Uncovering the Cryptic Gene Cluster <i>ahb</i> for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the <i>Streptomyces argillaceus</i> Genome
Genome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in <i>Streptomyces</i> genomes. In this work, we have used an alternative approach consisting in seeking “<i>Streptomyces</i> Anti...
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| Language: | English |
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8197 |
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| author | Suhui Ye Brian Molloy Ignacio Pérez-Victoria Ignacio Montero Alfredo F. Braña Carlos Olano Sonia Arca Jesús Martín Fernando Reyes José A. Salas Carmen Méndez |
| author_facet | Suhui Ye Brian Molloy Ignacio Pérez-Victoria Ignacio Montero Alfredo F. Braña Carlos Olano Sonia Arca Jesús Martín Fernando Reyes José A. Salas Carmen Méndez |
| author_sort | Suhui Ye |
| collection | DOAJ |
| description | Genome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in <i>Streptomyces</i> genomes. In this work, we have used an alternative approach consisting in seeking “<i>Streptomyces</i> 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 <i>ahb</i> cluster in <i>Streptomyces argillaceus</i>, which had not been retrieved before using antiSMASH. The <i>ahb</i> cluster is highly preserved in other <i>Streptomyces</i> 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 <i>ahb</i> 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 (<i>ahbH</i>, <i>ahbI,</i> and <i>ahbL2</i>) 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. |
| first_indexed | 2024-03-11T04:15:49Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:15:49Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0bf7bf73563d4615bf03b0e677fa34562023-11-17T23:06:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249819710.3390/ijms24098197Uncovering the Cryptic Gene Cluster <i>ahb</i> for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the <i>Streptomyces argillaceus</i> GenomeSuhui Ye0Brian Molloy1Ignacio Pérez-Victoria2Ignacio Montero3Alfredo F. Braña4Carlos Olano5Sonia Arca6Jesús Martín7Fernando Reyes8José A. Salas9Carmen Méndez10Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, SpainDepartamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, SpainFundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Armilla, 18016 Granada, SpainDepartamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, SpainDepartamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, SpainDepartamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, SpainDepartamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, SpainFundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Armilla, 18016 Granada, SpainFundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Armilla, 18016 Granada, SpainDepartamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, SpainDepartamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, SpainGenome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in <i>Streptomyces</i> genomes. In this work, we have used an alternative approach consisting in seeking “<i>Streptomyces</i> 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 <i>ahb</i> cluster in <i>Streptomyces argillaceus</i>, which had not been retrieved before using antiSMASH. The <i>ahb</i> cluster is highly preserved in other <i>Streptomyces</i> 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 <i>ahb</i> 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 (<i>ahbH</i>, <i>ahbI,</i> and <i>ahbL2</i>) 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.https://www.mdpi.com/1422-0067/24/9/81973,4-AHBA<i>Streptomyces</i>SARPahbamycinsgenome miningargimycin P |
| spellingShingle | Suhui Ye Brian Molloy Ignacio Pérez-Victoria Ignacio Montero Alfredo F. Braña Carlos Olano Sonia Arca Jesús Martín Fernando Reyes José A. Salas Carmen Méndez Uncovering the Cryptic Gene Cluster <i>ahb</i> for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the <i>Streptomyces argillaceus</i> Genome International Journal of Molecular Sciences 3,4-AHBA <i>Streptomyces</i> SARP ahbamycins genome mining argimycin P |
| title | Uncovering the Cryptic Gene Cluster <i>ahb</i> for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the <i>Streptomyces argillaceus</i> Genome |
| title_full | Uncovering the Cryptic Gene Cluster <i>ahb</i> for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the <i>Streptomyces argillaceus</i> Genome |
| title_fullStr | Uncovering the Cryptic Gene Cluster <i>ahb</i> for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the <i>Streptomyces argillaceus</i> Genome |
| title_full_unstemmed | Uncovering the Cryptic Gene Cluster <i>ahb</i> for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the <i>Streptomyces argillaceus</i> Genome |
| title_short | Uncovering the Cryptic Gene Cluster <i>ahb</i> for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the <i>Streptomyces argillaceus</i> Genome |
| title_sort | uncovering the cryptic gene cluster i ahb i for 3 amino 4 hydroxybenzoate derived ahbamycins by searching sarp regulator encoding genes in the i streptomyces argillaceus i genome |
| topic | 3,4-AHBA <i>Streptomyces</i> SARP ahbamycins genome mining argimycin P |
| url | https://www.mdpi.com/1422-0067/24/9/8197 |
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