Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products
- Autores
- Mazzaferro, Laura; Hüttel, Wolfgang; Fries, Alexander; Müller, Michael
- Año de publicación
- 2015
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- For almost 100 years, phenoxy radical coupling has been known to proceed in nature. Because of the linkage of their molecular halves (regiochemistry) and the configuration of the biaryl axis (stereochemistry), biaryls are notoriously difficult to synthesize. Whereas the intramolecular enzymatic coupling has been elucidated in detail for several examples, the bimolecular intermolecular coupling could not be assigned to one single enzyme in the biosynthesis of axially chiral biaryls. As these transformations often take place regio- and stereoselectively, enzyme-catalyzed control is reasonable. We now report the identification and expression of fungal cytochrome P450 enzymes that catalyze regio- and stereoselective intermolecular phenol couplings. The cytochrome P450 enzyme KtnC from the kotanin biosynthetic pathway of Aspergillus Niger was expressed in Saccharomyces cerevisiae. The recombinant cells catalyzed the coupling of the monomeric coumarin 7-demethylsiderin both regio- and stereoselectively to the 8,8′-dimer P-orlandin, a precursor of kotanin. The sequence information obtained from the kotanin biosynthetic gene cluster was used to identify in silico a similar gene cluster in the genome of Emericella desertorum, a producer of desertorin A, the 6,8′-regioisomer of orlandin. The cytochrome P450 enzyme DesC was also expressed in S. cerevisiae and was found to regio- and stereoselectively catalyze the coupling of 7-demethylsiderin to M-desertorin A. Our results show that fungi use highly specific cytochrome P450 enzymes for regio- and stereoselective phenol coupling. The enzymatic activities of KtnC and DesC are relevant for an understanding of the mechanism of this important biosynthetic step. These results suggest that bimolecular phenoxy radical couplings in nature can be catalyzed by phenol-coupling P450 heme enzymes, which might also apply to the plant kingdom.
Fil: Mazzaferro, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; Argentina. Albert-Ludwigs-Universitat Freiburg; Alemania
Fil: Hüttel, Wolfgang. Albert-Ludwigs-Universitat Freiburg; Alemania
Fil: Fries, Alexander. Albert-Ludwigs-Universitat Freiburg; Alemania
Fil: Müller, Michael. Albert-Ludwigs-Universitat Freiburg; Alemania - Materia
-
Bicoumarin Synthase
Biaryls
Atropisomers
Biocatalysis
Asymmetric Synthesis - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/81572
Ver los metadatos del registro completo
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Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural ProductsMazzaferro, LauraHüttel, WolfgangFries, AlexanderMüller, MichaelBicoumarin SynthaseBiarylsAtropisomersBiocatalysisAsymmetric Synthesishttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1For almost 100 years, phenoxy radical coupling has been known to proceed in nature. Because of the linkage of their molecular halves (regiochemistry) and the configuration of the biaryl axis (stereochemistry), biaryls are notoriously difficult to synthesize. Whereas the intramolecular enzymatic coupling has been elucidated in detail for several examples, the bimolecular intermolecular coupling could not be assigned to one single enzyme in the biosynthesis of axially chiral biaryls. As these transformations often take place regio- and stereoselectively, enzyme-catalyzed control is reasonable. We now report the identification and expression of fungal cytochrome P450 enzymes that catalyze regio- and stereoselective intermolecular phenol couplings. The cytochrome P450 enzyme KtnC from the kotanin biosynthetic pathway of Aspergillus Niger was expressed in Saccharomyces cerevisiae. The recombinant cells catalyzed the coupling of the monomeric coumarin 7-demethylsiderin both regio- and stereoselectively to the 8,8′-dimer P-orlandin, a precursor of kotanin. The sequence information obtained from the kotanin biosynthetic gene cluster was used to identify in silico a similar gene cluster in the genome of Emericella desertorum, a producer of desertorin A, the 6,8′-regioisomer of orlandin. The cytochrome P450 enzyme DesC was also expressed in S. cerevisiae and was found to regio- and stereoselectively catalyze the coupling of 7-demethylsiderin to M-desertorin A. Our results show that fungi use highly specific cytochrome P450 enzymes for regio- and stereoselective phenol coupling. The enzymatic activities of KtnC and DesC are relevant for an understanding of the mechanism of this important biosynthetic step. These results suggest that bimolecular phenoxy radical couplings in nature can be catalyzed by phenol-coupling P450 heme enzymes, which might also apply to the plant kingdom.Fil: Mazzaferro, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; Argentina. Albert-Ludwigs-Universitat Freiburg; AlemaniaFil: Hüttel, Wolfgang. Albert-Ludwigs-Universitat Freiburg; AlemaniaFil: Fries, Alexander. Albert-Ludwigs-Universitat Freiburg; AlemaniaFil: Müller, Michael. Albert-Ludwigs-Universitat Freiburg; AlemaniaAmerican Chemical Society2015-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/81572Mazzaferro, Laura; Hüttel, Wolfgang; Fries, Alexander; Müller, Michael; Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products; American Chemical Society; Journal of the American Chemical Society; 137; 38; 9-2015; 12289-122950002-7863CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/jacs.5b06776info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jacs.5b06776info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:26:33Zoai:ri.conicet.gov.ar:11336/81572instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:26:33.986CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products |
title |
Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products |
spellingShingle |
Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products Mazzaferro, Laura Bicoumarin Synthase Biaryls Atropisomers Biocatalysis Asymmetric Synthesis |
title_short |
Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products |
