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CATALYTIC ANTIBODIES.
Term Paper ID:22123
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Definition, process involving chemistry & immunology, problems, applications.... More...
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Paper Abstract:
Definition, process involving chemistry & immunology, problems, applications.
Paper Introduction:
Catalytic Antibodies
Abstract
Catalytic antibodies are derived from chemically stable hapten which mimic reactions' transitional states. Through their binding energy, the antibodies are able to increase both the specificity and rate of the reactions. These techniques were initially applied to chemical processes which did not require catalysts. Various investigators, for example, have used catalytic antibodies to facilitate the Claisen rearrangement. More recent research, however, has focused on disfavored reactions (i.e., ring closure transformations). One day these methods may find widespread application in various fields of scientific endeavor.
Introduction
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Inbacteria, fungi, and the higher plants, it is essential for thebiosynthesis of aromatic amino acids (Hilvert et al., 1988, p. Morerecent research, however, has focused on disfavored reactions (i.e., ringclosure transformations). Theseinclude, for example, the Claisen rearrangement and the Diels-Alderreaction (Danishefsky, 1993, p. In addition, catalytic antibodies' various biochemicalalterations may also enhance both the rate and the turnover of thereactions. New developments in the chemistry of catalytic antibodies. ReferencesBoger, D. Journal of the American Chemical Society, 11 , 4841- 4842.Janda, K. The tools and techniques of molecular biology have also madeit possible to screen entire antibody libraries for those able to bind invitro to a specific hapten (Leumann, 1993, p. Regardless though, Janda et al. These investigators usedcatalytic antibodies to control the Diels-Alder reaction pathways. The immune system is generallychallenged by the appropriate hapten; the results are then immortalized ashybridomas. Inaddition to carbonate and ester hydrolysis reactions, other antibody-catalyzed transformations include amide hydrolysis, redox processes, ß-eliminations, and cis-trans isomerizations. Hilvert et al. (1993), "Much of the potential of classical organic chemistrygoes wanting but for the ability to selectively direct a few kilocaloriesof energy". Chem. (1993) generated twodifferent catalytic antibodies. In fact, catalytic antibodiesmay be custom-fitted to a predesigned substrate. In acyclic systems, it is well recognizedthat anti elimination is favored over syn elimination. (1994). Leuman (1993) provides abrief overview of recent developments in catalytic antibody research. Janda et al. Hilvert, Carpenter, Nared, & Auditor (1988),for example, used catalytic antibodies to facilitate the Claisenrearrangement. (1994) were then used tocatalyze a disfavored reaction. It was during thatparticular year that the research groups of Schultz and Lerner raisedantibodies to tetrahedral, negatively charged phosphate and phosphonatetransition state analogs. This gave the hapten's primaryamine the ability to induce antibody functionality. A. 5 78). (1993). (1993) begins by noting the fact that organicreactions are often limited by stereoelectronic constraints. H.; Nared, K. Moreover, Diels-Alderreactions and metal chelating reactions have been performed as well.Various papers discussing these chemical reactions--some of which would bedifficult to achieve by conventional techniques--will be presented (Schultz& Lerner, 1993, p. D.; Auditor, M. 1292). The paper describes how thebinding forces of antibodies can be applied to catalysis. Through their binding energy, theantibodies are able to increase both the specificity and rate of thereactions. 469). (1993). W.; Sugasawara, R.; Reich, S. These might include, forexample, pharmacotherapeutic applications. Recognizing such phenomena, theresearchers created a catalytic antibody that facilitated one particularlydifficult reaction--i.e., the 6-endo-tet ring closure of an epoxy-alcohol.Normally, this reaction would be in violation of Baldwin's rules for ring-closure reactions. These variouskinetic and thermodynamic parameters may even determine the outcome ofcertain chemical transformations. With ideal hapten selection and a proper turnover rate,nearly all of an antibody's binding force may be directed towards reactionfacilitation. Since the early experiments of Schultz and Lerner, catalyticantibodies have received considerable attention. D., & Lerner, R. H.; Bartlett, P. M. (1993, October 8). (1993) used [2.2.2]bicyclic compounds which mimicked the Diels-Alder reaction's transitionstate (Gouverneur et al., 1993, p. Antibody catalysis of difficult chemical transformations. Int. G., & Lerner, R. Science, 259, 49 -493.Leumann, C. L.; Lerner, R. Thiscycloaddition reaction has been called the "most important carbon-carbonbond-forming process in chemistry" (Gouverneur et al., 1993, p. Discussion Clearly, catalytic antibodies are a very powerful tool. 2 4).Unfortunately though, its value in various applications often depends uponwhether or not stereocontrol can be achieved. 469). Engl., 32, 1291-1293.Schultz, P. Acc. Angew. (1988, July). A.; & Cravatt, B. With the further development ofthese molecular techniques, catalytic antibodies should ultimately have aconsiderable impact on such diverse fields as chemistry, biology, andmedicine. The Claisen rearrangement has particular biological relevance. To elicit the antibodies, Gouverneur et al. Chem. The rigid,eclipsed conformation of this ring system presented benzoyl and phenylsubstituents in the desired arrangement. 49 ). Compared to theuncatalyzed reaction, rate accelerations of more than 2 orders of magnitudewere observed. Res., 26, 391-395.