Class of cyclic ribosomal peptide synthetic genes in filamentous fungi.

Nozomi Nagano, Myco Umemura, Miho Izumikawa, Jin Kawano, Tomoko Ishii, Moto Kikuchi, Kentaro Tomii, Toshitaka Kumagai, Akira Yoshimi, Masayuki Machida, Keietsu Abe, Kazuo Shin-Ya, Kiyoshi Asai

Journal: Fungal genetics and biology : FG & B 2016;86():58-70

PMID: 26703898

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Abstract

Ustiloxins were found recently to be the first example of cyclic peptidyl secondary metabolites that are ribosomally synthesized in filamentous fungi. In this work, two function-unknown genes (ustYa/ustYb) in the gene cluster for ustiloxins from Aspergillus flavus were found experimentally to be involved in cyclization of the peptide. Their homologous genes are observed mainly in filamentous fungi and mushrooms. They have two "HXXHC" motifs that might form active sites. Computational genome analyses showed that these genes are frequently located near candidate genes for ribosomal peptide precursors, which have signal peptides at the N-termini and repeated sequences with core peptides for the cyclic portions, in the genomes of filamentous fungi, particularly Aspergilli, as observed in the ustiloxin gene cluster. Based on the combination of the ustYa/ustYb homologous genes and the nearby ribosomal peptide precursor candidate genes, 94 ribosomal peptide precursor candidates that were identified computationally from Aspergilli genome sequences were classified into more than 40 types including a wide variety of core peptide sequences. A set of the predicted ribosomal peptide biosynthetic genes was experimentally verified to synthesize a new cyclic peptide compound, designated as asperipin-2a, which comprises the amino acid sequence in the corresponding precursor gene, distinct from the ustiloxin precursors.

Address: Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan; Computational Biology Research Consortium (CBRC), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.; Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 17-2-1 Higashi-Nijo, Tsukisamu, Toyohira-ku, Sapporo, Hokkaido 062-8517, Japan. Electronic address: [email protected].; Japan Biological Informatics Consortium, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.; Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 17-2-1 Higashi-Nijo, Tsukisamu, Toyohira-ku, Sapporo, Hokkaido 062-8517, Japan.; Technology Research Association of Highly Efficient Gene Design, 17-2-1 Higashi-Nijo, Tsukisamu, Toyohira-ku, Sapporo, Hokkaido 062-8517, Japan.; Fermlab, Inc., 4-3-1-913 Shirakawa, Koto-ku, Tokyo 135-0021, Japan.; New Industry Creation Hatchery Center, Tohoku University, 6-6-10 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan.; Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.; Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan; Computational Biology Research Consortium (CBRC), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8561, Japan.

DOI: 10.1016/j.fgb.2015.12.010

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MeSH Terms: Amino Acid Sequence, Aspergillus flavus, Genes, Fungal, Genes, Synthetic, Genome, Fungal, Molecular Sequence Data, Multigene Family, Peptides, Cyclic, Ribosomes