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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...

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Detalles Bibliográficos
Autores principales: Kapoor, Iti, Olivares, Philip, Nair, Satish K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
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.
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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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