Chemically Reactive Immunogens Lead to Functional Convergence of the Immune Response

Abstract

An aldolase antibody, 24H6, which was obtained from immunization with the large hapten 2, is shown to possess an active-site lysine residue with a perturbed pKa of 7.0. This antibody catalyzes both the aldol addition and the retrograde aldol fragmentation with a broad range of substrates that are structurally different from the hapten. This observation suggests that in reactive immunization with 1,3-diketones, the hapten structure governs the chemistry but not the overall organization of the active site. Hammett correlation studies of the 38C2- and 24H6-catalyzed aldol and retroaldol reactions revealed that although the two antibodies exhibit broad substrate specificities, they utilize slightly different mechanisms. While antibody 38C2 adopts a mechanism that is reminiscent of an acid-catalyzed aldol reaction, antibody 24H6 follows a mechanism that is similar to the base-catalyzed reaction.