Back to Search Start Over

Analysis of Rhizonin Biosynthesis Reveals Origin of Pharmacophoric Furylalanine Moieties in Diverse Cyclopeptides.

Authors :
Ehinger FJ
Niehs SP
Dose B
Dell M
Krabbe J
Pidot SJ
Stinear TP
Scherlach K
Ross C
Lackner G
Hertweck C
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