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Abyzmes - Antibody Catalysis

Abyzmes - Antibody Catalysis

What does it take for a macromolecule (M) to be a catalyst - an enzyme. It seems the minimum criterion are:

  • M binds a reactant
  • M binds the transition state more tightly than the substrate

Anything above these is just "icing on the cake". If different functional group are present in the "active" site of the enzyme that would allow electrostatic, intramolecular, covalent, general acid and/or base catalysis, the better the catalyst.

Linus Pauling recognized the two key factors decades ago. He made the following hypothesis: Antibody molecules (immune system proteins that bind foreign molecules) that can be made to bind to transition state analogs of a substrate, should also presumably catalyze the conversion of substrate, through the transition state, to product. About a decade ago, his prediction was verified. Lerner et al. made a transition state analog of an ester. When an ester is hydrolyzed, the sp2 hybridized carbonyl carbon is converted to an sp3 hybridized center in the intermediate,, with the carbonyl oxygen becoming an oxyanion. The transition state presumably looks more like this unstable intermediate (sp3 oxyanion). Lerner synthesized a phosphonate, an ester mimic with a sp3 hybridized phosphorous replacing the carbonyl C. It also has a negatively charged oxygen as does the intermediate for the ester. This phosphonate ester is very resistant to hydrolysis. When injected into a mouse (after first being covalently attached to a carrier protein so the small molecule becomes "immunogenic"), the mouse makes a protein antibody which binds to the phosphonate. When the corresponding carboxylic acid ester is added to the antibody, it is cleaved with nominal \(k_{cat}\) and \(K_m\) values. Site specific mutagenesis can then be done to make it an even better catalyst! The antibody enzymes have been called abzymes. The structure below shows how phosphonamides act as transition state analogs as well.

Figure:; PHOSPHONAMIDES: TRANSITION STATE ANALOGS