Resistance Gene-Guided Genome Mining Reveals RPL10 as the Target of Ligustrone A
Danielle A Yee1, Ross D Overacker1, Michelle F Grau1
1Hexagon Bio, Menlo Park, California 94025, United States.
Journal of the American Chemical Society
|June 16, 2025
Summary
Researchers discovered a new natural product, ligustrone A, by mining a gene cluster. This compound targets human ribosomal protein RPL10, offering potential for new therapies.
Area of Science:
- Natural Product Drug Discovery
- Molecular Biology
- Chemical Biology
Background:
- The ribosome is crucial for protein synthesis and a target for drug development.
- Resistance gene-guided genome mining enables early identification of natural product compound targets.
Purpose of the Study:
- To identify the product of the novel 'lig' biosynthetic gene cluster (BGC).
- To validate ligustrone A as a compound that engages human ribosomal protein RPL10.
- To elucidate the biosynthesis of ligustrone A.
Main Methods:
- Resistance gene-guided genome mining to identify the 'lig' BGC.
- Heterologous expression and in situ BGC engineering to determine the BGC product.
- Chemical genetics and chemoproteomics to validate target engagement.
Main Results:
- The 'lig' BGC was identified, containing a resistance gene homologous to human ribosomal protein RPL10.
- Ligustrone A (1) was identified as the product of the 'lig' BGC.
- Ligustrone A was confirmed to engage human ribosomal protein RPL10.
Conclusions:
- Resistance gene-guided mining successfully identified a novel natural product and its target.
- Ligustrone A is a natural product that targets human ribosomal protein RPL10.
- The biosynthesis of ligustrone A was elucidated.
