Chemists at Scripps Research have effectively established three families of complicated, oxygen-containing molecules that are normally available only from crops.

These compounds, called terpenes, are possible starting points for new medications and other high-value products--marking an important development for multiple businesses. Additionally, the new strategy could allow chemists to develop a number of other classes of compounds.

The chemistry effort is comprehensive in the Aug. 13 edition of this journal Science.

The key to this new method of earning molecules is that the tapping, or hijacking, of natural enzymes--from germs, in this instance --to assist in complex chemical transformations which have been impractical or impossible with artificial chemistry methods alone, says principal investigator Hans Renata, PhD, an assistant professor at the Department of Chemistry at Scripps Research.

Natural enzymes which help construct molecules in cells usually perform just one or 2 highly specific activities. However, the Scripps Research team revealed that organic enzymes, even without modification, can be made to perform a wider range of tasks.

"We think that generally, enzymes are a largely untapped resource for solving problems in chemical synthesis," Renata states. "Enzymes have a tendency to possess some amount of promiscuous activity, in terms of their ability to spur chemical responses beyond their primary job, and we could take advantage of that here."

Enzymes help build molecules in all plant, animal and microbial species. Inspired by their efficiency in constructing highly complex molecules, chemists for over half a century have utilized enzymes from the laboratory to help assemble valuable compounds, including drug compounds--but generally these chemicals would be the same molecules that the enzymes help build in nature.

Implementing natural enzymes in a broader way, in accordance with their basic biochemical action, is a brand new strategy with huge potential.

<span style="color: #ff6600;"><a style="color: #ff6600;" href="https://www.scripps.edu/news-and-events/press-room/2020/20200813-renata-terpenes.html">"Our view now is that if we want to synthesize a complex molecule, the remedy probably already exists one of nature's enzymes--we just have to know how to discover the enzymes which will function," says senior author Ben Shen, PhD, chair of the Department of Chemistry on the Florida campus and also director of Scripps Research's Natural Products Discovery Center.</a></span>

The group succeeded in creating nine terpenes proven to be produced in Isodon, a family of flowering plants associated with mint. Members of these terpene families have a wide range of biological actions such as the suppression of inflammation and tumor growth.

<strong>A recipe for synthesis achievement</strong>
The synthesis of each compound, in under 10 measures for each, was a hybrid process combining present organic synthesis methods with enzyme-mediated synthesis starting in an inexpensive compound called stevioside, the main part of the artificial sweetener Stevia.

Current organic synthesis systems have a limited arsenal for these transformations.

<span style="color: #ff6600;"><a style="color: #ff6600;" href="https://www.scripps.edu/news-and-events/press-room/2020/20200813-renata-terpenes.html">However, nature has produced many enzymes which could enable those transformations--each capable of performing its own function with a degree of control unmatched by artificial procedures.</a></span>

Both enzymes utilized, which were characterized and identified by Shen, Renata and colleagues only annually, are produced naturally by a bacterium--one of the 200,000-plus species in the Microbial Strain Collection at Scripps Research's Natural Products Discovery Center.
"We were able to utilize these enzymes not only to modify the starting molecules, or scaffolds as we call them, but also to flip one scaffold into another so that we could transform a terpene from one family into a terpene from a different family," says second author Emma King-Smith, a PhD student in the Renata lab.

<em>Being an interdisciplinary research group, we were fully aware of the limitations of current organic synthesis methods, but also of the many unique ways that enzymes can overcome these limitations--and we had the insights to combine traditional synthetic chemistry with enzymatic methods in a synergistic fashion."-Hans Renata, PhD, Principal Investigator and Assistant Professor, Department of Chemistry, Scripps Research Institute</em>

The chemists now intend to utilize their new approach to make useful amounts of the nine chemicals, in addition to chemical variants of the chemicals, and, with cooperating laboratories, research their properties as possible drugs or other goods.

"With our strategy, we can create these highly oxidized diterpenes a lot more readily and in larger quantities than would be possible by isolating them from the plants in which they are found naturally," says author Xiao Zhang, PhD, a postdoctoral research associate in the Renata laboratory.

As importantly, the investigators saythey are working to identify enzymes and reactions that will enable them to extend their approach to other classes of molecules.

Central to these efforts is the ongoing development of approaches to sift through the DNA of microbes and other organisms to identify the enzymes they encode--and predict the actions of these enzymes.

Billions of different enzymes exist in crops, animals, and bacteria on Earth and only a very small fraction of these have been catalogued to date.

"We are excited about the potential of finding new and enzymes from our stress library here at Scripps Research," Renata says. "We believe that will enable us to address a number of different problems in chemical synthesis."

<strong>Source:</strong>

<span style="color: #ff6600;"><a style="color: #ff6600;" href="https://www.scripps.edu/news-and-events/press-room/2020/20200813-renata-terpenes.html" target="_blank" rel="noopener noreferrer">Scripps Research Institute</a></span>

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