Natural Catalytic Antibodies in Norm and in HIV-Infected Patients

Abstract

Antibodies (Abs) have been first characterized as proteins which are produced by the immune system and have a sole function of binding other molecules, called antigens, with the goal of eliciting an immune response. In this classical conception, Abs act similarly to enzymes in specific binding other molecules. However, in contrast to enzymes they do not have the ability to catalyze chemical conversions of their bound partners. For the vast majority of Abs, this observation is correct. However, in a 1946 consideration of enzyme function, Linus Pauling first hypothesized that the active center of an enzyme is closely juxtaposed to a “strained configuration” of its substrate (that is, targeted against the structure of the transition state) rather than to the native conformation of the substrate molecule (Pauling, 1946). This idea led Jencks in 1969 to propose that Abs generated in an anti-hapten immune response against chemically stable analogs of the transition-state of a reaction of interest could potentially display an enzymatic activity (Jencks, 1969). In 1985, a general method for generating catalytic monoclonal Abzs against transition state analogs, and a way to use those Abs to accelerate chemical reactions, was first described (Schochetman & Massey, 1985). One year later two groups were able to produce the first monoclonal Abs with catalytic properties, which were generated against hapten analogs of the transition states for p-nitrophenylphosphorylcholine (Pollack et al., 1986) or for monoaryl phosphonate esters (Tramontano et al., 1986a, 1986b). The artificial monoclonal anti-hapten catalytic Abs were termed abzymes (derived from antibody enzyme). The evolution of the technology of artificial Abzs during the last two decades has led not only to the rapid development of direct approaches for the generation of Abs with specified properties, but also to the creation of strategies to revise the targeting specificity of individual Abzs. Such modifications of antigen binding specificity can be achieved genetically in vitro, by application of the site-directed mutagenesis, or genetic selection or screening (using approaches such as phage display). Alternatively, modification can be induced directly on purified antibody, via selective chemical modification by direct introduction of catalytic groups into the Ab combining site. Some studies describing these approaches include (Keinan, 2005, and refs therein). The employment of the approaches have demonstrated that the substrate specificity (and/or the specific activity) of some artificial Abzs is comparable to or even higher than that of enzymes with the same catalytic activity (Barbas et al., 1997; Janda et al., 1997; Keinan, 2005, and refs therein).