A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Diverse Combinatorial Biosynthesis Strategies for C-H Functionalization of Anthracyclinones
Tekijät: Wang Rongbin, Nji Wandi Benjamin, Schwartz Nora, Hecht Jacob, Ponomareva Larissa, Paige Kendall, West Alexis, Desanti Kathryn, Nguyen Jennifer, Niemi Jarmo, Thorson Jon S., Shaaban Khaled A., Metsä-Ketelä Mikko, Nybo S. Eric
Kustantaja: American Chemical Society
Julkaisuvuosi: 2024
Journal: ACS Synthetic Biology
Tietokannassa oleva lehden nimi: ACS synthetic biology
Lehden akronyymi: ACS Synth Biol
Vuosikerta: 13
Numero: 5
Aloitussivu: 1523
Lopetussivu: 1536
ISSN: 2161-5063
eISSN: 2161-5063
DOI: https://doi.org/10.1021/acssynbio.4c00043
Verkko-osoite: https://pubs.acs.org/doi/full/10.1021/acssynbio.4c00043
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/393412598
Streptomyces spp. are "nature's antibiotic factories" that produce valuable bioactive metabolites, such as the cytotoxic anthracycline polyketides. While the anthracyclines have hundreds of natural and chemically synthesized analogues, much of the chemical diversity stems from enzymatic modifications to the saccharide chains and, to a lesser extent, from alterations to the core scaffold. Previous work has resulted in the generation of a BioBricks synthetic biology toolbox in Streptomyces coelicolor M1152ΔmatAB that could produce aklavinone, 9-epi-aklavinone, auramycinone, and nogalamycinone. In this work, we extended the platform to generate oxidatively modified analogues via two crucial strategies. (i) We swapped the ketoreductase and first-ring cyclase enzymes for the aromatase cyclase from the mithramycin biosynthetic pathway in our polyketide synthase (PKS) cassettes to generate 2-hydroxylated analogues. (ii) Next, we engineered several multioxygenase cassettes to catalyze 11-hydroxylation, 1-hydroxylation, 10-hydroxylation, 10-decarboxylation, and 4-hydroxyl regioisomerization. We also developed improved plasmid vectors and S. coelicolor M1152ΔmatAB expression hosts to produce anthracyclinones. This work sets the stage for the combinatorial biosynthesis of bespoke anthracyclines using recombinant Streptomyces spp. hosts.
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Research reported in this publication was supported by the National Science Foundation under grant nos. ENG-2015951 and ENG-2321976 (S.E.N.), by the National Cancer Institute of the National Institutes of Health under Award No. R15CA252830 (S.E.N.), by National Institutes of Health grant R37 AI052218 (J.S.T.), the Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology (CTCB, NIH P20 GM130456), the National Institute of Food and Agriculture (USDA-NIFA-CBGP, Grant No. 2023-38821-39584), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, and the National Center for Advancing Translational Sciences (UL1TR000117 and UL1TR001998). This work was supported by the Research Council of Finland (grants 340013 and 354998 to M.M.-K.) The authors also thank the College of Pharmacy PharmNMR Center for analytical support. NMR data was acquired on a Bruker AVANCE NEO 400 MHz NMR spectrometer funded or a Bruker AVANCE NEO 600 MHz high-performance digital
