Insights into Heterocycle Biosynthesis in the Cytotoxic Polyketide Alkaloid Janustatin A from a Plant-Associated Bacterium.
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| Format: | Artículo científico |
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Biochemistry
2025
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| author | Leopold-Messer, Stefan Chawengrum, Pornsuda Piel, Jörn |
| author_facet | Leopold-Messer, Stefan Chawengrum, Pornsuda Piel, Jörn Leopold-Messer, Stefan Chawengrum, Pornsuda Piel, Jörn |
| collection | PubMed - marine biology |
| 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. |
| format | Artículo científico |
| id | pubmed_39787262 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Biochemistry |
| record_format | pubmed |
| spellingShingle | 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 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. |
| title | Insights into Heterocycle Biosynthesis in the Cytotoxic Polyketide Alkaloid Janustatin A from a Plant-Associated Bacterium. |
| topic | Alkaloids Polyketides Polyketide Synthases Humans Structure-Activity Relationship Peptide Synthases Bacterial Proteins |
| url | https://pubmed.ncbi.nlm.nih.gov/39787262/ |