Proline racemase, inhibition

We turn now to compounds that provide the most intimate views of the catalytic process itself Linus Pauling proposed in 1948 that compounds resembling the transition state of a catalyzed reaction should be very effective inhibitors of enzymes. These mimics are called transition-state analogs. The inhibition of proline racemase is an instructive example. The racemization of proline proceeds through a transition state in which the tetrahedral a- carbon atom has become trigonal by loss of a proton (Figure 8.24). In the trigonal form, all three bonds are in the same plane C also carries a... 

Figure 8.24. Inhibition by Transition State Analogs. (A) The isomerization of 1-proline to d-proline by proline racemase, a bacterial enzyme, proceeds through a planar transition state in which the a carbon is trigonal rather than tetrahedral. (B) Pyrrole 2-carboxylate, a transition state analog because of its trigonal geometry, is a potent inhibitor of proline racemase.

A racemase is a difficult enzyme with which to study product inhibition, since Teq = I and, if one puts in enough product to inhibit the enzyme, one is near equilibrium or the reaction goes backward. In their epic studies on proline racemase, Knowles and co-workers solved this problem by using optical rotation to... 

A planar analog of proline is pyrrole 2-carboxylate, and this proves to be a potent inhibitor of the racemase it gives rise to 50 percent inhibition at a concentration 160 times less than the concentration of d- or L-proline that gives 50 percent binding. Thus, it is a good example of a transition-state analog. 

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