title_full |
Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products |
title_fullStr |
Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products |
title_full_unstemmed |
Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products |
title_sort |
Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products |
dc.creator.none.fl_str_mv |
Mazzaferro, Laura Hüttel, Wolfgang Fries, Alexander Müller, Michael |
author |
Mazzaferro, Laura |
author_facet |
Mazzaferro, Laura Hüttel, Wolfgang Fries, Alexander Müller, Michael |
author_role |
author |
author2 |
Hüttel, Wolfgang Fries, Alexander Müller, Michael |
author2_role |
author author author |
dc.subject.none.fl_str_mv |
Bicoumarin Synthase Biaryls Atropisomers Biocatalysis Asymmetric Synthesis |
topic |
Bicoumarin Synthase Biaryls Atropisomers Biocatalysis Asymmetric Synthesis |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.4 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
For almost 100 years, phenoxy radical coupling has been known to proceed in nature. Because of the linkage of their molecular halves (regiochemistry) and the configuration of the biaryl axis (stereochemistry), biaryls are notoriously difficult to synthesize. Whereas the intramolecular enzymatic coupling has been elucidated in detail for several examples, the bimolecular intermolecular coupling could not be assigned to one single enzyme in the biosynthesis of axially chiral biaryls. As these transformations often take place regio- and stereoselectively, enzyme-catalyzed control is reasonable. We now report the identification and expression of fungal cytochrome P450 enzymes that catalyze regio- and stereoselective intermolecular phenol couplings. The cytochrome P450 enzyme KtnC from the kotanin biosynthetic pathway of Aspergillus Niger was expressed in Saccharomyces cerevisiae. The recombinant cells catalyzed the coupling of the monomeric coumarin 7-demethylsiderin both regio- and stereoselectively to the 8,8′-dimer P-orlandin, a precursor of kotanin. The sequence information obtained from the kotanin biosynthetic gene cluster was used to identify in silico a similar gene cluster in the genome of Emericella desertorum, a producer of desertorin A, the 6,8′-regioisomer of orlandin. The cytochrome P450 enzyme DesC was also expressed in S. cerevisiae and was found to regio- and stereoselectively catalyze the coupling of 7-demethylsiderin to M-desertorin A. Our results show that fungi use highly specific cytochrome P450 enzymes for regio- and stereoselective phenol coupling. The enzymatic activities of KtnC and DesC are relevant for an understanding of the mechanism of this important biosynthetic step. These results suggest that bimolecular phenoxy radical couplings in nature can be catalyzed by phenol-coupling P450 heme enzymes, which might also apply to the plant kingdom. Fil: Mazzaferro, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; Argentina. Albert-Ludwigs-Universitat Freiburg; Alemania Fil: Hüttel, Wolfgang. Albert-Ludwigs-Universitat Freiburg; Alemania Fil: Fries, Alexander. Albert-Ludwigs-Universitat Freiburg; Alemania Fil: Müller, Michael. Albert-Ludwigs-Universitat Freiburg; Alemania |
description |
For almost 100 years, phenoxy radical coupling has been known to proceed in nature. Because of the linkage of their molecular halves (regiochemistry) and the configuration of the biaryl axis (stereochemistry), biaryls are notoriously difficult to synthesize. Whereas the intramolecular enzymatic coupling has been elucidated in detail for several examples, the bimolecular intermolecular coupling could not be assigned to one single enzyme in the biosynthesis of axially chiral biaryls. As these transformations often take place regio- and stereoselectively, enzyme-catalyzed control is reasonable. We now report the identification and expression of fungal cytochrome P450 enzymes that catalyze regio- and stereoselective intermolecular phenol couplings. The cytochrome P450 enzyme KtnC from the kotanin biosynthetic pathway of Aspergillus Niger was expressed in Saccharomyces cerevisiae. The recombinant cells catalyzed the coupling of the monomeric coumarin 7-demethylsiderin both regio- and stereoselectively to the 8,8′-dimer P-orlandin, a precursor of kotanin. The sequence information obtained from the kotanin biosynthetic gene cluster was used to identify in silico a similar gene cluster in the genome of Emericella desertorum, a producer of desertorin A, the 6,8′-regioisomer of orlandin. The cytochrome P450 enzyme DesC was also expressed in S. cerevisiae and was found to regio- and stereoselectively catalyze the coupling of 7-demethylsiderin to M-desertorin A. Our results show that fungi use highly specific cytochrome P450 enzymes for regio- and stereoselective phenol coupling. The enzymatic activities of KtnC and DesC are relevant for an understanding of the mechanism of this important biosynthetic step. These results suggest that bimolecular phenoxy radical couplings in nature can be catalyzed by phenol-coupling P450 heme enzymes, which might also apply to the plant kingdom. |
publishDate |
2015 |
dc.date.none.fl_str_mv |
2015-09 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/81572 Mazzaferro, Laura; Hüttel, Wolfgang; Fries, Alexander; Müller, Michael; Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products; American Chemical Society; Journal of the American Chemical Society; 137; 38; 9-2015; 12289-12295 0002-7863 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/81572 |
identifier_str_mv |
Mazzaferro, Laura; Hüttel, Wolfgang; Fries, Alexander; Müller, Michael; Cytochrome P450-Catalyzed Regio- and Stereoselective Phenol Coupling of Fungal Natural Products; American Chemical Society; Journal of the American Chemical Society; 137; 38; 9-2015; 12289-12295 0002-7863 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1021/jacs.5b06776 info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jacs.5b06776 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Chemical Society |
publisher.none.fl_str_mv |
American Chemical Society |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.070432 |