Chemists at Scripps Research have effectively created three families of complex oxygen-containing molecules that can usually only be obtained from plants.
These molecules, called terpenes, are potential starting points for new drugs and other high-value products ̵
Chemical feat. Is detailed in the magazine August 13 Science.
The key to this new method of making molecules is the utilization or capture of natural enzymes – from bacteria, in this case – to help with complex chemical transformations that have been impractical or impossible with synthetic chemistry techniques alone, says lead researcher Hans Renata, Ph.D. D., Assistant Professor at the Department of Chemistry at Scripps Research.
Natural enzymes that help build molecules in cells usually perform only one or two very specific tasks. But the Scripps Research team showed that natural enzymes, even without modifications, can be made to perform a wider range of tasks.
“We believe that enzymes are generally a largely untapped resource for solving problems in chemical synthesis,” says Renata. “Enzymes tend to have some promiscuous activity in terms of their ability to stimulate chemical reactions beyond their primary function, and we were able to take advantage of this.”
Utilization of enzymes’ hidden talents
Enzymes help build molecules in all plants, animals and microbial species. Inspired by their efficiency in constructing highly complex molecules, chemists have been using enzymes in the laboratory for more than half a century to help build valuable compounds, including drug compounds – but usually these compounds are the same molecules that enzymes help build in the nature.
Utilization of natural enzymes in a broader way is, according to their basic biochemical activity, a new strategy with great potential.
“Our view now is that when we want to synthesize a complex molecule, the solution probably already exists among nature’s enzymes – we just need to know how to find the enzymes that work,” says senior author Ben Shen, Ph.D., president of Department of Chemistry on the Florida campus and director of Scripps Research’s Natural Products Discovery Center.
The team succeeded in making nine terpenes known to be produced in Isodon, a family of flowering plants related to mint. The complex compounds belong to three terpene families with related chemical structures: ent-kaurans, ent-atisans and ent-trachylobans. Members of these terpene families have a wide range of biological activities, including suppression of inflammation and tumor growth.
A recipe for synthesis success
The synthesis of each compound, in less than 10 steps for each, was a hybrid process that combines current organic synthesis methods with enzyme-mediated synthesis from an inexpensive compound called stevioside, the main component of the artificial sweetener Stevia.
The main obstacle was the direct replacement of hydrogen atoms with oxygen atoms in a complex pattern on the carbon atom skeleton of the starting compound. Current organic synthesis methods have a limited arsenal for such transformations. However, nature has produced many enzymes that can enable these transformations – each capable of performing its function with a degree of control that cannot be matched by man-made methods.
“As an interdisciplinary research group, we were fully aware of the limitations of current organic synthesis methods, but also of the many unique ways in which enzymes can overcome these limitations – and we had insight into combining traditional synthetic chemistry with enzymatic methods in a synergistic mode. , ”Says Renata.
The three enzymes used, which were only identified and characterized by Shen, Renata and colleagues only last year, 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 use these enzymes not only to modify the starting molecules or scaffolds as we call them, but also to transform one scaffold into another so that we could transform a terpene from one family into a terpene from another. family, “says co-author Emma King-Smith, Ph.D. students in the Renata laboratory.
The chemists now intend to use their new approach to produce useful amounts of the nine compounds as well as chemical variants of the compounds and, together with collaborative laboratories, investigate their properties as potential drugs or other products.
“With our strategy, we can make these highly oxidized diterpenes much lighter and in larger quantities than would be possible by isolating them from the plants where they are found naturally,” says lead author Xiao Zhang, Ph.D., a postdoctoral researcher. affiliated with the Renata Laboratory.
Equally important, the researchers say, are working to identify reactions and enzymes that allow them to expand their approach to other molecular classes.
Central to all of this effort is the ongoing development of methods to sift through DNA from microbes and other organisms to identify the enzymes they encode – and predict the activities of those enzymes. Billions of different enzymes are found in plants, animals and bacteria on Earth, and only a small fraction of them have been cataloged so far.
“We are excited about the potential of discovering new and useful enzymes from our tribal library here at Scripps Research,” says Renata. “We think it will enable us to solve many other problems in chemical synthesis.”
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“Divergent synthesis of complex diterpenes through a hybrid oxidative approach” Science (2020). science.sciencemag.org/cgi/doi … 1126 / science.abb8271
Provided by The Scripps Research Institute
Citation: Bacterial enzymes “hijacked” to create complex molecules normally produced by plants (2020, August 13) Retrieved August 14, 2020 from https://phys.org/news/2020-08-bacterial-enzymes-hijacked -complex-molecules.html
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