a living system is to lower the energy barrier. In living cells, enzymes accomplish this task.

Enzymes bind specific reactant molecules

Catalysts increase the rate of chemical reactions. Most nonbi-ological catalysts are nonspecific. For example, powdered platinum catalyzes virtually any reaction in which molecular hydrogen (H2) is a reactant. In contrast, most biological catalysts are highly specific. These complex molecules of protein (enzymes) or RNA (ribozymes) catalyze relatively simple chemical reactions. An enzyme or ribozyme usually recognizes and binds to only one or a few closely related reactants, and it catalyzes only a single chemical reaction. In the discussion that follows, we focus on enzymes, but you should note that similar rules of chemical behavior apply to ribozymes as well.

In an enzyme-catalyzed reaction, the reactants are called substrates. Substrate molecules bind to a particular site on the enzyme, called the active site, where catalysis takes place (Figure 6.10). The specificity of an enzyme results from the exact three-dimensional shape and structure of its active site, into which only a narrow range of substrates can fit. Other molecules—with different shapes, different functional groups, and different properties—cannot properly fit and bind to the active site.

The names of enzymes reflect the specificity of their functions and often end with the suffix "-ase." For example, the

Product

Active

Substrates fit precisely into the active site...

...but nonsubstrate does not.

Active

Substrates fit precisely into the active site...

...but nonsubstrate does not.

Functional Shape Enzyme

Enzyme

6.10 Enzyme and Substrate An enzyme is a protein catalyst with an active site capable of binding one or more substrate molecules. The enzyme-substrate complex yields product and free enzyme.

Product

Enzyme Substrate Complex

Enzyme-substrate complex

Enzyme

The breakdown of the enzymesubstrate complex yields the product. The enzyme is now available to catalyze another reaction.

Enzyme

Enzyme-substrate complex

Enzyme

6.10 Enzyme and Substrate An enzyme is a protein catalyst with an active site capable of binding one or more substrate molecules. The enzyme-substrate complex yields product and free enzyme.

enzyme RNA polymerase catalyzes the formation of RNA, but not DNA, and the enzyme hexokinase accelerates the phosphorylation of hexose sugars, but not pentose sugars.

The binding of a substrate to the active site of an enzyme produces an enzyme-substrate complex (ES) held together by one or more means, such as hydrogen bonding, ionic attraction, or covalent bonding. The enzyme-substrate complex gives rise to product and free enzyme:

where E is the enzyme, S is the substrate, P is the product, and ES is the enzyme-substrate complex. The free enzyme (E) is in the same chemical form at the end of the reaction as at the beginning. While bound to the substrate, it may change chemically, but by the end of the reaction it has been restored to its initial form.

Enzymes lower the energy barrier but do not affect equilibrium

When reactants are part of an enzyme-substrate complex, they require less activation energy than the transition-state species of the corresponding uncatalyzed reaction (Figure

Uncatalyzed Reaction

An uncatalyzed reaction has a greater activation energy than does a catalyzed reaction.

A catalyzed reaction has a lower activation energy.

There is no difference in free energy between catalyzed and uncatalyzed reactions.

Course of reaction

Products -

An uncatalyzed reaction has a greater activation energy than does a catalyzed reaction.

A catalyzed reaction has a lower activation energy.

6.11). Thus the enzyme lowers the energy barrier for the reaction—it offers the reaction an easier path. When an enzyme lowers the energy barrier, both the forward and the reverse reactions speed up, so the enzyme-catalyzed overall reaction proceeds toward equilibrium more rapidly than the uncat-alyzed reaction. The final equilibrium (and AG) is the same with or without the enzyme.

Adding an enzyme to a reaction does not change the difference in free energy (AG) between the reactants and the products (see Figure 6.11). It does change the activation energy and, consequently, the rate of reaction. For example, if 600 molecules of a protein with arginine as its terminal amino acid just sit in solution, the proteins tend toward disorder, and the terminal peptide bonds break, releasing the arginines (AS increases). After 7 years, about half (300) of the proteins will have undergone this reaction. With the enzyme car-boxypeptidase A catalyzing the reaction, however, the 300 arginines are released in half a second!

What are the chemical events at active sites of enzymes?

After formation of the enzyme-substrate complex, chemical interactions occur. These interactions contribute directly to the breaking of old bonds and the formation of new ones (Figure 6.12). In catalyzing a reaction, an enzyme may use one or more of the following mechanisms:

enzymes orient substrates. While free in solution, substrates are rotating and tumbling around and may not have the proper orientation to interact when they collide. Part of the activation energy needed to start a reaction is used to make the substrates collide with the right atoms for bond formation next to each other. When proteins are synthe-

There is no difference in free energy between catalyzed and uncatalyzed reactions.

Course of reaction

Products -

¡.11 Enzymes Lower the Energy Barrier

, I Although the activation energy is lower in an

/ enzyme-catalyzed reaction than in an uncatalyzed reaction, the energy released is the same with or without catalysis. In other words, Ea is lower, but AG is unchanged.

^ The two substrates are oriented so they can react. ^

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