Abstract
Bacteria produce a large number of secondary metabolites with extraordinary chemical structures and bioactivities. Vioprolides are promising anticancer and antifungal lead compounds produced by the myxobacterium Cystobacter violaceus Cb vi35, which are initially synthesized as acylated precursors (previoprolides) by nonribosomal peptide synthetases (NRPS). Here, we describe and characterize an unprecedented glycerate esterification process in the biosynthesis of vioprolides. In vitro biochemical investigations revealed that the fatty acyl chain of previoprolides is adenylated by the starting fatty acyl-AMP ligase (FAAL) domain, while the glycerate moiety is incorporated by the FkbH domain. An unusual ester-bond forming condensation domain is shown responsible for the acylation of glycerate. LC-MS analysis and bioactivity assays suggest that the acylation serves for directed membrane transport rather than representing a prodrug mechanism.
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