Abstract
AbstractThe 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.
Highlights
Actinobacteria produce a wide range of bioactive aromatic polyketides, as exemplified by the members of the rubromycin family that feature a characteristic bisbenzannulated [5,6]-spiroketal pharmacophore,[1,2,3] e.g., b-rubromycin (1) and griseorhodin A (2)
Angewandte Chemie International Edition published by Wiley-VCH GmbH Angew
We characterized two functional homologs of the key tailoring enzyme involved in the biosynthesis of bacterial rubromycin-type polyketides, which mediate a drastic oxidative rearrangement of the pentangular precursor 3 to an intermediate [6,6]-spiroketal moiety en route to the mature natural products
Summary
Angewandte Chemie International Edition published by Wiley-VCH GmbH. Orthohydroxylation of phenolic ring E triggers two ring-cleaving retro-aldol condensations, carbonyl hydration and several tautomerizations in addition to a putative two-electron oxidation step that eventually re-install rings C and D in the form of the [6,6]-spiroketal (Figure 1).[6] The functional homolog RubL from rubromycin biosynthesis was shown to catalyze the same reaction sequence, pointing toward a universal strategy for spiroketal formation in the rubromycin family. The spiroketal synthases were mechanistically and structurally investigated to understand how they orchestrate and control the distinct redox reactions and backbone rearrangements
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