Enzyme Active Sites Are Most Complementary to the Transition State Structure

2 Enzyme Active Sites Are Most Complementary to the Transition State Structure 

We have just discussed several common strategies that enzymes can use to stabilize the transition state of chemical reactions. These strategies are most often used in concert with one another to lead to optimal stabilization of the binary enzyme-transition state complex. What is most critical to our discussion is the fact that the structures of enzyme active sites have evolved to best stabilize the reaction transition state over other structural forms of the reactant and product molecules. That is, the active-site structure (in terms of shape and electronics) is most complementary to the structure of the substrate in its transition state, as opposed to its ground state structure. One would thus expect that enzyme active sites would bind substrate transition state species with much greater affinity than the ground state substrate molecule. This expectation is consistent with transition state theory as applied to enzymatic catalysis. 

Sources Data taken from Radzicka and Wolfenden (1995) and from Bryant and Hansen (1996). 

1999 Miller and Wolfenden, 2002). This latter ratio is the inverse of the rate enhancement achieved by the enzyme. In other words, the enzyme active site will have greater affinity for the transition state structure than for the ground state substrate structure, by an amount equivalent to the fold rate enhancement of the enzyme (rearranging, we can calculate KJX = Ksik Jk, )). Table 2.2 provides some examples of enzymatic rate enhancements and the calculated values of the dissociation constant for the /A binary complex (Wolfenden, 1999). 

Many examples exist of potent enzyme inhibitors that function as transition state mimics (see Chapter 7 Schramm, 1998, and Wolfenden, 1999, for some examples). An understanding of the transition state structure is thus of great valuable for inhibitor design. As described in Chapter 1, the transition state is not the only inter- 

---