Biosynthetic Studies of Phomopsins Unveil Posttranslational Installation of Dehydroamino Acids by UstYa Family Proteins

• Published in: Angewandte Chemie International Edition 2021-12, Vol.60 (49), p.25729-25734
• Main Authors: Sogahata, Kaho, Ozaki, Taro, Igarashi, Yuya, Naganuma, Yuka, Liu, Chengwei, Minami, Atsushi, Oikawa, Hideaki
• Format: Article
• Language: English
• Subjects: Amino acid sequence; Amino acids; Amino Acids - chemistry; Amino Acids - metabolism; Aspergillus oryzae - chemistry; Biosynthesis; Chemical reactions; Desaturation; enzymes; Fungal Proteins - chemistry; Fungal Proteins - metabolism; Fungi; Genomes; halogenation; Homology; Metabolites; Molecular Structure; Mycotoxins - biosynthesis; Mycotoxins - chemistry; natural products; Network analysis; Peptides; Protein Processing, Post-Translational; Proteins
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202111076

UstYa family proteins (DUF3328) are widely and specifically distributed in fungi. They are known to be involved in the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs) and nonribosomal peptides, and possibly catalyze various reactions, including oxidative cyclization and chlorination. In this study, we focused on phomopsin A, a fungal RiPP consisting of unique nonproteinogenic amino acids. Gene knockout experiments demonstrated that three UstYa homologues, phomYc, phomYd, and phomYe, are essential for the desaturation of amino acid moieties, showing unprecedented function among UstYa family proteins. Sequence similarity network analysis indicated that their amino acid sequences are highly diverged and that most remain uncharacterized, paving the way for genome mining of fungal metabolites with unique modifications. The biosynthesis of the fungal ribosomally synthesized and posttranslationally modified peptide phomopsin was elucidated by gene inactivation experiments. Notably, chlorination by tyrosinase‐like enzyme PhomQ1 and desaturation of amino acid moieties by UstYa family (DUF3328) proteins PhomYc/Yd/Ye were uncovered. Besides the known function of UstYa homologues, this study unveiled the remarkable functional diversity of these fungi‐specific proteins.