Monasone naphthoquinone biosynthesis and resistance in monascus fungi

Mu Li, Lijing Kang, Xiaoli Ding, Jiao Liu, Qingpei Liu, Yanchun Shao, István Molnár, Fusheng Chen

Research output: Contribution to journalArticle

Abstract

Despite the important biological activities of natural product naphthoquinones, the biosynthetic pathways of and resistance mechanisms against such compounds remain poorly understood in fungi. Here, we report that the genes responsible for the biosynthesis of Monascus naphthoquinones (monasones) reside within the gene cluster for Monascus azaphilone pigments (MonAzPs). We elucidate the biosynthetic pathway of monasones by a combination of comparative genome analysis, gene knockouts, heterologous coexpression, and in vivo and in vitro enzymatic reactions to show that this pathway branches from the first polyketide intermediate of MonAzPs. Furthermore, we propose that the monasone subset of biosynthetic genes also encodes a two-tiered resistance strategy in which an inducible monasone-specific exporter expels monasones from the mycelia, while residual intracellular monasones may be rendered nontoxic through a multistep reduction cascade. IMPORTANCE The genes for Monascus naphthoquinone (monasone) biosynthesis are embedded in and form a composite supercluster with the Monascus azaphilone pigment biosynthetic gene cluster. Early biosynthetic intermediates are shared by the two pathways. Some enzymes encoded by the supercluster play double duty in contributing to both pathways, while others are specific for one or the other pathway. The monasone subcluster is independently regulated and inducible by elicita-tion with competing microorganisms. This study illustrates genomic and biosynthetic parsimony in fungi and proposes a potential path for the evolution of the mosaic-like azaphilone-naphthoquinone supercluster. The monasone subcluster also encodes a two-tiered self-resistance mechanism that models resistance determinants that may transfer to target microorganisms or emerge in cancer cells in case of naphthoquinone-type cytotoxic agents.

Original languageEnglish (US)
Article numbere02676-19
JournalmBio
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2020

    Fingerprint

Keywords

  • Monascus spp.
  • Naphthoquinone
  • Nested biosynthetic pathway
  • Resistance mechanism
  • Supercluster

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Li, M., Kang, L., Ding, X., Liu, J., Liu, Q., Shao, Y., Molnár, I., & Chen, F. (2020). Monasone naphthoquinone biosynthesis and resistance in monascus fungi. mBio, 11(1), [e02676-19]. https://doi.org/10.1128/mBio.02676-19