Baeyer–Villiger Oxidation of Acyl Carrier Protein-Tethered Thioester to Acyl Carrier Protein-Linked Thiocarbonate Catalyzed by a Monooxygenase Domain in FR901464 Biosynthesis
2016-02-19T20:22:56Z (GMT) by
Baeyer–Villiger monooxygenases (BVMOs), generally catalyzing the transformation of carbonylic compounds into the corresponding esters or lactones known as Baeyer–Villiger oxidation in organic chemistry, are widely distributed among microorganisms and have stimulated great interest as biocatalysts for organic synthesis. The physiological roles of this type of MOs are usually classified as degradation of organic compounds involved in primary metabolism. Recently, increasing numbers of BVMOs have been found to be involved in the biosynthesis of secondary metabolites, especially for postmodification; however, to date, none of them has been reported functionally as a tailoring domain within polyketide synthase (PKS) acting on carrier protein-tethered substrates. FR901464, an antitumor natural product that targets spliceosome and inhibits both splicing and nuclear retention of pre-mRNA, was elucidated to be biosynthesized by a hybrid acyltransferase-less PKS/nonribosomal peptide synthetase (NRPS) system. Within the hybrid system, an unprecedented domain that was proposed to mediate the chain release process was located in the termination module. In this paper, we report the in vitro biochemical characterization of this domain to be a BVMO tailoring domain that catalyzes the BV oxidation of an acyl carrier protein (ACP)-tethered thioester to an ACP-linked thiocarbonate, which represents the first example of BVMOs operating in cis within the PKS and NRPS biosynthetic paradigm.