With just a few chemical tweaks, cellular enzymes can turn some of the most common amino acids into unique compounds that possess antimicrobial or medicinal properties.

But in the lab, it’s much harder to derive these molecules when using conventional chemical reagents. Now, researchers have harnessed GriE, an enzyme produced by the microbe Streptomyces griseus, to perform a crucial step in their synthesis.

The impressive results “highlight the power of combining nature’s efficiency with chemical synthesis to make complex organic molecules,” says chemical biologist Bradley Moore of the University of California San Diego, who was not involved in the study. “Using an enzyme to help construct key chemical bonds really streamlines the process.”

GriE oxidizes the amino acid leucine, converting a bond between the fifth carbon atom and hydrogen to a carbon-oxygen bond instead. In the study, published in Journal of the American Chemical Society, Hans Renata and Christian Zwick of The Scripps Research Institute in Florida deployed the enzyme to synthesize—in just a few short steps—a rare alkaloid chemical and a series of compounds derived from the common amino acid proline.

Organic compounds are chock full of carbon-hydrogen bonds, so selectively targeting just one specific linkage using chemical reagents can be tricky. Typically, scientists need to design asymmetric reactions or use harsh reagents, and the synthesis results in a mix of products that can be hard to separate, Renata explains.

Enzymes, however, evolved to hone in and act on specific chemical bonds, making them ideal candidates to perform such synthesis. But they can actually be too precise, acting on too narrow a range of molecules to be useful for synthetic chemistry. Renata and Zwick began their current study by testing GriE’s range of activity, and found it can act on C-H bonds in at least three amino acids—it was precise enough, but not too precise. “We came into this with an open mind, just wanting to see what the enzyme does,” Renata says. “So we were pleasantly surprised to see it works this well.”

“Often, an enzyme might work on its native substrate but not on anything else,” notes organic chemist Huw Davies of Emory University, who was not involved with the research. “It’s pretty impressive that they find a variety of substrates that work well.”

The researchers then scaled the reaction up, and found they could produce approximately 80-100 milligrams of hydroxylated GriE product. To test its utility in making new chemicals, they used GriE to synthesize a marine alkaloid chemical known as manzacidin C from leucine. Conventional chemical reactions require six to 15 steps to produce manzacidin C. But using GriE, they made an intermediate compound that underwent subsequent reactions to form the end product in just five steps. The team also used GriE to produce analogs of the amino acid proline, which Renata calls a “useful building block in medicinal chemistry and peptide synthesis.”

“In general, the use of enzymes in organic chemistry is still relatively underexplored,” he adds. “We hope this provides an impetus to investigate applications of other enzymes for related processes.”

To industrialize the process of using enzymes to manufacture amino acid derivatives, reaction yields will need to be significantly larger. Nonetheless, even a few hundred milligrams of a novel compound—much more than is normally produced in nature—can advance synthetic chemistry efforts. “In the lab, a few hundred milligrams is a large amount to be able to study the synthesis of a complex molecule, work with that material for biological testing or anything else,” Moore says.

Understanding how and when to resort to enzymes rather than conventional chemical reagents can enhance efforts to develop novel drugs or new molecules. “It’s context-dependent,” Moore says. “An enzyme might be better in some situations but not others. This discovery really points to the power of enzymes and how we can learn to use them.”