Biosynthetic secrets: How fungi make bioactive compounds

The ‘alternate incorporation’ strategy used by fungal iterative NRPSs for product assembly. Credit: Jixun Zhan

Biological engineers at Utah State University have successfully decoded in addition to reprogrammed the biosynthetic machinery which produces a variety of natural compounds found in fungi.


Fungi in addition to bacteria produce a range of bioactive natural products which exhibit anti-cancer, anti-microbial, herbicidal, insecticidal in addition to anti-cholesterol properties, among others.

These useful molecules, known as nonribosomal peptides, are formed by a group of enzymes called nonribosomal peptide synthetases (NRPSs) which assemble a diverse group of natural products including penicillin (antibacterial), beauvericin (anticancer) in addition to vancomycin (antibacterial). While bacterial NRPSs are well understood, the fungal versions of these processes are only today coming to light.

Dr. Jixun Zhan, a professor of biological engineering at USU, studies the catalytic synthesis of natural products in bacteria in addition to fungi. He in addition to his team have reproduced many bio-active compounds in engineered microbes. Most recently, the team biosynthesized beauvericin in addition to bassianolide—natural compounds originally produced by the fungus Beauveria bassiana which are known to have multiple beneficial effects.

The team’s findings, published May 23 in Nature Communications, are the first to describe the difference between bacterial in addition to fungal iterative NRPS mechanisms. Zhan says a clearer understanding of NPRS processes could lead to advances in synthesizing existing in addition to completely new compounds for drug discovery.

“Our goal in This kind of research was to understand how fungal iterative NRPSs precisely in addition to repetitively use their catalytic units to make these different compounds,” said Zhan. “We’re specifically looking at the synthetases which assemble beauvericin in addition to bassianolide in addition to trying to understand how they are assembled in addition to how the NRPSs are programmed to control molecule length in addition to some other factors.”

NRPSs are modular enzymes which contain a series of modest catalytic units called domains. Zhan’s team studied two fungal NRPSs via B. bassiana which are responsible for the synthesis of the two compounds.

The researchers successfully cut the large enzymes into functional fragments in addition to reconstituted their activity in baker’s yeast. Through a combination of enzyme dissection, domain swapping, site-directed mutagenesis in addition to in vitro enzymatic reactions, the team has revealed fungal NRPSs’ chain elongation in addition to length control strategy.


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More information:
Dayu Yu et al, Decoding in addition to reprogramming fungal iterative nonribosomal peptide synthetases, Nature Communications (2017). DOI: 10.1038/NCOMMS15349

Journal reference:
Nature Communications

Provided by:
Utah State University

Biosynthetic secrets: How fungi make bioactive compounds

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