Cargando…
Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresp...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159254/ https://www.ncbi.nlm.nih.gov/pubmed/34122962 http://dx.doi.org/10.1039/d0sc02253e |
_version_ | 1783700042856529920 |
---|---|
author | Mangas-Sanchez, Juan Sharma, Mahima Cosgrove, Sebastian C. Ramsden, Jeremy I. Marshall, James R. Thorpe, Thomas W. Palmer, Ryan B. Grogan, Gideon Turner, Nicholas J. |
author_facet | Mangas-Sanchez, Juan Sharma, Mahima Cosgrove, Sebastian C. Ramsden, Jeremy I. Marshall, James R. Thorpe, Thomas W. Palmer, Ryan B. Grogan, Gideon Turner, Nicholas J. |
author_sort | Mangas-Sanchez, Juan |
collection | PubMed |
description | Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresponding secondary amines. Herein we describe structural and biochemical characterisation as well as synthetic applications of two RedAms from Neosartorya spp. (NfRedAm and NfisRedAm) that display a distinctive activity amongst fungal RedAms, namely a superior ability to use ammonia as the amine partner. Using these enzymes, we demonstrate the synthesis of a broad range of primary amines, with conversions up to >97% and excellent enantiomeric excess. Temperature dependent studies showed that these homologues also possess greater thermal stability compared to other enzymes within this family. Their synthetic applicability is further demonstrated by the production of several primary and secondary amines with turnover numbers (TN) up to 14 000 as well as continous flow reactions, obtaining chiral amines such as (R)-2-aminohexane in space time yields up to 8.1 g L(−1) h(−1). The remarkable features of NfRedAm and NfisRedAm highlight their potential for wider synthetic application as well as expanding the biocatalytic toolbox available for chiral amine synthesis. |
format | Online Article Text |
id | pubmed-8159254 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-81592542021-06-11 Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases Mangas-Sanchez, Juan Sharma, Mahima Cosgrove, Sebastian C. Ramsden, Jeremy I. Marshall, James R. Thorpe, Thomas W. Palmer, Ryan B. Grogan, Gideon Turner, Nicholas J. Chem Sci Chemistry Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresponding secondary amines. Herein we describe structural and biochemical characterisation as well as synthetic applications of two RedAms from Neosartorya spp. (NfRedAm and NfisRedAm) that display a distinctive activity amongst fungal RedAms, namely a superior ability to use ammonia as the amine partner. Using these enzymes, we demonstrate the synthesis of a broad range of primary amines, with conversions up to >97% and excellent enantiomeric excess. Temperature dependent studies showed that these homologues also possess greater thermal stability compared to other enzymes within this family. Their synthetic applicability is further demonstrated by the production of several primary and secondary amines with turnover numbers (TN) up to 14 000 as well as continous flow reactions, obtaining chiral amines such as (R)-2-aminohexane in space time yields up to 8.1 g L(−1) h(−1). The remarkable features of NfRedAm and NfisRedAm highlight their potential for wider synthetic application as well as expanding the biocatalytic toolbox available for chiral amine synthesis. The Royal Society of Chemistry 2020-05-05 /pmc/articles/PMC8159254/ /pubmed/34122962 http://dx.doi.org/10.1039/d0sc02253e Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Mangas-Sanchez, Juan Sharma, Mahima Cosgrove, Sebastian C. Ramsden, Jeremy I. Marshall, James R. Thorpe, Thomas W. Palmer, Ryan B. Grogan, Gideon Turner, Nicholas J. Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases |
title | Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases |
title_full | Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases |
title_fullStr | Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases |
title_full_unstemmed | Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases |
title_short | Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases |
title_sort | asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159254/ https://www.ncbi.nlm.nih.gov/pubmed/34122962 http://dx.doi.org/10.1039/d0sc02253e |
work_keys_str_mv | AT mangassanchezjuan asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases AT sharmamahima asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases AT cosgrovesebastianc asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases AT ramsdenjeremyi asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases AT marshalljamesr asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases AT thorpethomasw asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases AT palmerryanb asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases AT grogangideon asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases AT turnernicholasj asymmetricsynthesisofprimaryaminescatalyzedbythermotolerantfungalreductiveaminases |