Genome Mining of Oxidation Modules in trans‐Acyltransferase Polyketide Synthases Reveals a Culturable Source for Lobatamides. (19th March 2020)

• Record Type: Journal Article
• Authors: Ueoka, Reiko; Meoded, Roy A.; Gran‐Scheuch, Alejandro; Bhushan, Agneya; Fraaije, Marco W.; Piel, Jörn
• Is Part Of: Angewandte Chemie. Volume 132:Number 20(2020)
• Page Start: 7835
• Page End: 7839
• Publication Date: 2020-03-19
• Subjects: Bakterielle Naturstoffe -- Biosynthese -- Marine Naturstoffe -- Polyketide; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201916005
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Bacterial trans ‐acyltransferase polyketide synthases ( trans ‐AT PKSs) are multimodular megaenzymes that biosynthesize many bioactive natural products. They contain a remarkable range of domains and module types that introduce different substituents into growing polyketide chains. As one such modification, we recently reported Baeyer–Villiger‐type oxygen insertion into nascent polyketide backbones, thereby generating malonyl thioester intermediates. In this work, genome mining focusing on architecturally diverse oxidation modules in trans ‐AT PKSs led us to the culturable plant symbiont Gynuella sunshinyii, which harbors two distinct modules in one orphan PKS. The PKS product was revealed to be lobatamide A, a potent cytotoxin previously only known from a marine tunicate. Biochemical studies show that one module generates glycolyl thioester intermediates, while the other is proposed to be involved in oxime formation. The data suggest varied roles of oxygenation modules in the biosynthesis of polyketide scaffolds and support the importance of trans ‐AT PKSs in the specialized metabolism of symbiotic bacteria. Abstract : Im klassischen Modell der modularen Polyketid‐Synthasen (PKSs) erzeugt ein kleiner Satz von Reaktionen kombinatorisch substituierte Kohlenstoffketten. Architektonisch vielfältige PKS‐Module wurden identifiziert, die Polyketide durch Oxygenierung diversifizieren. Eine Orphan‐PKS mit zwei Oxygenase‐Modulen aus einem Pflanzensymbionten produziert Lobatamide, die in der Kette oxygenierte, oximhaltige Zytotoxine sind und bisher nur aus einem Manteltier bekannt waren.