Linking a gene cluster to atranorin, a major cortical substance of lichens, through genetic dereplication and heterologous expression

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Abstract

The depside and depsidone series compounds of polyketide origin accumulate in the cortical or medullary layers of lichen thalli. Despite the taxonomic and ecologi-cal significance of lichen chemistry and its pharmaceutical potentials, there has been no single piece of genetic evidence linking biosynthetic genes to lichen substances. Thus, we systematically analyzed lichen polyketide synthases (PKSs) for categorization and identification of the biosynthetic gene cluster (BGC) involved in depside/depsidone production. Our in-depth analysis of the interspecies PKS diversity in the genus Cladonia and a related Antarctic lichen, Stereocaulon alpinum, identified 45 BGC families, linking lichen PKSs to 15 previously characterized PKSs in nonlichenized fungi. Among these, we identified highly syntenic BGCs found exclusively in lichens producing atranorin (a depside). Heterologous expression of the putative atranorin PKS gene (coined atr1) yielded4-O-demethylbarbatic acid, found in many lichens as a precursor compound, indicating an intermolecular cross-linking activity of Atr1 for depside formation. Subsequent introductions of tailoring enzymes into the heterologous host yielded atranorin, one of the most common cortical substances of macrolichens. Phylogenetic analysis of fungal PKS revealed that the Atr1 is in a novel PKS clade that included two conserved lichen-specific PKS families likely involved in biosynthesis of depsides and depsidones. Here, we provide a comprehensive catalog of PKS families of the genus Cladonia and functionally characterize a biosynthetic gene cluster from lichens, establishing a cornerstone for studying the genetics and chemical evolution of diverse lichen substances.

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Kim, W., Liu, R., Woo, S., Kang, K. B., Park, H., Yu, Y. H., … Hur, J. S. (2021). Linking a gene cluster to atranorin, a major cortical substance of lichens, through genetic dereplication and heterologous expression. MBio, 12(3). https://doi.org/10.1128/mBio.01111-21

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