Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides
| العنوان: | Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides |
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| المؤلفون: | Chad M. Rienstra, Martin D. Burke, Douglas A. Mitchell, Justin D Lange, Emily Xiao, Xinyi Li, Xiaorui Guo, Jiabao Zhang |
| المصدر: | ACS Central Science, Vol 7, Iss 5, Pp 781-791 (2021) ACS Central Science |
| بيانات النشر: | American Chemical Society, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Ergosterol, biology, 010405 organic chemistry, Mechanism (biology), General Chemical Engineering, General Chemistry, 010402 general chemistry, Polyene, biology.organism_classification, 01 natural sciences, Sterol, 0104 chemical sciences, chemistry.chemical_compound, Sponge, Chemistry, chemistry, Biochemistry, Gene, QD1-999, Research Article |
| الوصف: | Amphotericin-like glycosylated polyene macrolides (GPMs) are a clinically and industrially important family of natural products, but the mechanisms by which they exert their extraordinary biological activities have remained unclear for more than half a century. Amphotericin B exerts fungicidal action primarily via self-assembly into an extramembranous sponge that rapidly extracts ergosterol from fungal membranes, but it has remained unclear whether this mechanism is applicable to other GPMs. Using a highly conserved polyene–hemiketal region of GPMs that we hypothesized to represent a conserved ergosterol-binding domain, we bioinformatically mapped the entirety of the GPM sequence-function space and expanded the number of GPM biosynthetic gene clusters (BGCs) by 10-fold. We further leveraged bioinformatic predictions and tetrazine-based reactivity screening targeting the electron-rich polyene region of GPMs to discover a first-in-class methyltetraene- and diepoxide-containing GPM, kineosporicin, and to assign BGCs to many new producers of previously reported members. Leveraging a range of structurally diverse known and newly discovered GPMs, we found that the sterol sponge mechanism of fungicidal action is conserved. A combination of genome-mining and chemical reactivity identified new antifungal natural products. Such glycosylated polyene macrolides share a common mode of action via ergosterol extraction. |
| اللغة: | English |
| تدمد: | 2374-7951 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6441d2808d2e6e2bf7c36a0fe6023ad https://doaj.org/article/cc2034a38a7147c28f93ebf292553ff7 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e6441d2808d2e6e2bf7c36a0fe6023ad |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 23747951 |
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