----------------------- 9 N.; Pascual-Teresa, B.; Beno, B.; Janda, K. 391). These researchers used catalytic antibodies ina disfavored reaction to synthesize a tetrahydropyran (Danishefsky, 1993,p. The immune response waselicited from an endo bicyclic transition-state analogue. In many instances, however, such difficulties may be overcome. E.; Houk, K. (1993) not onlyachieved the reaction, they also produced a stereochemically pure productas well (Janda et al., 1993, p. One such antibody facilitated the favoredendo pathway to yield enantiomerically pure cis adducts; the othercatalyzed the disfavored exo pathway to produce enantiomerically pure transadducts. These techniques were initially applied to chemical processeswhich did not require catalysts. Ed. The first investigations involving chemical reactionscatalyzed by antibodies were published in 1986. A second disfavored reaction was described by Gouverneur, Houk,Pascual-Teresa, Beno, Janda, & Lerner (1993). 4841-4842). One strategy which has been foundto work though involves the immune system. (1988). Control of the exo and endo pathways of the Diels-Alder reaction by antibody catalysis. Unfortunately though, numerousdifficulties have been encountered. (1988) generated antibodies against a transition stateanalog of chorismate mutase. Introduction The study of catalytic antibodies combines both chemistry andimmunology. The researchershypothesized that the relevant chemical mechanism involved some form ofenvironmental complementarity to the reaction's conformationally restrictedtransition state (Jackson et al., 1988, pp. Science, 262, 2 4-2 8.Hilvert, D.; Carpenter, S. 469). Catalytic Antibodies Abstract Catalytic antibodies are derived from chemically stable hapten whichmimic reactions' transitional states. Yet another group of researchers, Jackson, Jacobs, Sugasawara, Reich,Bartlett, & Schultz (1988), also investigated the Claisen rearrangement.Likewise, they additionally generated a monoclonal antibody which catalyzedthe reaction of chorismate to prephrenate. Gouverneur et al. Y.; Jacobs, J. In addition to the more ordinary organic reactions though,Danishefsky (1993) also notes that catalytic antibodies may be used indisfavored reactions. Catalytic antibodies and disfavored reactions. Proceedings of the National Academy of Science, 85, 4953-4955.Jackson, D. This energy may then be used to generate nonnatural chemicalreactions. Researchers primarilyfocused on reactions that might be sensitive to such antibody effects asinduced strain and proximity. Synthesis of a functionalized rigid bicyclo[2.2.1]heptane: A useful hapten for eliciting catalytic antibodies. Similarly, Boger, Lerner, & Cravatt (1994) employed abicyclo[2.2.1]heptane ring system to elicit antibodies. 4953-4955). Catalysis of concerted reactions by antibodies: The Claisen rearrangement. 2 4). Essentially,catalytic antibodies prompt "reactants to take on the character of thetransition state required for a chemical transformation" (Danishefsky,1993, p. Science, 259, 469-47 .Gouverneur, V. I think that such techniques may one day find widespread practicaluse. The paper, Danishefsky (1993), reviews this quest forimproved catalytic efficiency. A. G., & Lerner, R. For instance, the author mentions the paper, Janda,Shevlin, and Lerner (1993). Accordingly, Danishefsky (1993) goes on to delineate thevarious organic reactions to which the techniques have been applied. One day these methods may find widespreadapplication in various fields of scientific endeavor. Rationally designed immunogens may be synthesized to produceantibodies for specific chemical purposes. It notes that researchers have attempted toapply enzymes to nonnatural systems. The binding energy of antibodies can be used to alter the course ofchemical reactions. Danishefsky (1993) delineates some ofthe complications associated with trying to make finely tuned enzymaticstructures perform unnatural reactions. The antibodies generated by Boger et al. Consequently, considerableresearch has been performed on control of the exo/endo and absoluteconfiguration reaction products. In addition, the catalystscould also be used as diagnostic tools. According toJanda et al. 1291). D.; Shevlin, C. G. However, using themonoclonal antibodies elicited by the bicyclic ring system, the researcherswere able to catalyze a syn elimination to produce a cis olefin. Review The ongoing research involving catalytic antibodies comprises manydifferent aspects. These catalytic antibodies were then used tocatalyze the rearrangement of chorismate to phrenate. Some of the earliest chemical processes to employ catalyticantibodies did not actually require catalysis. The papersuggests that this effect was achieved through the catalytic antibodies'ability to act as a base in the abstraction of the reactants' (-proton(Boger et al., 1994, p. Antibody catalysis of a disfavored chemical transformation. Hence, the specificity oftheir catalyzed reactions is often greater than that of normal enzymaticreactions. Various investigators, for example, haveused catalytic antibodies to facilitate the Claisen rearrangement. In recent years, significant advances have been made in the methodsused to prepare catalytic antibodies. An antibody-catalyzed Claisen rearrangement. A., & Schultz, P. These analogs were then used to catalyze thehydrolysis of carbonates and esters, respectively (Leumann, 1993, p. (1993, January 22). They give their hapten-derived antibodies the ability tobind specific ligands with high affinity. A. (1993, January 22). F. Journal of Organic Chemistry, 59, 5 78-5 79.Danishefsky, S. Catalytic antibodies are derived from chemically stable hapten.These haptens typically mimic the structure and electronic properties of agiven reaction's transition state; they are hence synthetic analogs of thetransition state.
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