The chemists at Scripps Research have effectively created three families of complex, oxygenated molecules that can normally only be obtained from plants.
These molecules, called terpenes, are potential starting points for new drugs and other high-value products ̵1; marking an important developmental step for many industries. In addition, the new approach could allow chemists to create a variety of other compounds.
The chemistry feat is detailed in the August 13 issue of the journal Science.
The key to this new method of molecular generation is to exploit, or capture, natural enzymes – from bacteria, in this case – to support complex chemical transformations that are either impracticable or impossible. done with only synthetic chemistry techniques, said lead investigator Hans Renata, Ph.D., an assistant professor in the Department of Chemistry at Scripps Research.
The natural enzymes that help build molecules in cells typically perform only one or two exceptionally high tasks. But the Scripps Research team has shown that natural enzymes, even when left unmodified, can still be made to perform more tasks.
“We think in general, enzymes are the most under-exploited resource to solve problems in chemical synthesis,” says Renata. “Enzymes tend to have some degree of activity individually, in terms of their ability to induce chemical reactions beyond their primary role, and we were able to take advantage of that here.”
Harness the enzyme’s potential
Enzymes help build molecules in all plants, animals and microorganisms. Inspired by their effectiveness in building highly complex molecules, chemists for more than half a century have used enzymes in the lab to help create valuable compounds, These include medicinal compounds – but often these compounds are like molecules that enzymes help make in nature.
Mining natural enzymes in a broader way, according to their basic biochemical activity, is a new strategy with vast potential.
“Our view now is that whenever we want to synthesize a complex molecule, the solution may already exist among nature’s enzymes – we just need to know how to find the active enzymes. “, senior author Ben Shen, Ph.D., said. Dean of the Florida campus Chemistry and director of Scripps Research’s Natural Product Discovery Center.
The team succeeded in creating nine terpenes known to be produced in Isodon, a family of mint-related flowering plants. The complex compounds belong to three families of terpene with related chemical structures: ent-kauranes, ent-atisanes and ent-trachylobanes. Members of these terpene families have a wide range of biological activities including suppression of inflammation and tumor growth.
Successful synthesis formula
The synthesis of each compound, in less than 10 steps per compound, is a hybrid process that combines existing methods of organic synthesis with enzyme-mediated synthesis starting from an inexpensive compound called stevioside, the main ingredient of the artificial sweetener stevia.
The main hurdle is the direct replacement of hydrogen atoms with oxygen atoms in a complex pattern on the carbon atom frame of the original compound. Current organic synthesis methods have a limited arsenal for such transformations. However, nature has produced many enzymes that can perform these changes – each capable of performing its own functions with unprecedented levels of control by artificial methods.
“As an interdisciplinary team, we’re fully aware of the limitations of current methods of organic synthesis, but there are also unique ways that enzymes can overcome these limitations – and they are. I had the insight to combine traditional synthetic chemistry with enzyme methods in a fashionable synthesis, ”says Renata.
The three enzymes used, identified and characterized by Shen, Renata and colleagues last year, were produced naturally by a bacterium – one of the 200,000 species in the strain Collection at Scripps Research’s Natural Products Discovery Center.
“We were able to use these enzymes not only to modify the original molecules, or scaffolds as we call them, but also to turn one scaffold into another so that we could transform. a terpen from one family to a terpen from another, “Second author Emma King-Smith, a Ph.D. student in the Renata laboratory.
Chemists now intend to use their new approach to generate useful quantities of nine compounds, as well as chemical variations of these compounds and together with collaborative laboratories, destroy their properties as a potential drug or other product.
“With our strategy, we are able to make these highly oxidized diterpenes easier and in much greater quantities than possible by isolating them from the plants where they are found. natural, “first author Xiao Zhang, PhD, a postdoctoral study, said the link in the Renata laboratory.
Equally important, they are working to identify the reactions and enzymes that will allow them to extend their approach to other molecular layers, the researchers said.
At the heart of all these efforts is the continued development of methods of screening for the DNA of microorganisms and other organisms to identify the enzymes they encode – and predict the activity of those enzymes. . Billions of different enzymes exist 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 strain library at Scripps Research,” Renata said. “We think that will allow us to tackle many other problems in chemical synthesis.”
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“Various synthesis of complex diterpenes through hybrid oxidation methods” Science (Year 2020). Science.sciencemag.org/cgi/doi… 1126 / science.abb8271
Provided by Scripps Research Institute
Quote: Bacterial enzymes ‘take over’ to create complex molecules usually generated by plants (2020, August 13) retrieved August 14, 2020 from https: // phys .org / news / 2020-08-bacte-enzyme-hijacked-complex-molecules.html
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