A Mechanism for Reductive Amination Catalyzed by Fungal Reductive Aminases (RedAms)

Mahima Sharma; Juan Mangas-Sanchez; Scott France; Godwin Aleku; Sarah L Montgomery; Jeremy Ramsden; Nicholas Turner; Gideon James Grogan

doi:10.1021/acscatal.8b03491

A Mechanism for Reductive Amination Catalyzed by Fungal Reductive Aminases (RedAms)

Mahima Sharma, Juan Mangas-Sanchez, Scott France, Godwin Aleku, Sarah L Montgomery, Jeremy Ramsden, Nicholas Turner, Gideon James Grogan

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Reductive Aminases (RedAms) catalyze the asymmetric reductive amination of ketones with primary amines to give secondary amine products. RedAms have great potential for the synthesis of bioactive chiral amines, however, insights into their mechanism are currently limited. Comparative studies on reductive amination of cyclohexanone with allylamine in the presence of RedAms, imine reductases (IREDs) or NaBH3CN support the distinctive activity of RedAms in catalyzing both imine formation and reduction in the reaction. Structures of AtRedAm from Aspergillus terreus, in complex with NADPH and ketone and amine substrates, along with kinetic analysis of active-site mutants, reveal modes of substrate binding, the basis for the specificity of RedAms for reduction of imines over ketones, and the importance of domain flexibility in bringing the reactive participants together for the reaction. This information is used to propose a mechanism for their action and also to expand the substrate specificity of RedAms using protein engineering.

Original language	English
Pages (from-to)	11534–11541
Number of pages	8
Journal	ACS Catalysis
Volume	2018
Issue number	8
Early online date	26 Oct 2018
DOIs	https://doi.org/10.1021/acscatal.8b03491
Publication status	E-pub ahead of print - 26 Oct 2018

Bibliographical note

© 2018 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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10.1021/acscatal.8b03491

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Cite this

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title = "A Mechanism for Reductive Amination Catalyzed by Fungal Reductive Aminases (RedAms)",

abstract = "Reductive Aminases (RedAms) catalyze the asymmetric reductive amination of ketones with primary amines to give secondary amine products. RedAms have great potential for the synthesis of bioactive chiral amines, however, insights into their mechanism are currently limited. Comparative studies on reductive amination of cyclohexanone with allylamine in the presence of RedAms, imine reductases (IREDs) or NaBH3CN support the distinctive activity of RedAms in catalyzing both imine formation and reduction in the reaction. Structures of AtRedAm from Aspergillus terreus, in complex with NADPH and ketone and amine substrates, along with kinetic analysis of active-site mutants, reveal modes of substrate binding, the basis for the specificity of RedAms for reduction of imines over ketones, and the importance of domain flexibility in bringing the reactive participants together for the reaction. This information is used to propose a mechanism for their action and also to expand the substrate specificity of RedAms using protein engineering.",

author = "Mahima Sharma and Juan Mangas-Sanchez and Scott France and Godwin Aleku and Montgomery, {Sarah L} and Jeremy Ramsden and Nicholas Turner and Grogan, {Gideon James}",

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T1 - A Mechanism for Reductive Amination Catalyzed by Fungal Reductive Aminases (RedAms)

AU - Sharma, Mahima

AU - Mangas-Sanchez, Juan

AU - France, Scott

AU - Aleku, Godwin

AU - Montgomery, Sarah L

AU - Ramsden, Jeremy

AU - Turner, Nicholas

AU - Grogan, Gideon James

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N2 - Reductive Aminases (RedAms) catalyze the asymmetric reductive amination of ketones with primary amines to give secondary amine products. RedAms have great potential for the synthesis of bioactive chiral amines, however, insights into their mechanism are currently limited. Comparative studies on reductive amination of cyclohexanone with allylamine in the presence of RedAms, imine reductases (IREDs) or NaBH3CN support the distinctive activity of RedAms in catalyzing both imine formation and reduction in the reaction. Structures of AtRedAm from Aspergillus terreus, in complex with NADPH and ketone and amine substrates, along with kinetic analysis of active-site mutants, reveal modes of substrate binding, the basis for the specificity of RedAms for reduction of imines over ketones, and the importance of domain flexibility in bringing the reactive participants together for the reaction. This information is used to propose a mechanism for their action and also to expand the substrate specificity of RedAms using protein engineering.

AB - Reductive Aminases (RedAms) catalyze the asymmetric reductive amination of ketones with primary amines to give secondary amine products. RedAms have great potential for the synthesis of bioactive chiral amines, however, insights into their mechanism are currently limited. Comparative studies on reductive amination of cyclohexanone with allylamine in the presence of RedAms, imine reductases (IREDs) or NaBH3CN support the distinctive activity of RedAms in catalyzing both imine formation and reduction in the reaction. Structures of AtRedAm from Aspergillus terreus, in complex with NADPH and ketone and amine substrates, along with kinetic analysis of active-site mutants, reveal modes of substrate binding, the basis for the specificity of RedAms for reduction of imines over ketones, and the importance of domain flexibility in bringing the reactive participants together for the reaction. This information is used to propose a mechanism for their action and also to expand the substrate specificity of RedAms using protein engineering.

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