IMMUNE VERSUS NATURAL-SELECTION - ANTIBODY ALDOLASES WITH ENZYMATIC RATES BUT BROADER SCOPE

Structural and mechanistic studies show that when the selection criter ia of the immune system are changed, catalytic antibodies that have th e efficiency of natural enzymes evolve, but the catalytic antibodies a re much more accepting of a wide range of substrates. The catalytic an tibodies were prepared by reactive immunization, a process whereby the selection criteria of the immune system are changed from simple bindi ng to chemical reactivity. This process yielded aldolase catalytic ant ibodies that approximated the rate acceleration of the natural enzyme used in glycolysis. Unlike the natural enzyme, however, the antibody a ldolases catalyzed a variety of aldol reactions and decarboxylations. The crystal structure of one of these antibodies identified the reacti ve lysine residue that was selected in the immunization process. This lysine is deeply buried in a hydrophobic pocket at the base of the bin ding site, thereby accounting for its perturbed pK(a).