How Enzymes Work:- Binding Energy Contributes to Reaction Specificity and Catalysis

Can we demonstrate quantitatively that binding energy accounts for the huge rate accelerations brought about by enzymes? Yes. As a point of reference, Equation 6–6 allows us to calculate that ΔG‡ must be lowered by about 5.7 kJ/mol to accelerate a first-order reaction by a fac tor of ten, under conditions commonly found in cells. The energy available from formation of a single weak in teraction is generally estimated to be 4 to 30 kJ/mol. The overall energy available from a number of such in teractions is therefore sufficient to lower activation energies by the 60 to 100 kJ/mol required to explain the large rate enhancements observed for many enzymes. The same binding energy that provides energy for catalysis also gives an enzyme its specificity, the ability to discriminate between a substrate and a competing molecule. Conceptually, specificity is easy to distinguish from catalysis, but this distinction is much more difficult to make experimentally, because catalysis and specificity arise from the same phenomenon. If an enzyme active site has functional groups arranged optimally to form a variety of weak interactions with a particular substrate in the transition state, the enzyme will not be able to interact to the same degree with any other molecule. For example, if the substrate has a hydroxyl group that forms a hydrogen bond with a specific Glu residue on the en zyme, any molecule lacking a hydroxyl group at that particular position will be a poorer substrate for the enzyme. In addition, any molecule with an extra functional group for which the enzyme has no pocket or binding site is likely to be excluded from the enzyme. In general, specificity is derived from the formation of many weak in teractions between the enzyme and its specific substrate molecule. The importance of binding energy to catalysis can be readily demonstrated. For example, the glycolytic enzyme triose phosphate isomerase catalyzes the inter conversion of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate:

FIGURE 6–6 Role of binding energy in catalysis. To lower the activation energy for a reaction, the system must acquire an amount of energy equivalent to the amount by which ΔG‡ is lowered. Much of this energy comes from binding energy (ΔGB) contributed by formation of weak noncovalent interactions between substrate and enzyme in the transition state. The role of ΔGB is analogous to that of ΔGM in Figure 6–5.

This reaction rearranges the carbonyl and hydroxyl groups on carbons 1 and 2. However, more than 80% of the enzymatic rate acceleration has been traced to enzyme-substrate interactions involving the phosphate group on carbon 3 of the substrate. This was determined by a careful comparison of the enzyme-catalyzed reactions with glyceraldehyde 3-phosphate and with glyceraldehyde (no phosphate group at position 3) as substrate. The general principles outlined above can be illustrated by a variety of recognized catalytic mechanisms. These mechanisms are not mutually exclusive, and a given enzyme might incorporate several types in its overall mechanism of action. For most enzymes, it is difficult to quantify the contribution of any one catalytic mechanism to the rate and/or specificity of a particular enzyme-catalyzed reaction.

As we have noted, binding energy makes an important, and sometimes the dominant, contribution to catalysis. Consider what needs to occur for a reaction to take place. Prominent physical and thermodynamic factors contributing to ΔG‡, the barrier to reaction, might include (1) a reduction in entropy, in the form of de creased freedom of motion of two molecules in solution; (2) the solvation shell of hydrogen-bonded water that surrounds and helps to stabilize most biomolecules in aqueous solution; (3) the distortion of substrates that must occur in many reactions; and (4) the need for proper alignment of catalytic functional groups on the enzyme. Binding energy can be used to overcome all these barriers.

First, a large restriction in the relative motions of two substrates that are to react, or entropy reduction, is one obvious benefit of binding them to an enzyme. Binding energy holds the substrates in the proper ori entation to react—a substantial contribution to cataly sis, because productive collisions between molecules in solution can be exceedingly rare. Substrates can be precisely aligned on the enzyme, with many weak interactions between each substrate and strategically located groups on the enzyme clamping the substrate molecules into the proper positions. Studies have shown that con straining the motion of two reactants can produce rate enhancements of many orders of magnitude (Fig. 6–7). Second, formation of weak bonds between substrate and enzyme also results in desolvation of the substrate. Enzyme-substrate interactions replace most or all of the hydrogen bonds between the substrate and water. Third, binding energy involving weak interactions formed only in the reaction transition state helps to compensate thermodynamically for any distortion, primarily electron redistribution, that the substrate must undergo to react.

Finally, the enzyme itself usually undergoes a change in conformation when the substrate binds, induced by multiple weak interactions with the substrate.

FIGURE 6–7 Rate enhancement by entropy reduction. Shown here are reactions of an ester with a carboxylate group to form an anhydride. The R group is the same in each case. (a)For this bimolecular reaction, the rate constant k is second order, with units of M^-1s^-1. (b)When the two reacting groups are in a single molecule, the reaction is much faster. For this unimolecular reaction, k has units of s 1. Dividing the rate constant for (b)by the rate constant for (a)gives a rate enhancement of about 105M. (The enhancement has units of molarity because we are comparing a unimolecular and a bimolecular reaction.) Put another way, if the reactant in(b)were present at a con centration of 1 M, the reacting groups would behave as though they were present at a concentration of 10⁵M. Note that the reactant in (b) has freedom of rotation about three bonds (shown with curved arrows), but this still represents a substantial reduction of entropy over (a). If the bonds that rotate in (b)are constrained as in (c), the entropy is reduced further and the reaction exhibits a rate enhancement of 108Mrelative to (a).

This is referred to as induced fit, a mechanism postulated by Daniel Koshland in 1958. Induced fit serves to bring specific functional groups on the enzyme into the proper position to catalyze the reaction. The conformational change also permits formation of additional weak bonding interactions in the transition state. In either case, the new enzyme conformation has enhanced catalytic properties. As we have seen, induced fit is a common feature of the reversible binding of ligands to proteins. Induced fit is also important in the interaction of almost every enzyme with its substrate.

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مواضيع ذات صلة

Enzyme Kinetics as an Approach to Understanding Mechanism: -Kinetic Parameters Are Used to Compare Enzyme Activities

Enzyme Kinetics as an Approach to Understanding Mechanism: -The Relationship between Substrate Concentration and Reaction Rate Can Be Expressed Quantitatively

Enzyme Kinetics as an Approach to Understanding Mechanism: -Substrate Concentration Affects the Rate of Enzyme-Catalyzed Reactions

How Enzymes Work:- Specific Catalytic Groups Contribute to Catalysis

How Enzymes Work:- Weak Interactions between Enzyme and Substrate Are Optimized in the Transition State

Protein Interactions Modulated by Chemical Energy: Actin, Myosin, and Molecular Motors: -Additional Proteins Organize the Thin and Thick Filaments into Ordered Structures

Protein Interactions Modulated by Chemical Energy: Actin, Myosin, and Molecular Motors: - The Major Proteins of Muscle Are Myosin and Actin

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -The Antibody-Antigen Interaction Is the Basis for a Variety of Important Analytical Procedures

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Antibodies Bind Tightly and Specifically to Antigen

Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -Antibodies Have Two Identical Antigen-Binding Sites

Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -Self Is Distinguished from Nonself by the Display of Peptides on Cell Surfaces

Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -The Immune Response Features a Specialized Array of Cells and Proteins