Catalytic Control of Spiroketal Formation in Rubromycin Polyketide Biosynthesis

Abstract

The medically important bacterial aromatic polyketide natural products typically feature a planar, polycyclic core structure. An exception is found for the rubromycins, whose backbones are disrupted by a bisbenzannulated [5,6]‐spiroketal pharmacophore that was recently shown to be assembled by flavin‐dependent enzymes. In particular, a flavoprotein monooxygenase proved critical for the drastic oxidative rearrangement of a pentangular precursor and the installment of an intermediate [6,6]‐spiroketal moiety. Here we provide structural and mechanistic insights into the control of catalysis by this spiroketal synthase, which fulfills several important functions as reductase, monooxygenase, and presumably oxidase. The enzyme hereby tightly controls the redox state of the substrate to counteract shunt product formation, while also steering the cleavage of three carbon‐carbon bonds. Our work illustrates an exceptional strategy for the biosynthesis of stable chroman spiroketals.

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

“…Examples include EncM, which catalyzes a Favorskii‐type rearrangement via a cyclopropanone intermediate to afford a rearranged skeleton in enterocin biosynthesis; [10] RslO9, which can mediate a tandem sequence of Baeyer–Villiger oxidation and aldol condensation and ultimately gives rise to structurally distinct rishirilide; [11] AlpJ, which is able to contract a 6/6/6/6‐ring to a unique 6/6/5/6‐ring in kinamycin biosynthesis [12, 13] . In addition, FlsO1 can convert prejadomycin to xanthone‐containing products through a tandem of oxidations such as hydroxylation, epoxidation and Baeyer–Villiger oxidation; [14] and GrhO5 is a multifunctional FPMO that oxidatively rearranges the carbon skeleton to a unique [5,6]‐spiroketal moiety in the biosynthesis of griseorhodin A [15, 16] . MrqO6 can convert the linear tricyclic‐ring system into the angular framework in murayaquinone biosynthesis [17] (Figure 1).…”