Catalytic Antibodies

Benoît Gigant, CNRS, Gif sur Yvette, France, France
Marcel Knossow, CNRS, Gif sur Yvette, France

Published online: April 2001

DOI: 10.1038/npg.els.0000872

It is possible to elicit antibodies that catalyse a target reaction by raising them against stable molecules mimicking intermediate species on the chemical pathway from substrate to product. These artificial biocatalysts are closer to enzymes than any other enzyme mimic. Recent progress and new strategies bode well for the practical use of catalytic antibodies.

Keywords: abzyme; enzyme mimic; transition state analogue; antibody

Figure 1. Examples of target reactions for catalytic antibodies (left) and transition state analogue (TSA) used to elicit them (right). (a) Hydrolytic reaction; (b) unimolecular reaction – chorismate mutase rearrangement; (c) bimolecular reaction – Diels–Alder cycloaddition; (d) oxidation.
Figure 2. Mechanism of an esterolytic antibody investigated by X-ray crystallography. The antibody catalyses the ester hydrolysis reaction shown at the top and was raised against the phosphonate TSA whose formula is on the second row (right). The formula of a stable substrate analogue used for the structural analysis is also shown on the second row (left). Bottom: schematic view of the antibody-combining site (green) complexed either with an amide (a stable substrate analogue) (left) or with the TSA (right) (ligands are in blue). Hydrogen bonds are shown as dotted lines. In addition to the hydrogen bonds planned in the TSA design, two hydrogen bonds are made by the acid moiety of the ligand; one of them, with Tyr L96, was shown to affect substrate specificity.
Scheme 1. Generalized hydrolysis of an ester. The TSA mimics the geometric and charge properties of the high energy oxyanion intermediate and of its flanking transition states.
Scheme 2. Chemical formulae of a chiral substrate and of the TSA hapten used to generate an antibody hydrolysing it stereospecifically.
Scheme 3. Chemical formulae of a TSA used to generate a catalytic antibody with relaxed substrate specificity and of its ester substrates. R may be varied from methyl to 4-hydroxyphenyl.
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 References
    Barbas CF, Heine A, Zhong G et al. (1997) Immune versus natural selection: antibody aldolases with enzymic rates but broader scope. Science 278: 2085–2092.
    Gigant B, Charbonnier JB, Eshhar Z, Green BS and Knossow M (1997) X-ray structures of a hydrolytic antibody and of complexes elucidate catalytic pathway from substrate binding and transition state stabilization through water attack and product release. Proceedings of the National Academy of Sciences of the USA 94(15): 7857–7861.
    Hilvert D, Hill KW, Nared KD and Auditor M-TM (1989) Antibody catalysis of a Diels–Alder reaction. Journal of the American Chemical Society 111: 9261–9262.
    Izadyar L, Friboulet A, Remy M-H, Roseto A and Thomas D (1993) Monoclonal anti-idiotypic antibodies as functional internal images of enzyme active sites: production of a catalytic antibody with a cholinesterase activity. Proceedings of the National Academy of Sciences of the USA 90: 8876–8880.
    Mets B, Winger G, Cabrera C et al. (1998) A catalytic antibody against cocaine prevents cocaine’s reinforcing and toxic effects in rats. Proceedings of the National Academy of Sciences of the USA 95: 10176–10181.
    Sinha SC, Barbas CF and Lerner RA (1998) The antibody catalysis route to the total synthesis of epothilones. Proceedings of the National Academy of Sciences of the USA 95: 14603–14608.
    Tanaka F, Kinoshita K, Tanimura R and Fujii I (1996) Relaxing substrate specificity in antibody-catalyzed reactions: enantioselective hydrolysis of N-Cbz-amino acid esters. Journal of the American Chemical Society 118: 2332–2339.
    Tawfik DS, Green BS, Chap R, Sela M and Eshhar Z (1993) CatELISA: a facile general route to catalytic antibodies. Proceedings of the National Academy of Sciences of the USA 90: 373–377.
    Thomas NR (1996) Catalytic antibodies – Reaching adolescence? Reviewing the literature published up to the end of February 1996. Natural Product Reports 13(6): 479–511.
    Wade H and Scanlan TS (1996) P1–S1 interactions control the enantioselectivity and hydrolytic activity of the norleucine phenylesterase catalytic antibody 17E8. Journal of the American Chemical Society 118: 6510–6511.
 Further Reading
    Baca M, Scanlan TS, Stephenson RC and Wells JA (1997) Phage display of a catalytic antibody to optimize affinity for transition-state analog binding. Proceedings of the National Academy of Sciences of the USA 94: 10063–10068.
    Benkovic SJ (1992) Catalytic antibodies. Annual Review of Biochemistry 61: 29–54.
    Charbonnier J-B, Gigant B, Golinelli-Pimpaneau B and Knossow M (1997) Similarities of hydrolytic antibodies revealed by their X-ray structures: a review. Biochimie 79: 653–660.
    book Jencks WP (1969) Catalysis in Chemistry and Enzymology. New-York: McGraw-Hill.
    Kirby AJ (1996) The potential of catalytic antibodies. Acta Chemica Scandinavica 50(3): 203–210.
    Lerner RA, Benkovic SJ and Schultz PG (1991) At the crossroads of chemistry and immunology: catalytic antibodies. Science 252: 659–667.
    Mader M and Bartlett P (1997) Binding energy and catalysis: the implications for transition-state analogs and catalytic antibodies. Chemical Review 97: 1281–1301.
    Patten PA, Gray NS, Yang PL et al. (1996) The immunological evolution of catalysis. Science 271: 1086–1091.
    Schultz PG and Lerner RA (1995) From molecular diversity to catalysis: lessons from the immune system. Science 269: 1835–1842.
    Stewart JD, Krebs JF, Siuzdak G et al. (1994) Dissection of an antibody-catalyzed reaction. Proceedings of the National Academy of Sciences of the USA 91: 7404–7409.

Related Sub-Topics:

Antibodies | Biochemical and Biophysical Techniques | Enzymes: Structure and Action Mechanism
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Article Title: Catalytic Antibodies
 
How to Cite close
Gigant, Benoît, and Knossow, Marcel(Apr 2001) Catalytic Antibodies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0000872]