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SspH, a Novel HATPase Family Regulator, Controls Antibiotic Biosynthesis in Streptomyces

Streptomyces can produce a wealth of pharmaceutically valuable antibiotics and other bioactive compounds. Production of most antibiotics is generally low due to the rigorously controlled regulatory networks, in which global/pleiotropic and cluster-situated regulatory proteins coordinate with various...

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Autores principales: Yang, Xue, Zhang, Yanyan, Li, Shanshan, Ye, Lan, Wang, Xiangjing, Xiang, Wensheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137472/
https://www.ncbi.nlm.nih.gov/pubmed/35625182
http://dx.doi.org/10.3390/antibiotics11050538
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author Yang, Xue
Zhang, Yanyan
Li, Shanshan
Ye, Lan
Wang, Xiangjing
Xiang, Wensheng
author_facet Yang, Xue
Zhang, Yanyan
Li, Shanshan
Ye, Lan
Wang, Xiangjing
Xiang, Wensheng
author_sort Yang, Xue
collection PubMed
description Streptomyces can produce a wealth of pharmaceutically valuable antibiotics and other bioactive compounds. Production of most antibiotics is generally low due to the rigorously controlled regulatory networks, in which global/pleiotropic and cluster-situated regulatory proteins coordinate with various intra- and extracellular signals. Thus, mining new antibiotic regulatory proteins, particularly the ones that are widespread, is essential for understanding the regulation of antibiotic biosynthesis. Here, in the biopesticide milbemycin producing strain Streptomyces bingchenggensis, a novel global/pleiotropic regulatory protein, SspH, a single domain protein containing only the HATPase domain, was identified as being involved in controlling antibiotic biosynthesis. The sspH overexpression inhibited milbemycin production by repressing the expression of milbemycin biosynthetic genes. The sspH overexpression also differentially influenced the expression of various antibiotic biosynthetic core genes. Site-directed mutagenesis revealed that the HATPase domain was essential for SspH’s function, and mutation of the conserved amino acid residues N54A and D84A led to the loss of SspH function. Moreover, cross-overexpression experiments showed that SspH and its orthologs, SCO1241 from Streptomyces coelicolor and SAVERM_07097 from Streptomyces avermitilis, shared identical functionality, and all exerted a positive effect on actinorhodin production but a negative effect on avermectin production, indicating that SspH-mediated differential control of antibiotic biosynthesis may be widespread in Streptomyces. This study extended our understanding of the regulatory network of antibiotic biosynthesis and provided effective targets for future antibiotic discovery and overproduction.
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spelling pubmed-91374722022-05-28 SspH, a Novel HATPase Family Regulator, Controls Antibiotic Biosynthesis in Streptomyces Yang, Xue Zhang, Yanyan Li, Shanshan Ye, Lan Wang, Xiangjing Xiang, Wensheng Antibiotics (Basel) Article Streptomyces can produce a wealth of pharmaceutically valuable antibiotics and other bioactive compounds. Production of most antibiotics is generally low due to the rigorously controlled regulatory networks, in which global/pleiotropic and cluster-situated regulatory proteins coordinate with various intra- and extracellular signals. Thus, mining new antibiotic regulatory proteins, particularly the ones that are widespread, is essential for understanding the regulation of antibiotic biosynthesis. Here, in the biopesticide milbemycin producing strain Streptomyces bingchenggensis, a novel global/pleiotropic regulatory protein, SspH, a single domain protein containing only the HATPase domain, was identified as being involved in controlling antibiotic biosynthesis. The sspH overexpression inhibited milbemycin production by repressing the expression of milbemycin biosynthetic genes. The sspH overexpression also differentially influenced the expression of various antibiotic biosynthetic core genes. Site-directed mutagenesis revealed that the HATPase domain was essential for SspH’s function, and mutation of the conserved amino acid residues N54A and D84A led to the loss of SspH function. Moreover, cross-overexpression experiments showed that SspH and its orthologs, SCO1241 from Streptomyces coelicolor and SAVERM_07097 from Streptomyces avermitilis, shared identical functionality, and all exerted a positive effect on actinorhodin production but a negative effect on avermectin production, indicating that SspH-mediated differential control of antibiotic biosynthesis may be widespread in Streptomyces. This study extended our understanding of the regulatory network of antibiotic biosynthesis and provided effective targets for future antibiotic discovery and overproduction. MDPI 2022-04-19 /pmc/articles/PMC9137472/ /pubmed/35625182 http://dx.doi.org/10.3390/antibiotics11050538 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Xue
Zhang, Yanyan
Li, Shanshan
Ye, Lan
Wang, Xiangjing
Xiang, Wensheng
SspH, a Novel HATPase Family Regulator, Controls Antibiotic Biosynthesis in Streptomyces
title SspH, a Novel HATPase Family Regulator, Controls Antibiotic Biosynthesis in Streptomyces
title_full SspH, a Novel HATPase Family Regulator, Controls Antibiotic Biosynthesis in Streptomyces
title_fullStr SspH, a Novel HATPase Family Regulator, Controls Antibiotic Biosynthesis in Streptomyces
title_full_unstemmed SspH, a Novel HATPase Family Regulator, Controls Antibiotic Biosynthesis in Streptomyces
title_short SspH, a Novel HATPase Family Regulator, Controls Antibiotic Biosynthesis in Streptomyces
title_sort ssph, a novel hatpase family regulator, controls antibiotic biosynthesis in streptomyces
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137472/
https://www.ncbi.nlm.nih.gov/pubmed/35625182
http://dx.doi.org/10.3390/antibiotics11050538
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