Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold
Abstract Nearly 10,000 plant species are represented by RNA-seq datasets in the NCBI sequence read archive, which are difficult to search in unassembled format due to database size. Here, we optimize RNA-seq assembly to transform most of this public RNA-seq data to a searchable database for biosynth...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59428-4 |
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| author | Xiaofeng Wang Khadija Shafiq Derrick A. Ousley Desnor N. Chigumba Dulciana Davis Kali M. McDonough Lisa S. Mydy Jonathan Z. Sexton Roland D. Kersten |
| author_facet | Xiaofeng Wang Khadija Shafiq Derrick A. Ousley Desnor N. Chigumba Dulciana Davis Kali M. McDonough Lisa S. Mydy Jonathan Z. Sexton Roland D. Kersten |
| author_sort | Xiaofeng Wang |
| collection | DOAJ |
| description | Abstract Nearly 10,000 plant species are represented by RNA-seq datasets in the NCBI sequence read archive, which are difficult to search in unassembled format due to database size. Here, we optimize RNA-seq assembly to transform most of this public RNA-seq data to a searchable database for biosynthetic gene discovery. We test our transcriptome mining pipeline towards the diversification of moroidins, which are plant ribosomally-synthesized and posttranslationally-modified peptides (RiPPs) biosynthesized from copper-dependent peptide cyclases. Moroidins are bicyclic compounds with a conserved stephanotic acid scaffold, which becomes cytotoxic to non-small cell lung adenocarcinoma cells with an additional C-terminal macrocycle. We discover moroidin analogs with second ring structures diversified at the crosslink and the non-crosslinked residues including a moroidin analog from water chickweed, which exhibits higher cytotoxicity against lung adenocarcinoma cells than moroidin. Our study expands stephanotic acid-type peptides to grasses, Lowiaceae, mints, pinks, and spurges while demonstrating that large-scale transcriptome mining can broaden the medicinal chemistry toolbox for chemical and biological exploration of eukaryotic RiPP lead structures. |
| format | Article |
| id | doaj-art-edb976804d364e47b9e37b5f7c49bd40 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-edb976804d364e47b9e37b5f7c49bd402025-08-20T02:15:11ZengNature PortfolioNature Communications2041-17232025-05-0116111810.1038/s41467-025-59428-4Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffoldXiaofeng Wang0Khadija Shafiq1Derrick A. Ousley2Desnor N. Chigumba3Dulciana Davis4Kali M. McDonough5Lisa S. Mydy6Jonathan Z. Sexton7Roland D. Kersten8Department of Medicinal Chemistry, University of MichiganDepartment of Medicinal Chemistry, University of MichiganDepartment of Medicinal Chemistry, University of MichiganDepartment of Medicinal Chemistry, University of MichiganDepartment of Medicinal Chemistry, University of MichiganDepartment of Medicinal Chemistry, University of MichiganDepartment of Medicinal Chemistry, University of MichiganDepartment of Medicinal Chemistry, University of MichiganDepartment of Medicinal Chemistry, University of MichiganAbstract Nearly 10,000 plant species are represented by RNA-seq datasets in the NCBI sequence read archive, which are difficult to search in unassembled format due to database size. Here, we optimize RNA-seq assembly to transform most of this public RNA-seq data to a searchable database for biosynthetic gene discovery. We test our transcriptome mining pipeline towards the diversification of moroidins, which are plant ribosomally-synthesized and posttranslationally-modified peptides (RiPPs) biosynthesized from copper-dependent peptide cyclases. Moroidins are bicyclic compounds with a conserved stephanotic acid scaffold, which becomes cytotoxic to non-small cell lung adenocarcinoma cells with an additional C-terminal macrocycle. We discover moroidin analogs with second ring structures diversified at the crosslink and the non-crosslinked residues including a moroidin analog from water chickweed, which exhibits higher cytotoxicity against lung adenocarcinoma cells than moroidin. Our study expands stephanotic acid-type peptides to grasses, Lowiaceae, mints, pinks, and spurges while demonstrating that large-scale transcriptome mining can broaden the medicinal chemistry toolbox for chemical and biological exploration of eukaryotic RiPP lead structures.https://doi.org/10.1038/s41467-025-59428-4 |
| spellingShingle | Xiaofeng Wang Khadija Shafiq Derrick A. Ousley Desnor N. Chigumba Dulciana Davis Kali M. McDonough Lisa S. Mydy Jonathan Z. Sexton Roland D. Kersten Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold Nature Communications |
| title | Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold |
| title_full | Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold |
| title_fullStr | Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold |
| title_full_unstemmed | Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold |
| title_short | Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold |
| title_sort | large scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold |
| url | https://doi.org/10.1038/s41467-025-59428-4 |
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