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Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones
Diffusible small molecule microbial hormones drastically alter the expression profiles of antibiotics and other drugs in actinobacteria. For example, avenolide (a butenolide) regulates the production of avermectin, derivatives of which are used in the treatment of river blindness and other parasitic...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347384/ https://www.ncbi.nlm.nih.gov/pubmed/32510324 http://dx.doi.org/10.7554/eLife.57824 |
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author | Kapoor, Iti Olivares, Philip Nair, Satish K |
author_facet | Kapoor, Iti Olivares, Philip Nair, Satish K |
author_sort | Kapoor, Iti |
collection | PubMed |
description | Diffusible small molecule microbial hormones drastically alter the expression profiles of antibiotics and other drugs in actinobacteria. For example, avenolide (a butenolide) regulates the production of avermectin, derivatives of which are used in the treatment of river blindness and other parasitic diseases. Butenolides and γ-butyrolactones control the production of pharmaceutically important secondary metabolites by binding to TetR family transcriptional repressors. Here, we describe a concise, 22-step synthetic strategy for the production of avenolide. We present crystal structures of the butenolide receptor AvaR1 in isolation and in complex with avenolide, as well as those of AvaR1 bound to an oligonucleotide derived from its operator. Biochemical studies guided by the co-crystal structures enable the identification of 90 new actinobacteria that may be regulated by butenolides, two of which are experimentally verified. These studies provide a foundation for understanding the regulation of microbial secondary metabolite production, which may be exploited for the discovery and production of novel medicines. |
format | Online Article Text |
id | pubmed-7347384 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-73473842020-07-13 Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones Kapoor, Iti Olivares, Philip Nair, Satish K eLife Biochemistry and Chemical Biology Diffusible small molecule microbial hormones drastically alter the expression profiles of antibiotics and other drugs in actinobacteria. For example, avenolide (a butenolide) regulates the production of avermectin, derivatives of which are used in the treatment of river blindness and other parasitic diseases. Butenolides and γ-butyrolactones control the production of pharmaceutically important secondary metabolites by binding to TetR family transcriptional repressors. Here, we describe a concise, 22-step synthetic strategy for the production of avenolide. We present crystal structures of the butenolide receptor AvaR1 in isolation and in complex with avenolide, as well as those of AvaR1 bound to an oligonucleotide derived from its operator. Biochemical studies guided by the co-crystal structures enable the identification of 90 new actinobacteria that may be regulated by butenolides, two of which are experimentally verified. These studies provide a foundation for understanding the regulation of microbial secondary metabolite production, which may be exploited for the discovery and production of novel medicines. eLife Sciences Publications, Ltd 2020-06-08 /pmc/articles/PMC7347384/ /pubmed/32510324 http://dx.doi.org/10.7554/eLife.57824 Text en © 2020, Kapoor et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Kapoor, Iti Olivares, Philip Nair, Satish K Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones |
title | Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones |
title_full | Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones |
title_fullStr | Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones |
title_full_unstemmed | Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones |
title_short | Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones |
title_sort | biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347384/ https://www.ncbi.nlm.nih.gov/pubmed/32510324 http://dx.doi.org/10.7554/eLife.57824 |
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