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Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome

Genome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in Streptomyces genomes. In this work, we have used an alternative approach consisting in seeking “Streptomyces Antibiotic Regulatory Proteins” (SARP) enc...

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Autores principales: Ye, Suhui, Molloy, Brian, Pérez-Victoria, Ignacio, Montero, Ignacio, Braña, Alfredo F., Olano, Carlos, Arca, Sonia, Martín, Jesús, Reyes, Fernando, Salas, José A., Méndez, Carmen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10179220/
https://www.ncbi.nlm.nih.gov/pubmed/37175904
http://dx.doi.org/10.3390/ijms24098197
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author Ye, Suhui
Molloy, Brian
Pérez-Victoria, Ignacio
Montero, Ignacio
Braña, Alfredo F.
Olano, Carlos
Arca, Sonia
Martín, Jesús
Reyes, Fernando
Salas, José A.
Méndez, Carmen
author_facet Ye, Suhui
Molloy, Brian
Pérez-Victoria, Ignacio
Montero, Ignacio
Braña, Alfredo F.
Olano, Carlos
Arca, Sonia
Martín, Jesús
Reyes, Fernando
Salas, José A.
Méndez, Carmen
author_sort Ye, Suhui
collection PubMed
description Genome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in Streptomyces genomes. In this work, we have used an alternative approach consisting in seeking “Streptomyces Antibiotic Regulatory Proteins” (SARP) encoding genes and analyzing their surrounding DNA region to unearth cryptic gene clusters that cannot be identified using standard bioinformatics tools. This strategy has allowed the unveiling of the new ahb cluster in Streptomyces argillaceus, which had not been retrieved before using antiSMASH. The ahb cluster is highly preserved in other Streptomyces strains, which suggests a role for their encoding compounds in specific environmental conditions. By combining overexpression of three regulatory genes and generation of different mutants, we were able to activate the ahb cluster, and to identify and chemically characterize the encoded compounds that we have named ahbamycins (AHBs). These constitute a new family of metabolites derived from 3-amino-4-hydroxybenzoate (3,4-AHBA) known for having antibiotic and antitumor activity. Additionally, by overexpressing three genes of the cluster (ahbH, ahbI, and ahbL2) for the synthesis and activation of 3,4-AHBA, a new hybrid compound, AHB18, was identified which had been produced from a metabolic crosstalk between the AHB and the argimycin P pathways. The identification of this new BGC opens the possibility to generate new compounds by combinatorial biosynthesis.
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spelling pubmed-101792202023-05-13 Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome Ye, Suhui Molloy, Brian Pérez-Victoria, Ignacio Montero, Ignacio Braña, Alfredo F. Olano, Carlos Arca, Sonia Martín, Jesús Reyes, Fernando Salas, José A. Méndez, Carmen Int J Mol Sci Article Genome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in Streptomyces genomes. In this work, we have used an alternative approach consisting in seeking “Streptomyces Antibiotic Regulatory Proteins” (SARP) encoding genes and analyzing their surrounding DNA region to unearth cryptic gene clusters that cannot be identified using standard bioinformatics tools. This strategy has allowed the unveiling of the new ahb cluster in Streptomyces argillaceus, which had not been retrieved before using antiSMASH. The ahb cluster is highly preserved in other Streptomyces strains, which suggests a role for their encoding compounds in specific environmental conditions. By combining overexpression of three regulatory genes and generation of different mutants, we were able to activate the ahb cluster, and to identify and chemically characterize the encoded compounds that we have named ahbamycins (AHBs). These constitute a new family of metabolites derived from 3-amino-4-hydroxybenzoate (3,4-AHBA) known for having antibiotic and antitumor activity. Additionally, by overexpressing three genes of the cluster (ahbH, ahbI, and ahbL2) for the synthesis and activation of 3,4-AHBA, a new hybrid compound, AHB18, was identified which had been produced from a metabolic crosstalk between the AHB and the argimycin P pathways. The identification of this new BGC opens the possibility to generate new compounds by combinatorial biosynthesis. MDPI 2023-05-03 /pmc/articles/PMC10179220/ /pubmed/37175904 http://dx.doi.org/10.3390/ijms24098197 Text en © 2023 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
Ye, Suhui
Molloy, Brian
Pérez-Victoria, Ignacio
Montero, Ignacio
Braña, Alfredo F.
Olano, Carlos
Arca, Sonia
Martín, Jesús
Reyes, Fernando
Salas, José A.
Méndez, Carmen
Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome
title Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome
title_full Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome
title_fullStr Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome
title_full_unstemmed Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome
title_short Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome
title_sort uncovering the cryptic gene cluster ahb for 3-amino-4-hydroxybenzoate derived ahbamycins, by searching sarp regulator encoding genes in the streptomyces argillaceus genome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10179220/
https://www.ncbi.nlm.nih.gov/pubmed/37175904
http://dx.doi.org/10.3390/ijms24098197
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