Adenylation domain substrate selectivity in fungal nonribosomal peptide biosynthesis Stephanie Heard and Jaclyn M. Winter University of Utah, USA Marine fungi have historically been a prolific source of bioactive natural products, including those of the well- studied nonribosomal peptide class. Beyond traditional methods, the advent of whole genome sequencing has allowed for the discovery and investigation of new cellular machinery that was previously inaccessible. Using the power of bioinformatics, researchers can predict new chemical structures in a more high-throughput manner. Though fungal natural product biosynthesis shares some similarities with bacterial systems, eukaryotic systems have tended to be less well characterized. We have contributed to these characterization efforts using bioinformatic-guided natural product isolation to interrogate nonribosomal peptides from marine fungi. Fungal nonribosomal peptide synthetases are notorious for incorporating a wide range of unique, nonproteinogenic building blocks that increase product diversity and functionalization. Both the adenylation and condensation domains of each synthetase module appear to play gatekeeping roles in the incorporation of new building blocks. Through my work with the marine-derived strain Aspergillus flavipes CNL-338, I have combined bioinformatics and biochemistry to elucidate the substrate selectivity of several fungal adenylation domains. By focusing on conserved active site residues, the function of uncharacterized adenylation domains can now be more accurately predicted, particularly for novel substrates. These fungal pathways have proven to be more divergent from bacteria than originally thought, but continuing to decipher higher order systems is critical.
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© The Author(s), 2022
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