Biosynthesis of the bacterial antibiotic 3,7-dihydroxytropolone through enzymatic salvaging of catabolic shunt products

The non-benzenoid aromatic tropone ring is a structural motif of numerous microbial and plant natural products with potent bioactivities. In bacteria, tropone biosynthesis involves early steps of the widespread CoA-dependent phenylacetic acid (paa) catabolon, from which a shunt product is sequestere...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2024-05, Vol.15 (2), p.7749-7756
Main Authors: Höing, Lars, Sowa, Sven T, Toplak, Marina, Reinhardt, Jakob K, Jakob, Roman, Maier, Timm, Lill, Markus A, Teufel, Robin
Format: Article
Language:English
Subjects:
Antibiotics
Bacteria
Biosynthesis
Chemistry
Decarboxylation
Enzymes
Hydroxylation
Microorganisms
Natural products
Oxidation
Phenylacetic acid
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Summary:The non-benzenoid aromatic tropone ring is a structural motif of numerous microbial and plant natural products with potent bioactivities. In bacteria, tropone biosynthesis involves early steps of the widespread CoA-dependent phenylacetic acid (paa) catabolon, from which a shunt product is sequestered and surprisingly further utilized as a universal precursor for structurally and functionally diverse tropone derivatives such as tropodithietic acid or (hydroxy)tropolones. Here, we elucidate the biosynthesis of the antibiotic 3,7-dihydroxytropolone in Actinobacteria by in vitro pathway reconstitution using paa catabolic enzymes as well as dedicated downstream tailoring enzymes, including a thioesterase (TrlF) and two flavoprotein monooxygenases (TrlCD and TrlE). We furthermore mechanistically and structurally characterize the multifunctional key enzyme TrlE, which mediates an unanticipated ipso -substitution involving a hydroxylation and subsequent decarboxylation of the CoA-freed side chain, followed by ring oxidation to afford tropolone. This study showcases a remarkably efficient strategy for 3,7-dihydroxytropolone biosynthesis and illuminates the functions of the involved biosynthetic enzymes. The biosynthesis of the bacterial antibiotic dihydroxytropolone was reconstituted in vitro starting from a catabolic shunt product. The involved key flavoprotein monooxygenase TrlE was further structurally and mechanistically characterized.
ISSN:2041-6520
2041-6539
DOI:10.1039/d4sc01715c