Mapping the biosynthetic pathway of a hybrid polyketide-nonribosomal peptide in a metazoan
Polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) hybrid systems typically use complex protein-protein interactions to facilitate direct transfer of intermediates between these multimodular megaenzymes. In the canal-associated neurons (CANs) of Caenorhabditis elegans , PKS-1 and N...
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Veröffentlicht in: | Nature communications 2021-08, Vol.12 (1), p.4912-4912, Article 4912 |
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Sprache: | eng |
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Zusammenfassung: | Polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) hybrid systems typically use complex protein-protein interactions to facilitate direct transfer of intermediates between these multimodular megaenzymes. In the canal-associated neurons (CANs) of
Caenorhabditis elegans
, PKS-1 and NRPS-1 produce the nemamides, the only known hybrid polyketide-nonribosomal peptides biosynthesized by animals, through a poorly understood mechanism. Here, we use genome editing and mass spectrometry to map the roles of individual PKS-1 and NRPS-1 enzymatic domains in nemamide biosynthesis. Furthermore, we show that nemamide biosynthesis requires at least five additional enzymes expressed in the CANs that are encoded by genes distributed across the worm genome. We identify the roles of these enzymes and discover a mechanism for trafficking intermediates between a PKS and an NRPS. Specifically, the enzyme PKAL-1 activates an advanced polyketide intermediate as an adenylate and directly loads it onto a carrier protein in NRPS-1. This trafficking mechanism provides a means by which a PKS-NRPS system can expand its biosynthetic potential and is likely important for the regulation of nemamide biosynthesis.
The only known animal polyketide-nonribosomal peptides, the nemamides, are biosynthesized by two megasynthetases in the canal-associated neurons (CANs) of
C. elegans
. Here, the authors map the biosynthetic roles of individual megasynthetase domains and identify additional enzymes in the CANs required for nemamide biosynthesis. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-021-24682-9 |