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Molecular Rumba: The Dance of the Protein Intermediates

Andrew Skulan
Stanford University
November 2002

If your body was a book, then enzymes would be the verbs, the doing words. Each enzyme performs a specific chemical reaction in the body, helping change molecule "A" into molecule "B". A group of enzymes may have very similar chemical structures but very different functions. I study why this occurs in a particular class of enzymes by investigating differences in their reaction intermediates, the steps through which a reaction occurs. I do this by shining light on the enzyme as it performs a reaction and observe the changes in the light beam from this interaction. This tells me how the enzyme is interacting with its target as it proceeds through the reaction. Understanding the steps by which an enzyme performs a reaction is important in drug design as medicines typically act to turn a particular enzyme on or off. This knowledge is also important to the biotechnology industry as it is helps engineer enzymes to perform complex reactions under safe conditions. These replace currently used industrial processes which require toxic solvents or generate dangerous pollutants.

When an enzyme performs a chemical reaction it undergoes a sequence of steps, or reaction intermediates. In this way a chemical reaction is akin to a dance where the partner is lead through a series of steps. The enzyme recognizes its target molecule, binds to it and prepares it for reaction much as a lead prepares his partner for a dance step by changing their stance.

My goal is to understand how these interactions between the enzyme and its target allow the chemical dance to occur, for without the exact pairing of an enzyme and its specific target, no reaction occurs, much like someone knowing only how to polka while his partner can only salsa. I watch this dance by mixing the enzyme and its target together, waiting for the reaction to proceed for a short period of time, then suddenly freezing the mixture in liquid nitrogen to stop the reaction. Because enzymatic reactions are typically very fast waiting time is on the order of milliseconds. Freezing gives me a snapshot of the reaction. I then shine light on the sample and measure how much of the light beam is absorbed by the sample. This tells me how the enzyme and target are interacting with each other at that particular moment in the reaction sequence. Repeating this process at different waiting times allows the identity of the reaction intermediates to be established. These can be pieced together just as watching someone moving under a strobe light gives individual images from which the subject's movement can be determined.

I study a class of enzymes which are very similar in structure, but perform very different functions. One member of this class performs the final step in building DNA, while another allows bacteria to change methane into methanol to use as a food source. These roles are very different, but utilize many similar reaction steps. Understanding how nature tunes the reactivity of an enzyme through subtle changes in enzyme structure is important as much of biotechnology is concerned with engineering proteins to perform new functions or to work outside of their natural environments. An example of this from my research would be to use the enzyme which changes methane into methanol not to feed bacteria, but to produce methanol for use as a replacement fuel for gasoline. In addition to biotechnological application of this research, understanding the details of reaction pathways is vital to drug design. Many modern pharmaceuticals act by preventing a particular enzyme from functioning. These inhibitor molecules cut in on the dance between the enzyme and the target, binding to the enzyme and preventing the interactions which are needed for the reaction to proceed. Identifying the point in the reaction pathway most vulnerable to interruption allows for the design of an effective inhibitor. An inhibitor to the enzyme which completes the synthesis of DNA would prevent a cell from reproducing. If this molecule was targeted at a tumor, it could be used to fight cancer.