Evolution, structure and function of the putative biosynthetic gene cluster of the fungal secondary metabolite myriocin, a potent inhibitory sphingolipid
Myriocin is a fungal secondary metabolite exploited worldwide as a powerful inhibitor of sphingolipid biosynthesis through its structural similarity to sphingosine. We identify the putative myriocin biosynthesis gene cluster (BGC) through de novo sequencing of two producing fungi, Isaria sinclairii and Mycelia sterilia, yielding genomes of 25.2 Mb and 34.2 Mb encoding 27 and 20 secondary metabolite BGCs, respectively. BGCs #5 in I. sinclairii and #18 in M. sterilia both shared and expressed the polyketide synthase (PKS) and alpha oxo-amine synthase (AOS) predicted for myriocin biosynthesis, with 74% and 79% sequence similarity, respectively. Analysis of a 2,236-fungal-genome database suggests the pathway originated in the Sordariomycete ancestor, presenting in two major clades distinguished by PKS gene orientation. The placement of thermophilic M. sterilia suggests myriocin BGC acquisition through horizontal gene transfer, but its origin in I. sinclairii is ambiguous. Heterologously-expressed IsMyrA bound aminomalonate, and a protein-protein docking interface was identified between the acyl carrier protein and IsMyrA. A model of PKS domain function, the roles of the PKS and AOS genes and the synteny of the putative myriocin biosynthetic gene cluster across 34 carrier species of ascomycetes is presented.
Authors
- Stephen J. Mondo (ORCID: https://orcid.org/0000-0001-5797-0647)
- Alexandra Brand (ORCID: https://orcid.org/0000-0002-7381-131X)
- Marius A. Wenzel (ORCID: https://orcid.org/0000-0003-0093-368X)
- Ben Ashley (ORCID: https://orcid.org/0000-0001-6545-3738)
- Ben Rutter (ORCID: https://orcid.org/0000-0003-0466-4923)
- Qinxi Ma (ORCID: https://orcid.org/0000-0001-9892-4997)
- Jason C. Slot (ORCID: https://orcid.org/0000-0001-6731-3405)
- Michael A. Herrera (ORCID: https://orcid.org/0000-0001-8693-8910)
- Nicolas Helmstetter (ORCID: https://orcid.org/0000-0003-0260-023X)
- Dominic J. Campopiano (ORCID: https://orcid.org/0000-0001-8573-6735)
- Rhys A. Farrer (ORCID: https://orcid.org/0000-0001-8456-7458)
- Hai Deng (ORCID: https://orcid.org/0000-0002-0047-0622)
- Claudio Greco (ORCID: https://orcid.org/0000-0003-3067-0999)
- Cameron Bedford
- Zachary Konkel (ORCID: https://orcid.org/0000-0003-3628-8336)
- Gustavo Perez Ortiz (ORCID: https://orcid.org/0000-0002-6521-3096)
- Abigail Hay
Institutions
- Lawrence Berkeley National Laboratory (US)
- University of Aberdeen (GB)
- Joint Genome Institute (US)
- University of Exeter (GB)
- Swansea University (GB)
- The Ohio State University (US)
- Medical Research Council (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Communications Biology
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1038/s42003-026-10708-9
- Primary Topic
- Sphingolipid Metabolism and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Wellcome Trust
- National Institute for Health and Care Research
- Department of Health and Social Care
- University of Exeter
- University of Aberdeen
- Medical Research Council Centre for Medical Mycology
- Medical Research Council
- Biotechnology and Biological Sciences Research Council