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Researchers reveal how fungi produce compounds with potential pharmaceutical applications

2019/9/26 9:54:37   source:Xinhua

Research led by the University of Michigan (UM) Life Sciences Institute has solved a nearly 50-year-old mystery of how nature produces a large class of bioactive chemical compounds.

The findings were published on Monday in the journal Nature Chemistry.

The compounds, called prenylated indole alkaloids, were first discovered in fungi in the 1970s. Since then, they have attracted considerable interest for their wide range of potential applications as useful drugs. One compound is already used worldwide as an antiparasitic for livestock, according to the study.

The fungi's genes encode enzymes, and these enzymes use very simple building blocks to perform each step to build the complex molecule. But despite the longstanding knowledge about these compounds, researchers were not able to tease apart the precise enzymes and reactions that the fungi use to produce them.

Through their efforts to isolate the genes involved and recreate the entire bio-assembly line in a test tube, researchers have revealed the process with a collaborative approach that combined synthetic chemistry, genetics, enzymology, computational chemistry and structural biology.

The final step in the assembly process is the Diels-Alder reaction, and researchers believe their findings open two paths forward: the particular enzyme that catalyzes this Diels-Alder reaction could help improve one of the most commonly used chemical reactions, and they now have a clear picture of how the enzyme directs the reaction in nature and how it might be harnessed to create new compounds in the future.

"This is a very good example of the explanatory power of crystal structures," said Sean Newmister, a researcher in Sherman's lab and a lead author on the study. "We gain mechanistic insight into the activity of the enzyme we're studying, but also insight into how to use this as a tool to synthesize new chemical compounds with biological activities. And that's really exciting." 

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