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| Main Authors: | , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Biochemistry
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/39787262/ |
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Table of Contents:
- Insights into Heterocycle Biosynthesis in the Cytotoxic Polyketide Alkaloid Janustatin A from a Plant-Associated Bacterium. Leopold-Messer, Stefan Chawengrum, Pornsuda Piel, Jörn Alkaloids Polyketides Polyketide Synthases Humans Structure-Activity Relationship Peptide Synthases Bacterial Proteins Janustatin A is a potently cytotoxic polyketide alkaloid produced at trace amounts by the marine bacterial plant symbiont . Its biosynthetic terminus features an unusual pyridine-containing bicyclic system of unclear origin, in which polyketide and amino acid extension units appear reversed compared to the order of enzymatic modules in the polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) assembly line. To elucidate unknown steps in heterocycle formation, we first established robust genome engineering tools in . . A combination of gene deletion, complementation, production improvement, and NMR experiments then demonstrated that two desaturase homologues, JanA and JanB, are involved in hydroxylation and pyridine formation by desaturation, respectively. Structure-activity relationship studies showed that these modifications substantially increase the cytotoxicity and that the fully functionalized heterocyclic system is crucial for sub-nanomolar cytotoxicity. Isolation of the early post-PKS intermediate janustatin D with an already reversed heterocycle topology supports a noncanonical rearrangement process occurring on the PKS-NRPS assembly line.