Chemists from the University of California – Los Angeles (UCLA) and the University of Washington (UW) have succeeded in creating designer enzymes for reactions not normally catalyzed in nature, opening the door for scientists to control the very reactions that sustain life. Reporting their results in the journal Nature, the researchers said the designer enzymes will have applications in biological warfare and for creating more effective medications. The work to date has been funded by DARPA, the U.S. Defense Department’s central research and development organization.
“The design of new enzymes for reactions not normally catalyzed in nature is finally feasible,” said UCLA team leader Kendall Houk. “The goal of our research is to use computational methods to design the arrangement of groups inside a protein to cause any desired reaction to occur.” To demonstrate the feasibility of this approach, the researchers created designer enzymes for a chemical reaction known as the Kemp elimination, a non-natural chemical transformation in which hydrogen is pulled off a carbon atom.
The researchers also reported another successful chemical reaction that used designer enzymes to catalyze a retro-aldol reaction, which involves breaking a carbon-carbon bond. The aldol reaction is a key process in living organisms associated with the processing and synthesis of carbohydrates. This reaction is also widely used in the large-scale production of commodity chemicals and in the pharmaceutical industry.
The implementation of the aldol reaction was an important challenge, according to Houk, as the reaction involves at least six chemical transformations, requiring UCLA scientists to compute all six chemical steps with their corresponding transition states. The structures were then combined in such a way to allow all six steps to occur.
Houk’s group uses computational methods based on the physical laws of quantum mechanics to study in detail the mechanisms of chemical reactions. By exploring multiple combinations of chemical groups, they can determine those that are most suitable to facilitate any given chemical transformation. Then, they determine the precise three-dimensional arrangement of these chemical groups, which is critical for the specificity and activity of the enzyme.
The UCLA researchers then provide a blueprint for the active site to their UW colleagues, headed up by biochemist David Baker, who then design a sequence of amino acids that fold to produce an active site like the one designed by Houk’s group.
How far off are designer enzymes with important applications? “I think we’re there,” said UCLA’s DeChancie. “These papers are showing the technology is now in place.”