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Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants

Benzylisoquinoline alkaloid derived pharmaceuticals are widely applied in modern medicines. Recent studies on the microbial production of benzylisoquinolines have highlighted key biological syntheses towards these natural products. Routes to non-natural benzylisoquinolines have been less explored, p...

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Autores principales: Wang, Yu, Subrizi, Fabiana, Carter, Eve M., Sheppard, Tom D., Ward, John M., Hailes, Helen C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481557/
https://www.ncbi.nlm.nih.gov/pubmed/36114194
http://dx.doi.org/10.1038/s41467-022-33122-1
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author Wang, Yu
Subrizi, Fabiana
Carter, Eve M.
Sheppard, Tom D.
Ward, John M.
Hailes, Helen C.
author_facet Wang, Yu
Subrizi, Fabiana
Carter, Eve M.
Sheppard, Tom D.
Ward, John M.
Hailes, Helen C.
author_sort Wang, Yu
collection PubMed
description Benzylisoquinoline alkaloid derived pharmaceuticals are widely applied in modern medicines. Recent studies on the microbial production of benzylisoquinolines have highlighted key biological syntheses towards these natural products. Routes to non-natural benzylisoquinolines have been less explored, particularly halogenated compounds which are more challenging. Here, we show the use of a tyrosinase, tyrosine decarboxylase, transaminase, and norcoclaurine synthase which are combined in a parallel cascade design, in order to generate halogenated benzylisoquinoline alkaloids in high enantiomeric excess. Notably, mutagenesis studies are applied to generate tyrosinase mutants, which enhance the acceptance of halogenated tyrosines for use in the biocatalytic cascades developed.
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spelling pubmed-94815572022-09-18 Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants Wang, Yu Subrizi, Fabiana Carter, Eve M. Sheppard, Tom D. Ward, John M. Hailes, Helen C. Nat Commun Article Benzylisoquinoline alkaloid derived pharmaceuticals are widely applied in modern medicines. Recent studies on the microbial production of benzylisoquinolines have highlighted key biological syntheses towards these natural products. Routes to non-natural benzylisoquinolines have been less explored, particularly halogenated compounds which are more challenging. Here, we show the use of a tyrosinase, tyrosine decarboxylase, transaminase, and norcoclaurine synthase which are combined in a parallel cascade design, in order to generate halogenated benzylisoquinoline alkaloids in high enantiomeric excess. Notably, mutagenesis studies are applied to generate tyrosinase mutants, which enhance the acceptance of halogenated tyrosines for use in the biocatalytic cascades developed. Nature Publishing Group UK 2022-09-16 /pmc/articles/PMC9481557/ /pubmed/36114194 http://dx.doi.org/10.1038/s41467-022-33122-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Yu
Subrizi, Fabiana
Carter, Eve M.
Sheppard, Tom D.
Ward, John M.
Hailes, Helen C.
Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants
title Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants
title_full Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants
title_fullStr Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants
title_full_unstemmed Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants
title_short Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants
title_sort enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481557/
https://www.ncbi.nlm.nih.gov/pubmed/36114194
http://dx.doi.org/10.1038/s41467-022-33122-1
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