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Saturday, March 06, 2010

Catalytic Antibodies Simply Explained

Catalysis is the process of speeding up a chemical reaction by lowering its activation energy - the energy hump a reaction has to go over before it can roll downhill. Efficient catalysts of chemical reactions are extremely commercially valuable and widely researched.

Enzyme Catalysis Basics: Biological enzymes are known to catalyze (speed up) chemical reactions, in part, by stabilizing the transition state (halfway point at the top of the hump) of an otherwise energetically-favorable (downhill) reaction. Some catalysts work by moving chemicals next to each other that would otherwise not randomly meet that often. (1) Some enzymes are known to change their shape (conformation) after binding and during the reaction - driving catalysis (2).

The immune system can be stimulated to respond to a incredibly diverse range of molecules by producing antibodies which bind (cling, stick) to these molecules. The theory of "catalytic antibodies" was that if an antibody was purified that bound to the transition state of a reaction, it would, in the same manner as an enzyme (above), stabilize that state (drag it up the hill) and accelerate the reaction. In order to generate such an antibody, a "transitions state analog" (TSA) - molecule that looks like the known transition state of a reaction - is used. Antibodies that are generated (usually by injection into a mouse) to bind to that TSA are then screened until one is found that catalyzes the reaction. Surprisingly, to me, this works very well. (3)

However, these "abzyme" catalysts are never as efficient as enzymes for many reasons. The abzyme may strongly bind to the product of the reaction (not letting go when it's done), greatly inhibiting its effectiveness. Also there is the difficulty of creating a TSA - they may differ in bond angles or polarity, etc. Many enzymes form strong (covalent) bonds during their catalysis mechanism, but this is not known to be possible with abzymes. Enzymes also employ conformational changes, metals and other cofactors to accelerate catalysis.

Abzymes are being aggressively researched, however. For example, it may be possible to engineer abzymes which bind to prosthetic groups to be used in metal-catalyzed reactions. Abzyme reactions which employ several cofactors have already been demonstrated. (4,5)

(1) "Chemical basis for enzyme catalysis", 2000, TC Bruice, SJ Benkovic
(2) "Catalysis by Enzyme Conformational Change", 2004 Jiali Gao1, Kyoungrim Lee Byun, and Ronald Kluger
(3) "Catalytic antibodies" (Biochem. J.), 1989, G. Michael BLACKBURN,t Angray S. KANG
(4) "Pyridoxal 5?-Phosphate-dependent Catalytic Antibody" (1996) Svetlana I. Gramatikova, Philipp Christen
(5) "A cofactor approach to copper-dependent catalytic antibodies" Kenneth M. Nicholas, Paul Wentworth, Jr

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