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

The Journal of Antibiotics volume 76, pages 3–13 (2023)Cite this article

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Abstract

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.

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References

  1. Montalbán-López M, et al. New developments in RiPP discovery, enzymology and engineering. Nat Prod Rep. 2021;38:130–239.

    Article  Google Scholar 

  2. Arnison PG, et al. Ribosomally synthesized and post-translationally modified peptide natural products: Overview and recommendations for a universal nomenclature. Nat Prod Rep. 2013;30:108–60.

    Article  CAS  Google Scholar 

  3. Kessler SC, Chooi YH. Out for a RiPP: challenges and advances in genome mining of ribosomal peptides from fungi. Nat Prod Rep. 2022;39:222–30.

    Article  CAS  Google Scholar 

  4. Vogt E, Künzler M. Discovery of novel fungal RiPP biosynthetic pathways and their application for the development of peptide therapeutics. Appl Microbiol Biotechnol. 2019;103:5567–81.

    Article  CAS  Google Scholar 

  5. Le Marquer M, San Clemente H, Roux C, Savelli B, Frei Dit Frey N. Identification of new signalling peptides through a genome-wide survey of 250 fungal secretomes. BMC Genomics. 2019;20:1–15.

    Google Scholar 

  6. Hallen HE, Luo H, Scott-Craig JS, Walton JD. Gene family encoding the major toxins of lethal Amanita mushrooms. Proc Natl Acad Sci USA. 2007;104:19097–101.

    Article  CAS  Google Scholar 

  7. Luo H, et al. Peptide macrocyclization catalyzed by a prolyl oligopeptidase involved in α-amanitin biosynthesis. Chem Biol. 2014;21:1610–7.

    Article  CAS  Google Scholar 

  8. Luo H, et al. Genes and evolutionary fates of the amanitin biosynthesis pathway in poisonous mushrooms. Proc Natl Acad Sci USA. 2022;119:e2201113119.

    Article  CAS  Google Scholar 

  9. Sgambelluri RM, Smith MO, Walton JD. Versatility of prolyl oligopeptidase B in peptide macrocyclization. ACS Synth Biol. 2018;7:145–52.

    Article  CAS  Google Scholar 

  10. Czekster CM, Naismith JH. Kinetic landscape of a peptide bond-forming prolyl oligopeptidase. Biochemistry. 2017;56:2086–95.

    Article  CAS  Google Scholar 

  11. Czekster CM, Ludewig H, McMahon SA, Naismith JH. Characterization of a dual function macrocyclase enables design and use of efficient macrocyclization substrates. Nat Commun. 2017;8:1–10.

    Article  CAS  Google Scholar 

  12. Van Der Velden NS, et al. Autocatalytic backbone N-methylation in a family of ribosomal peptide natural products. Nat Chem Biol. 2017;13:833–5.

    Article  Google Scholar 

  13. Ramm S, et al. A self-sacrificing N-methyltransferase is the precursor of the fungal natural product omphalotin. Angew Chem Int Ed. 2017;56:9994–7.

    Article  CAS  Google Scholar 

  14. Song H, et al. A molecular mechanism for the enzymatic methylation of nitrogen atoms within peptide bonds. Sci Adv. 2018;4:eaat2720.

    Article  CAS  Google Scholar 

  15. Ongpipattanakul C, Nair SK. Molecular basis for autocatalytic backbone N-methylation in RiPP natural product biosynthesis. ACS Chem Biol. 2018;13:2989–99.

    Article  CAS  Google Scholar 

  16. Umemura M, Kuriiwa K, Viet Dao L. Tandem repeats in precursor protein stabilize transcript levels and production levels of the fungal ribosomally synthesized and post-translationally modified peptide ustiloxin B. Fungal Genet Biol. 2022;160:103691.

    Article  CAS  Google Scholar 

  17. Yoshimi A, et al. Expression of ustR and the Golgi protease KexB are required for ustiloxin B biosynthesis in Aspergillus oryzae. AMB Express. 2016;6:1–8.

    Article  CAS  Google Scholar 

  18. Umemura M. Peptides derived from Kex2-processed repeat proteins are widely distributed and highly diverse in the Fungi kingdom. Fungal Biol Biotechnol 2020;7:1–23.

    Article  Google Scholar 

  19. Johnson RD, et al. A novel family of cyclic oligopeptides derived from ribosomal peptide synthesis of an in planta-induced gene, gigA, in Epichloë endophytes of grasses. Fungal Genet Biol. 2015;85:14–24.

    Article  CAS  Google Scholar 

  20. Green KA, et al. Lolium perenne apoplast metabolomics for identification of novel metabolites produced by the symbiotic fungus Epichloë festucae. N. Phytol. 2020;227:559–71.

    Article  CAS  Google Scholar 

  21. Nagano N, et al. Class of cyclic ribosomal peptide synthetic genes in filamentous fungi. Fungal Genet Biol. 2016;86:58–70.

