Enzymatic spiroketal formation via oxidative rearrangement of pentangular polyketides

Britta Frensch, Thorsten Lechtenberg, Michel Kather, Zeynep Yunt, Martin Betschart, Bernd Kammerer, Steffen Lüdeke, Michael Müller, Jörn Piel and Robin Teufel ()
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Britta Frensch: University of Freiburg
Thorsten Lechtenberg: University of Freiburg
Michel Kather: University of Freiburg
Zeynep Yunt: Koç University
Martin Betschart: University of Freiburg
Bernd Kammerer: University of Freiburg
Steffen Lüdeke: University of Freiburg
Michael Müller: University of Freiburg
Jörn Piel: Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zürich
Robin Teufel: University of Freiburg

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract The structural complexity and bioactivity of natural products often depend on enzymatic redox tailoring steps. This is exemplified by the generation of the bisbenzannulated [5,6]-spiroketal pharmacophore in the bacterial rubromycin family of aromatic polyketides, which exhibit a wide array of bioactivities such as the inhibition of HIV reverse transcriptase or DNA helicase. Here we elucidate the complex flavoenzyme-driven formation of the rubromycin pharmacophore that is markedly distinct from conventional (bio)synthetic strategies for spiroketal formation. Accordingly, a polycyclic aromatic precursor undergoes extensive enzymatic oxidative rearrangement catalyzed by two flavoprotein monooxygenases and a flavoprotein oxidase that ultimately results in a drastic distortion of the carbon skeleton. The one-pot in vitro reconstitution of the key enzymatic steps as well as the comprehensive characterization of reactive intermediates allow to unravel the intricate underlying reactions, during which four carbon-carbon bonds are broken and two CO2 become eliminated. This work provides detailed insight into perplexing redox tailoring enzymology that sets the stage for the (chemo)enzymatic production and bioengineering of bioactive spiroketal-containing polyketides.

Date: 2021
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DOI: 10.1038/s41467-021-21432-9

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