Total Biosynthesis of Mutaxanthene Unveils a Flavoprotein Monooxygenase Catalyzing Xanthene Ring Formation

Abstract

Flavoprotein monooxygenases (FPMOs) play important roles in generating structural complexity and diversity in natural products biosynthesized by type II polyketide synthases (PKSs). In this study, we used genome mining to discover novel mutaxanthene analogues and investigated the biosynthesis of these aromatic polyketides and their unusual xanthene framework. We determined the complete biosynthetic pathway of mutaxathene through in vivo gene deletion and in vitro biochemical experiments. We show that a multifunctional FPMO, MtxO4, catalyzes ring rearrangement and generates the required xanthene ring through a multistep transformation. In addition, we successfully obtained all necessary enzymes for in vitro reconstitution and completed the total biosynthesis of mutaxanthene in a stepwise manner. Our results revealed the formation of a rare xanthene ring in type II polyketide biosynthesis, and demonstrate the potential of using total biosynthesis for the discovery of natural products synthesized by type II PKSs.

Tuning Benzylic C−H Functionalization of (Thio)xanthenes with Electrochemistry

“…Currently, significant progress has been achieved in the direct functionalization of benzylic C(sp 3 )−H bond with strategies of transition metal catalysis, photochemistry and electrochemistry, thus effectively enhancing the efficiency of organic molecules syntheses [5][6][7][8][9][10]. Notably, (thio)xanthenes containing unique benzylic C(sp 3 )−H bonds are synthetic intermediates and also have received increasing attention due to their broad applications in the fields of photodynamic therapy, pharmaceuticals and fluorescent materials, among others (Figure 1) [11][12][13][14][15]. Accordingly, a number of methods have been established for the direct benzylic C(sp 3 )−H functionalization of (thio)xanthenes [16][17][18][19][20][21][22][23][24][25][26][27][28][29].…”

Hot off the Press

“…Genome mining has led to the discovery of novel mutaxanthene analogues such as mutaxanthene G 20 and total biosynthesis by in vitro reconstitution of the 14 purified enzymes. 20 One of the enzymes characterised, a flavoprotein monooxygenase, MtxO4, was shown to generate the xanthene ring via a multistep process.…”