Researchers Create Passage to Greener, More Robust Chemistry

A new study from the University of Michigan Life Sciences Institute is constructing a bridge from nature's chemistry to greener, more efficient artificial chemistry.

Researchers in the lab of Alison Narayan examined biocatalysts evolved by nature for their efficacy in a range of synthetic chemical reactions. The results, scheduled for publication November 13 in Nature Chemistry, pave the way to potential practices for chemists, highlighting not only more efficient but more robust tools for chemists.

The researchers began with microorganisms that have, over the millennia, formed intricate chemical reactions to develop molecules with crucial biological activity for a range of purposes, such as defense mechanisms. The team then tested the chemical pathways that give rise to these possibly useful molecules to establish how they can be repurposed to produce compounds synthetically in the lab.

"Nature has evolved catalytic tools that would enable chemists to build molecules that we can't easily build just using traditional chemistry," said Narayan, the senior study author and assistant professor at the LSI, where her lab is located. "Our work bridges the two worlds of biosynthesis and synthetic chemistry."

To construct complex, bioactive molecules—like the molecules that allow drugs to locate the correct biological targets in the human bodies—synthetic chemists frequently use a process known as oxidative dearomatization. This process transforms flat molecules into 3D structures that are more reactive. But traditional oxidative dearomatization approaches have a number of flaws.

Since they require the application of a chemical reagent to convert the starting material into the preferred end product, the reactions themselves are moderately wasteful. Furthermore, the reagents exhibit poor selectivity in the transformation, resulting in a blend of compounds that has several needless, and occasionally harmful, variants of the preferred product molecule.

"It's not a very efficient process," said Narayan, who is also an assistant professor of chemistry in the U-M College of Literature, Science, and the Arts. "You can end up with various structures when you really want only this one specific structure—and you generate a lot of waste in the process."

In this latest study, the Narayan lab proved that enzyme catalysts have the potential to solve these matters.

Enzymes are efficient catalysts, producing many product molecules from a single molecule of the catalyst, resulting in less waste. Narayan's lab discovered that the catalysts perform the reactions with better selectivity—meaning that the reactions create only the anticipated molecular structure.

These enzymes have not yet been extensively adopted by chemists because their whole utility and robustness for chemistry have not been established, Narayan said.

The work being done in the field of biosynthesis primarily focuses on understanding how molecules are made in nature and identifying the single reaction an enzyme does in its natural context, we have to figure out how an enzyme is useful in the field of synthetic chemistry—what can it do, what types of molecules it works with—so that chemists can just go to the literature and see how they can use this tool.

Alison Narayan, assistant professor of chemistry, U-M College of Literature, Science, and the Arts.

Narayan's research program initiates closing the gap between these two fields by analyzing enzymes not just for their natural roles, but for the roles they could play in a range of reactions. The lab also has developed techniques to make these enzymes easy to work in bulk and share with other chemists.

"We're showing that these enzymes can do more than the one specific task they evolved to do in nature," said graduate student Summer Baker Dockrey, the lead study author. "They can be surprisingly generalizable and could prove to be highly selective tools."

The lab is currently engaged in engineering these enzymes to perform further reactions.

"We are really starting to build the library of new, efficient, powerful tools for chemists," Narayan said.

The research received funding from the LSI, U-M Department of Chemistry, National Institutes of Health and U.S. Department of Education.

The paper’s authors are Narayan, Baker Dockrey, April Lukowski and Mark Becker, all of U-M.

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