A1 Refereed original research article in a scientific journal
Three-Enzyme Cascade Catalyzes Conversion of Auramycinone to Resomycin in Chartreusin Biosynthesis
Authors: Niemczura, Magdalena; Nuutila, Aleksi; Wang, Rongbin; Rauhanen, Katariina; Nybo, S. Eric; Metsä-Ketelä, Mikko
Publisher: American Chemical Society (ACS)
Publishing place: WASHINGTON
Publication year: 2025
Journal: ACS Chemical Biology
Journal name in source: ACS Chemical Biology
Journal acronym: ACS CHEM BIOL
Volume: 20
Issue: 7
First page : 1457
Last page: 1463
Number of pages: 7
ISSN: 1554-8929
eISSN: 1554-8937
DOI: https://doi.org/10.1021/acschembio.5c00205
Web address : https://doi.org/10.1021/acschembio.5c00205
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/499245790
Chartreusin is a potent antiproliferative agent that contains a unique aromatic pentacyclic bislactone carbon scaffold. The biosynthesis of type II polyketide aglycone has been extensively investigated and shown to proceed through a tetracyclic anthracycline intermediate. The last remaining unknown steps are the conversion of auramycinone to resomycin C. Here we have discovered three enzymes that play crucial roles in two mechanistically distinct dehydration reactions. We show that ChaX is an NAD(P)H-dependent auramycinone quinone reductase that allows the cyclase-like ChaU to catalyze the formation of 9,10-dehydroauramycinone via a carbanion intermediate. In contrast, the cyclase-like ChaJ, homologous to ChaU, is responsible for subsequent 7,8-dehydration via a canonical carbocation intermediate, yielding resomycin C. The results were confirmed via assembly of the biosynthetic pathway for production of resomycin C in Streptomyces coelicolor M1152 Delta matAB. The work expands the catalytic repertoire of the SnoaL protein family, which has previously been associated with anthracycline fourth-ring cyclization and two-component 1-hydroxylation.
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Funding information in the publication:
The authors would like to acknowledge funding from the Academy of Finland (Grant Nos. 340013 and 354998 to M.M.- K.), the National Science Foundation (Grant Nos. ENG-2015951, ENG-2321976, and CHE-2348596 to S.E.N.) and the Turku University Foundation (to M.N.).
