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Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase

Benzylisoquinoline alkaloids (BIAs) are a structurally diverse family of plant secondary metabolites, which have been exploited to develop analgesics, antibiotics, antitumor agents, and other therapeutic agents. Biosynthesis of BIAs proceeds via a common pathway from tyrosine to (S)‐reticulene at wh...

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Autores principales: Bennett, Matthew R., Thompson, Mark L., Shepherd, Sarah A., Dunstan, Mark S., Herbert, Abigail J., Smith, Duncan R. M., Cronin, Victoria A., Menon, Binuraj R. K., Levy, Colin, Micklefield, Jason
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099451/
https://www.ncbi.nlm.nih.gov/pubmed/29791083
http://dx.doi.org/10.1002/anie.201805060
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author Bennett, Matthew R.
Thompson, Mark L.
Shepherd, Sarah A.
Dunstan, Mark S.
Herbert, Abigail J.
Smith, Duncan R. M.
Cronin, Victoria A.
Menon, Binuraj R. K.
Levy, Colin
Micklefield, Jason
author_facet Bennett, Matthew R.
Thompson, Mark L.
Shepherd, Sarah A.
Dunstan, Mark S.
Herbert, Abigail J.
Smith, Duncan R. M.
Cronin, Victoria A.
Menon, Binuraj R. K.
Levy, Colin
Micklefield, Jason
author_sort Bennett, Matthew R.
collection PubMed
description Benzylisoquinoline alkaloids (BIAs) are a structurally diverse family of plant secondary metabolites, which have been exploited to develop analgesics, antibiotics, antitumor agents, and other therapeutic agents. Biosynthesis of BIAs proceeds via a common pathway from tyrosine to (S)‐reticulene at which point the pathway diverges. Coclaurine N‐methyltransferase (CNMT) is a key enzyme in the pathway to (S)‐reticulene, installing the N‐methyl substituent that is essential for the bioactivity of many BIAs. In this paper, we describe the first crystal structure of CNMT which, along with mutagenesis studies, defines the enzymes active site architecture. The specificity of CNMT was also explored with a range of natural and synthetic substrates as well as co‐factor analogues. Knowledge from this study could be used to generate improved CNMT variants required to produce BIAs or synthetic derivatives.
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spelling pubmed-60994512018-08-24 Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase Bennett, Matthew R. Thompson, Mark L. Shepherd, Sarah A. Dunstan, Mark S. Herbert, Abigail J. Smith, Duncan R. M. Cronin, Victoria A. Menon, Binuraj R. K. Levy, Colin Micklefield, Jason Angew Chem Int Ed Engl Communications Benzylisoquinoline alkaloids (BIAs) are a structurally diverse family of plant secondary metabolites, which have been exploited to develop analgesics, antibiotics, antitumor agents, and other therapeutic agents. Biosynthesis of BIAs proceeds via a common pathway from tyrosine to (S)‐reticulene at which point the pathway diverges. Coclaurine N‐methyltransferase (CNMT) is a key enzyme in the pathway to (S)‐reticulene, installing the N‐methyl substituent that is essential for the bioactivity of many BIAs. In this paper, we describe the first crystal structure of CNMT which, along with mutagenesis studies, defines the enzymes active site architecture. The specificity of CNMT was also explored with a range of natural and synthetic substrates as well as co‐factor analogues. Knowledge from this study could be used to generate improved CNMT variants required to produce BIAs or synthetic derivatives. John Wiley and Sons Inc. 2018-06-28 2018-08-13 /pmc/articles/PMC6099451/ /pubmed/29791083 http://dx.doi.org/10.1002/anie.201805060 Text en © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Communications
Bennett, Matthew R.
Thompson, Mark L.
Shepherd, Sarah A.
Dunstan, Mark S.
Herbert, Abigail J.
Smith, Duncan R. M.
Cronin, Victoria A.
Menon, Binuraj R. K.
Levy, Colin
Micklefield, Jason
Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase
title Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase
title_full Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase
title_fullStr Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase
title_full_unstemmed Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase
title_short Structure and Biocatalytic Scope of Coclaurine N‐Methyltransferase
title_sort structure and biocatalytic scope of coclaurine n‐methyltransferase
topic Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099451/
https://www.ncbi.nlm.nih.gov/pubmed/29791083
http://dx.doi.org/10.1002/anie.201805060
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