Recent advances in the biosynthesis of ribosomally synthesized and posttranslationally modified peptides of fungal origin.

Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are growing class of natural products with potent biological activities. Although the core scaffolds of RiPPs are composed of proteinogenic amino acids, remarkable structural diversity is generated through posttranslational modifications (PTMs) of precursor peptides. In addition, ribosomal origin of biosynthetic precursors enables supply of its analogs through genetic approach such as site-directed mutagenesis on corresponding genes. As PTM enzymes often exhibit substrate tolerance, RiPP biosynthetic machineries are considered as efficient tools for generation of unique peptide derivatives. RiPP pathways are distributed among all domains of life and those derived from bacteria and plants have been known for decades. In contrast, fungal RiPPs (F-RiPPs) have fewer examples. Amatoxins and omphalotins are F-RiPPs produced by Basidiomycota fungi. In the biosynthesis of these compounds, macrocyclization by prolyl oligopeptidase homologs and N-methylations of back bone amides have been characterized, respectively. Ustiloxins and related compounds are another group of F-RiPPs with characteristic macrocyclic ethers. UstYa family proteins, which are fungi-specific putative oxidases, have been identified as common proteins involved in PTMs of these compounds. Despite a limited number of characterized examples, recent progress in sequencing of fungal genomes indicated that a number of RiPP pathways are hidden in fungal resources, making F-RiPPs as attractive target for genome mining studies while more detailed understandings of key biosynthetic enzymes are still necessary. This review seeks to describe recent advances on the F-RiPP biosynthesis with slight emphasis on the function of UstYa family proteins.