Structural Biochemistry/Enzyme/Catalytic antibodies

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Catalytic antibodies are antibodies that can enhance a couple of chemical and metabolic reactions in the body by binding a chemical group, resembling the transition state of a given reaction. Catalytic antibodies are produced when an antibody is immunized with a hapten molecule. The hapten molecule is usually designed to resemble the transition state of metabolic reaction.

Antibodies act like soldiers to the body, fighting unwanted materials. They are secreted, for instance, when the body is infected with a bacterium or virus. The animal produces antibodies with binding sites that are exactly complementary to some molecular feature of the invader. The antibodies can thus recognize and bind only to the invader, identifying it as foreign and leading to its destruction by the rest of the immune system. Antibodies are also elicited in large quantity when an animal is injected with molecules, a process known as immunization. A small molecule used for immunization is called a hapten. Ordinarily, only large molecules effectively elicit antibodies via immunization, so small-molecule haptens must be attached to a large protein molecule, called a carrier protein, prior to the actual immunization. Antibodies that are produced after immunization with the hapten-carrier protein conjugate are complementary to, and thus specifically bind, the hapten.

Ordinarily, antibody molecules simply bind; they do not catalyze reactions. However, catalytic antibodies are produced when animals are immunized with hapten molecules that are specially designed to elicit antibodies that have binding pockets capable of catalyzing chemical reactions. For example, in the simplest cases, binding forces within the antibody binding pocket are enlisted to stabilize transition states and intermediates, thereby lowering a reaction's energy barrier and increasing its rate. This can occur when the antibodies have a binding site that is complementary to a transition state or intermediate structure in terms of both three-dimensional geometry and charge distribution. This complementarity leads to catalysis by encouraging the substrate to adopt a transition-state-like geometry and charge distribution. Not only is the energy barrier lowered for the desired reaction, but other geometries and charge distributions that would lead to unwanted products can be prevented, increasing reaction selectivity.

Making antibodies with binding pockets complementary to transition states is complicated by the fact that true transition states and most reaction intermediates are unstable. Thus, true transition states or intermediates cannot be isolated or used as haptens for immunization. Instead, so-called transition-state analog molecules are used. Transition-state analog molecules are stable molecules that simply resemble a transition state (or intermediate) for a reaction of interest in terms of geometry and charge distribution. To the extent that the transition-state analog molecule resembles a true reaction transition state or intermediate, the elicited antibodies will also be complementary to that transition state or intermediate and thus lead to the catalytic acceleration of that reaction.

Catalytic antibodies bind very tightly to the transition-state analog haptens that were used to produce them during the immunization process. The transition-state analog haptens only bind and do not react with catalytic antibodies. It is the substrates, for example, the analogous ester molecules, that react. For this reason, transition-state analog haptens can interfere with the catalytic reaction by binding in the antibody binding pocket, thereby preventing any substrate molecules from binding and reacting. This inhibition by the transition-state analog hapten is always observed with catalytic antibodies, and is used as a first level of proof that catalytic antibodies are responsible for any observed catalytic reaction.

The important feature of catalysis by antibodies is that, unlike enzymes, desired reaction selectivity can be programmed into the antibody by using an appropriately designed hapten. Catalytic antibodies almost always demonstrate a high degree of substrate selectivity. In addition, catalytic antibodies have been produced that have regioselectivity sufficient to produce a single product for a reaction in which other products are normally observed in the absence of the antibody.

Finally, catalytic antibodies have been produced by immunization with a single-handed version (only left- or only right-handed) of a hapten, and only substrates with the same handedness can act as substrates for the resulting catalytic antibodies. The net result is that a high degree of stereoselectivity is observed in the antibody-catalyzed reaction.

Abyzymes are artificial catalytic antibodies and come from the words “antibody” and “enzyme” They are monoclonal antibodies that have catalytic properties, or carry out catalysis. The figure bellow shows the active of site of the abyzyme chorismate mutase and side-chain interactions with the transition state analog.