Chemists at Scripps Research have efficiently created three families of complex, oxygen-containing 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 development for many industries. Moreover, the new approach could allow chemists to build many other classes of compounds.
The topic of chemistry is detailed in the August 13 issue of the diary science.
At the heart of this new method of making molecules is the use, or abduction, of natural enzymes – by bacteria, in this case to aid in complex chemical transformations that have been impractical or impossible with only synthetic chemistry techniques, says lead investigator Hans. Renata, Ph.D., Assistant Professor in the Department of Chemistry at Scriptps Research.
Natural enzymes that help build molecules in cells usually perform only one or two very specific tasks. But the Scriptps Research team showed that natural enzymes, even without modifications, can be made to perform a wider range of tasks.
“We think that in general, enzymes are a largely unused resource for solving problems in chemical synthesis,” says Renata. “Enzymes tend to have a degree of promising activity, in terms of their ability to induce chemical reactions beyond their primary task, and we have been able to take advantage of that here.”
Using the hidden talents of enzymes
Enzymes help build molecules in all plant, animal and microbial species. Inspired by their efficiency in building very complex molecules, chemists have used enzymes in the laboratory for more than half a century to help build valuable compounds, including drug compounds – but these compounds are usually the same molecules that enzymes help in outdoor construction.
Utilizing natural enzymes in a wider way, according to their basic biochemical activity, is a new strategy with wide potential.
“Our view now is that whenever 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 will work,” says old author Ben Shen, Ph.D. .D., Chairman of the Department of Chemistry on campus in Florida and director of the Scripps Research Natural Products Discovery Center.
The team managed to make nine well-known terpenes produced in Isodon, a family of flowering plants related to mint. The complex compounds belong to three terpene families with related chemical structures: ent-kauran, ent-atizane and ent-trachylobane. Members of these terpene families have a wide range of biological activities, including suppressing inflammation and tumor growth.
A recipe for success in synthesis
The synthesis of each compound, in less than 10 steps for each, was a hybrid process that combined current methods of organic synthesis with enzyme-mediated synthesis, starting with a free complex 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 in the carbon atom skeleton of the initial composition. Current organic synthesis methods have a limited arsenal for such conversions. However, nature has produced many enzymes that can enable these transformations – each able to perform its function with a degree of control unmatched by man-made methods.
“Being an interdisciplinary study 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 have had the knowledge to combine traditional synthetic chemistry with methods. enzymatic in a synergistic fashion “, says Renata.
The three enzymes used, which were identified and characterized by Shen, Renata and colleagues just last year, are produced naturally by a bacterium – one of 200,000 plus species in the Microbial Strain collection at the Scripps Research Natural Products Discovery Center.
“We were able to use these enzymes not only to modify the initial molecules, or scaffolds as we call them, but also to turn one scaffold into another so that we could convert one terpene from one family to one terpene. from a different family, “says second author Emma King-Smith, a Ph.D. student in the Renata laboratory.
Chemists now intend to use their new approach to make useful quantities of nine compounds as well as chemical variants of compounds, and, with collaborating laboratories, to explore their properties as potential medicines or other products.
“With our strategy, we can make these highly oxidized diterpenes much easier and in larger quantities than would be possible by isolating them from plants, where they are found naturally,” says the first author. Xiao Zhang, Ph.D., a postdoctoral research fellow at Renata Laboratory.
Equally important, the researchers say, they are working to identify reactions and enzymes that will allow them to extend their access to other classes of molecules.
Central to all of these efforts is the ongoing development of methods to sift through the DNA of microbes and other organisms to identify the enzymes they encode – and predict the activities of those enzymes. Billions of distinct enzymes exist in plants, animals and bacteria on Earth and only a handful of them have been cataloged so far.
“We are excited about the potential for discovering new and useful enzymes from our strain library here at Scriptps Research,” says Renata. “We think this will enable us to solve many other problems in chemical synthesis.”
Chemists build a natural anticancer compound with a new efficient process
“Divergent synthesis of complex diterpenes through a hybrid oxidative approach” science (2020). science.sciencemag.org/cgi/doi… 1126 / science.abb8271
Provided by Scriptps Research Institute
citation: ‘Abducted’ bacterial enzymes to create complex molecules normally made from 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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