The “alternate incorporation” strategy used by fungal iterative NRPSs for product assembly. [Jixun Zhan/Utah State University]

Utah State University (USU) scientists say they have successfully decoded and reprogrammed the biosynthetic machinery that produces a variety of natural compounds found in fungi. Bacteria and fungi produce a range of bioactive natural products that exhibit anticancer, antimicrobial, herbicidal, insecticidal, and anticholesterol properties, among others. 

Such nonribosomal peptides are formed by nonribosomal peptide synthetases (NRPSs) that assemble a diverse group of natural products, including penicillin (antibacterial), beauvericin (anticancer), and vancomycin (antibacterial). While bacterial NRPSs are well understood, the fungal versions of these processes are only now coming to light.

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

The team's findings (“Decoding and Reprogramming Fungal Iterative Nonribosomal Peptide Synthetases”), published in Nature Communications, reportedly are the first to describe the difference between bacterial and fungal iterative NRPS mechanisms. Dr. Zhan says a clearer understanding of NPRS processes could lead to advances in synthesizing existing and new compounds for drug discovery.

“Our goal in this research was to understand how fungal iterative NRPSs precisely and repetitively use their catalytic units to make these different compounds,” he explained. “We're specifically looking at the synthetases that assemble beauvericin and bassianolide and trying to understand how they are assembled and how the NRPSs are programmed to control molecule length and other factors.”

Dr. Zhan's team studied two fungal NRPSs, which are modular enzymes, from B. bassiana that are responsible for the synthesis of the two compounds. The investigators successfully cut the large enzymes into functional fragments and reconstituted their activity in baker's yeast. Through a combination of enzyme dissection, domain swapping, site-directed mutagenesis, and in vitro enzymatic reactions, the team has revealed fungal NRPSs' chain elongation and length control strategy.

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