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Analysis of Rhizonin Biosynthesis Reveals Origin of Pharmacophoric Furylalanine Moieties in Diverse Cyclopeptides.
- Source :
-
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2023 Oct 16; Vol. 62 (42), pp. e202308540. Date of Electronic Publication: 2023 Sep 13. - Publication Year :
- 2023
-
Abstract
- Rhizonin A and B are hepatotoxic cyclopeptides produced by bacterial endosymbionts (Mycetohabitans endofungorum) of the fungus Rhizopus microsporus. Their toxicity critically depends on the presence of 3-furylalanine (Fua) residues, which also occur in pharmaceutically relevant cyclopeptides of the endolide and bingchamide families. The biosynthesis and incorporation of Fua by non-ribosomal peptide synthetases (NRPS), however, has remained elusive. By genome sequencing and gene inactivation we elucidated the gene cluster responsible for rhizonin biosynthesis. A suite of isotope labeling experiments identified tyrosine and l-DOPA as Fua precursors and provided the first mechanistic insight. Bioinformatics, mutational analysis and heterologous reconstitution identified dioxygenase RhzB as necessary and sufficient for Fua formation. RhzB is a novel type of heme-dependent aromatic oxygenases (HDAO) that enabled the discovery of the bingchamide biosynthesis gene cluster through genome mining.<br /> (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Details
- Language :
- English
- ISSN :
- 1521-3773
- Volume :
- 62
- Issue :
- 42
- Database :
- MEDLINE
- Journal :
- Angewandte Chemie (International ed. in English)
- Publication Type :
- Academic Journal
- Accession number :
- 37650335
- Full Text :
- https://doi.org/10.1002/anie.202308540