    Article  CAS  Google Scholar 

  22. Umemura M, et al. MIDDAS-M: Motif-independent de novo detection of secondary metabolite gene clusters through the integration of genome sequencing and transcriptome data. PLoS One. 2013;8:e84028.

    Article  Google Scholar 

  23. Umemura M, et al. Characterization of the biosynthetic gene cluster for the ribosomally synthesized cyclic peptide ustiloxin B in Aspergillus flavus. Fungal Genet Biol. 2014;68:23–30.

    Article  CAS  Google Scholar 

  24. Ye Y, et al. Unveiling the biosynthetic pathway of the ribosomally synthesized and post-translationally modified peptide ustiloxin B in filamentous fungi. Angew Chem Int Ed 2016;55:8072–5.

    Article  CAS  Google Scholar 

  25. Ellis JM, et al. Biocatalytic synthesis of non-standard amino acids by a decarboxylative aldol reaction. Nat Catal. 2022;5:136–43.

    Article  CAS  Google Scholar 

  26. Ding W, et al. Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes. Proc Natl Acad Sci USA. 2016;113:3521–6.

    Article  CAS  Google Scholar 

  27. Sogahata K, et al. Biosynthetic studies of phomopsins unveil posttranslational installation of dehydroamino acids by UstYa family proteins. Angew Chem Int Ed 2021;60:25729–34.

    Article  CAS  Google Scholar 

  28. Kessler SC, et al. Victorin, the host-selective cyclic peptide toxin from the oat pathogen Cochliobolus victoriae, is ribosomally encoded. Proc Natl Acad Sci. 2020;117:24243–50.

    Article  CAS  Google Scholar 

  29. Ye Y, et al. Heterologous production of asperipin-2a: Proposal for sequential oxidative macrocyclization by a fungi-specific DUF3328 oxidase. Org Biomol Chem 2019;17:39–43.

    Article  CAS  Google Scholar 

  30. Shabani S, White JM, Hutton CA. Total synthesis of the putative structure of asperipin-2a and stereochemical reassignment. Org Lett. 2020;22:7730–4.

    Article  CAS  Google Scholar 

  31. Jiang Y, et al. Biosynthesis of cyclochlorotine: identification of the genes involved in oxidative transformations and intramolecular O,N-Transacylation. Org Lett 2021;23:2616–20.

    Article  Google Scholar 

  32. Schafhauser T, et al. The cyclochlorotine mycotoxin is produced by the nonribosomal peptide synthetase CctN in Talaromyces islandicus (‘ Penicillium islandicum’). Environ Microbiol. 2016;18:3728–41.

    Article  CAS  Google Scholar 

  33. Schafhauser T, et al. Antitumor astins originate from the fungal endophyte Cyanodermella asteris living within the medicinal plant Aster tataricus. Proc Natl Acad Sci USA. 2019;116:26909–17.

    Article  CAS  Google Scholar 

  34. Gadsby DC, Vergani P, Csanády L. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature. 2006;440:477–83.

    Article  CAS  Google Scholar 

  35. Kim H, Nelson MA. Molecular and functional analyses of poi-2, a novel gene highly expressed in sexual and perithecial tissues of Neurospora crassa. Eukaryot Cell. 2005;4:900–10.

    Article  CAS  Google Scholar 

  36. Kersten RD, Weng JK. Gene-guided discovery and engineering of branched cyclic peptides in plants. Proc Natl Acad Sci USA. 2018;115:E10961–E10969.

    Article  CAS  Google Scholar 

  37. Chigumba DN, et al. Discovery and biosynthesis of cyclic plant peptides via autocatalytic cyclases. Nat Chem Biol. 2022;18:18–28.

    Article  CAS  Google Scholar 

  38. Macko V, et al. Characterization of victorin C, the major host-selective toxin from Cochliobolus victoriae: Structure of degradation products. Experientia. 1985;41:1366–70.

    Article  CAS  Google Scholar 

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Funding

This work was financially supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (JSPS KAKENHI Grant Number JP19H02891 (HO), JP22H02204 (AM), JP16H06446 (AM) and JP19H04635 (TO) and Institute for Fermentation, Osaka (IFO, Grant Number G-2022-3-011) (AM).

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, 060-0810, Japan

    Taro Ozaki, Atsushi Minami & Hideaki Oikawa

  2. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan

    Taro Ozaki

  3. Innovation Center of Marine Biotechnology and Pharmaceuticals, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, Guangdong, China

    Hideaki Oikawa

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  1. Taro Ozaki
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TO, AM, and HO wrote and revised the manuscript.

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Correspondence to Hideaki Oikawa.

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Ozaki, T., Minami, A. & Oikawa, H. Recent advances in the biosynthesis of ribosomally synthesized and posttranslationally modified peptides of fungal origin. J Antibiot 76, 3–13 (2023). https://doi.org/10.1038/s41429-022-00576-w

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