Evolving Enzymes to Enable New Chemistry for Human Health
California Institute of Technology
The Arnold Group develops enzyme catalysts by guiding their evolution to perform chemical reactions not found in nature.
With Mathers Foundation funding, the group began exploring a new class of proteins called protoglobins (Pgb), moving beyond the cytochrome P450 enzymes used in earlier work. These small, stable proteins have no known natural function, making them ideal for studying how catalytic activity can emerge through directed evolution. Because protoglobins are easier to characterize, researchers can better track how enzymes gain new abilities in the lab.
The team has successfully evolved protoglobins to catalyze C–C and C–N bond formation through reactions like C–H activation and olefin functionalization—key steps in making pharmaceutical compounds. They are also using crystallography and advanced spectroscopy to study the active-site structures that drive these reactions.
By uncovering how enzymes can be evolved to perform entirely new chemistry, this work could ultimately support the development of safer, more efficient ways to produce drugs and other molecules relevant to human health.
Summary of achievements from this grant: New-to-nature enzymes made by directed evolution in the laboratory can catalyze nitrogen insertion into C-H bonds, in analogy to similar enzymes that naturally insert oxygen. Comparison of enzyme intermediates to the biological nitrogen cycle allowed us to discover novel nitrogen sources for this reaction.
