A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Biosynthesis of Diverse Type II Polyketide Core Structures in Streptomyces coelicolor M1152
Tekijät: Zhu Xuechen, Siitonen Vilja, Melancon III Charles E, Metsä-Ketelä Mikko
Kustantaja: AMER CHEMICAL SOC
Julkaisuvuosi: 2021
Journal: ACS Synthetic Biology
Tietokannassa oleva lehden nimi: ACS SYNTHETIC BIOLOGY
Lehden akronyymi: ACS SYNTH BIOL
Vuosikerta: 10
Numero: 2
Aloitussivu: 243
Lopetussivu: 251
Sivujen määrä: 9
ISSN: 2161-5063
DOI: https://doi.org/10.1021/acssynbio.0c00482
Tiivistelmä
Synthetic biology-based approaches have been employed to generate advanced natural product (NP) pathway intermediates to overcome obstacles in NP drug discovery and production. Type II polyketides (PK-IIs) comprise a major subclass of NPs that provide attractive structures for antimicrobial and anticancer drug development. Herein, we have assembled five biosynthetic pathways using a generalized operon design strategy in Streptomyces coelicolor M1152 to allow comparative analysis of metabolite production in an improved heterologous host. The work resulted in production of four distinct PK-II core structures, namely benzoisochromanequinone, angucycline, tetracenomycin, and pentangular compounds, which serve as precursors to diverse pharmaceutically important NPs. Our bottom-up design strategy provided evidence that the biosynthetic pathway of BE-7585A proceeds via an angucycline core structure, instead of rearrangement of an anthracycline aglycone, and led to the discovery of a novel 26-carbon pentangular polyketide. The synthetic biology platform presented here provides an opportunity for further controlled production of diverse PK-IIs in a heterologous host.
Synthetic biology-based approaches have been employed to generate advanced natural product (NP) pathway intermediates to overcome obstacles in NP drug discovery and production. Type II polyketides (PK-IIs) comprise a major subclass of NPs that provide attractive structures for antimicrobial and anticancer drug development. Herein, we have assembled five biosynthetic pathways using a generalized operon design strategy in Streptomyces coelicolor M1152 to allow comparative analysis of metabolite production in an improved heterologous host. The work resulted in production of four distinct PK-II core structures, namely benzoisochromanequinone, angucycline, tetracenomycin, and pentangular compounds, which serve as precursors to diverse pharmaceutically important NPs. Our bottom-up design strategy provided evidence that the biosynthetic pathway of BE-7585A proceeds via an angucycline core structure, instead of rearrangement of an anthracycline aglycone, and led to the discovery of a novel 26-carbon pentangular polyketide. The synthetic biology platform presented here provides an opportunity for further controlled production of diverse PK-IIs in a heterologous host.
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