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Production of novel pladienolide analogues through native expression of a pathway-specific activator
- Source :
- Chemical Science
- Publication Year :
- 2021
-
Abstract
- Aberrant splicing of pre-mRNA is implicated in many human genetic disorders. Small molecules that target the spliceosome are important leads as therapeutics and research tools, and one compound of significant interest is the polyketide natural product pladienolide B. Here, we describe the reactivation of quiescent pladienolide B production in the domesticated lab strain Streptomyces platensis AS6200 by overexpression of the pathway-specific activator PldR. The resulting dysregulation of the biosynthetic genes led to the accumulation and isolation of five additional intermediate or shunt metabolites of pladienolide B biosynthesis, including three previously unreported congeners. These compounds likely comprise the entire pladienolide biosynthetic pathway and demonstrate the link between polyketide tailoring reactions and bioactivity, particularly the importance of the 18,19-epoxide. Each congener demonstrated specific inhibitory activity against mammalian cell lines, with successive modifications leading to increased activity (IC50: 8 mM to 5 μM).<br />Reactivation of quiescent polyketide production in a domesticated lab strain.
- Subjects :
- 0106 biological sciences
0303 health sciences
Spliceosome
Natural product
Activator (genetics)
Chemistry
General Chemistry
01 natural sciences
Small molecule
03 medical and health sciences
Polyketide
chemistry.chemical_compound
Biochemistry
Biosynthesis
010608 biotechnology
IC50
030304 developmental biology
Biosynthetic genes
Subjects
Details
- ISSN :
- 20416520
- Volume :
- 11
- Issue :
- 31
- Database :
- OpenAIRE
- Journal :
- Chemical science
- Accession number :
- edsair.doi.dedup.....25df87e5a3ca4ed286eff30f0b8dde8a