Enzyme catalysis is the increase in the rate of a chemical reaction by the active site of a protein. In principle, the mechanism of enzyme catalysis is similar to other types of chemical catalysis. The enzyme reduces the energy required to reach the highest energy transition state of the reaction by providing an alternative reaction route. The reduction of activation energy increases the amount of reactant molecules that achieve a sufficient level of energy, such that they reach the activation energy and form the product. Enzymes catalyze chemical reactions at astounding rates relative to uncatalyzed chemistry at the same conditions. Each catalytic event requires a minimum of three or often more steps, all of which occur within the few milliseconds that characterize typical enzymatic reactions. According to transition state theory, the transition state is spent in the most important step, which is the smallest fraction of the catalytic cycle. One of the mechanism of enzyme catalysis is bond strain, where the affinity of the enzyme to the transition state is greater than to the substrate itself.

Transition State Theory

The transition state of a chemical reaction is a particular configuration along the reaction coordinate. The lifetime for chemical transition states is the time for conversion of a bond vibrational mode to a translational mode, which is really short. The transition state is defined as the state corresponding to the highest potential energy along this reaction coordinate. It has more free energy in comparison to the substrate or product, thus, it is the least stable state. The specific form of the transition state depends on the mechanisms of the particular reaction. In the equation S→X→P, X is the transition state, which is located at the peak of the curve on the Gibbs free energy graph (Figure 1). This theory requires reexamination for enzymes, because the protein domain motion resulting in transition state formation may stabilize the altered bond lengths of the bound transition state for a lifetime sufficient for 10¹–10⁶ vibrations.

Figure 1. Transition state theory. The transition state is located at the peak of the curve on the Gibbs free energy graph.

Tight Binding of the Enzyme and the Transition State

Bond strain is the principal effect of induced fit binding, where the affinity of the enzyme to the transition state is greater than to the substrate itself. This induces structural rearrangements which strain substrate bonds into a position closer to the conformation of the transition state, so lowering the energy difference between the substrate and transition state and helping catalyze the reaction. However, in fact, the strain effect is a ground state destabilization effect, rather than transition state stabilization effect.

Linus Pauling proposed that the powerful catalytic action of enzymes could be explained by specific tight binding to the transition state species. The enzyme was proposed to increase the concentration of the reactive species, because reaction rate is proportional to the fraction of the reactant in the transition state complex. Binding energies of enzymatic transition states are generated by the realignment of substrate contacts as the enzyme and substrate mutually change their structures toward the transition state. The strong dependence of hydrogen and ionic bond energy on bond distance, angle, solvent environment, and relative pK_a values can be invoked to explain the increases in binding forces of the transition state complex relative to the Michaelis complex. Structural rearrangements tighten the protein around the catalytic site to exclude solvent and to make stronger electrostatic contacts. These are shown as well-aligned H-bonds at the transition state and as ionic attraction and repulsion as catalytic forces.

Figure 2. Enzyme catalytic mechanism of bond strain. The affinity of the enzyme to the transition state is greater than to the substrate.

Transition State Analogs Are Enzyme Inhibitions

The transition state theory described that the occurrence of enzymatic catalysis is equivalent to an enzyme binding to the transition state more strongly than it binds to the ground-state substrates. Therefore, transition state analogs should be effective inhibitors of enzymes. These molecules are mimics of transition states of the substrate in a particular enzyme reaction. They can bind to the enzyme and oftentimes much more tightly than the substrate can, because they are so similar to the transition states of the substrate. The fact that these transition state analogs bind so tightly to enzymes makes it an effective enzyme inhibitor.

Reference

1. Schramm V L. Enzymatic transition states and transition state analogues. Annual Review of Biochemistry, 2005, 15(6):604-613.

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