Catalytic antibodies: Antibodies as targeting enzymes

(First of two parts)

When we digest the food that we eat, our body breaks it up into simpler molecules (breakdown is known as catabolism) which we then use as building blocks to make new proteins and new cells (buildup or biosynthesis is known as anabolism). Eventually, these cells will form our muscles, our fat, our skin, and the rest of our body. For example, when we digest the protein in meat, our body breaks it up into amino acids, which are then reassembled to make our own protein molecules (catabolism and anabolism make up the two phases of our body’s metabolism).

Proteins (and other molecules) will spontaneously break up into their constituent parts — eventually — but that could take a long, long time. To speed up the digestion, our body uses enzymes — biological catalysts — which are proteins themselves. Enzymes work as “middlemen” in a chemical reaction. They help the starting material (called reactants or substrates) transform into products of different properties in a faster and more efficient manner. Moreover, enzymes don’t get consumed (or they are regenerated) in the process. They are good for several more rounds and so only minute or “catalytic” quantities of enzyme are needed to produce large quantities of products.

Enzymes catalyze most of the chemical reactions that occur in our body. There are specific enzymes for specific applications. Aside from metabolism, enzymes are also active participants in various biological processes. Our DNA gets duplicated before a cell divides into two daughter cells. Enzymes catalyze several steps in the synthesis of DNA. Enzymes also play major roles in the signaling within and between cells. When we take our daily vitamins, we are actually taking in the precursors of “co-enzymes” — substances that act as co-substrates of our various metabolic enzymes. When a person with a heart condition takes an aspilet (80 milligrams of aspirin), the drug works to inhibit an enzyme in his platelets and this prevents blood clots or thrombosis. Enzymes are indeed important in health and medicine. They are the targets of many drugs that we use today.

To help us understand how enzyme catalysis occurs, we need to appreciate the transition state theory which was proposed simultaneously in 1935 by Henry Eyring of Princeton University (Journal of Chemical Physics 3:107-115) and by Meredith Gwynne Evans and Michael Polanyi of the University of Manchester (Transactions of the Faraday Society 31:875-894). According to the transition state theory, in a chemical reaction, reactants undergo a “transition state” in which they temporarily become an activated complex. This intermediate transition state is an unstable one wherein the energy of the activated complex is at its maximum (the maximum energy is called the activation energy).

In order to form or break chemical bonds and complete the transformation of the reactants into the desired chemical products, the activated complex has to overcome this activation energy. One way to achieve this is to increase the temperature (and kinetic energy) so that reactants collide with one another more often which then increases the reaction rate. This unfortunately is not possible in living systems since high temperatures will kill cells.

Another way is to bring down the activation energy of the reaction. Enzymes are able to catalyze chemical reactions by stabilizing the transition state and significantly lowering the activation energy. The transition state represents a halfway point where the bonds of the substrate are distorted sufficiently so that conversion to product becomes possible. Based on a number of proposed mechanisms and factors, in short, what an enzyme does is to capture the substrate in its active site, restrict its rotational freedom, “freeze” it into a unique conformation, bind with some chemical groups in the substrate so that a susceptible bond within the substrate is distorted, and the result of this is that the activated transition state is more readily produced. (An enzyme-catalyzed reaction at room temperature may proceed a million to a quadrillion times faster than the same uncatalyzed reaction.)

In his Silliman Lecture delivered at Yale University in 1947 (later published in the American Scientist 1948; 36:51-58), Linus Pauling proposed that an enzyme preferentially binds the transition state of the reaction and that the active site of an enzyme has a structure that is complementary to that of the transition state.

This led William P. Jencks to suggest (in his book, Catalysis in Chemistry and Enzymology, New York:McGraw-Hill, 1969; p. 288): “If complementarity between the active site and the transition state contributes significantly to enzymatic catalysis, it should be possible to synthesize an enzyme by constructing such an active site. One way to do this is to prepare an antibody to a haptenic group which resembles the transition state of a given reaction. The combining sites of such antibodies should be complementary to the transition state and should cause an acceleration by forcing bound substrates to resemble the transition state.”

(To be continued)

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Jo Erika T. Narciso is an MS Molecular Biology and Biotechnology student at the National Institute of Molecular Biology and Biotechnology and a research associate in the Marine Natural Products Laboratory, Marine Science Institute, University of the Philippines Diliman. She may be contacted at [email protected].

Eduardo A. Padlan is a corresponding member of the NAST and an adjunct professor in the UP Marine Science Institute. He can be reached at [email protected].