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7. Imine reductases (IREDs)

Author

Mangas-Sanchez, Juan, France, Scott P, Montgomery, Sarah L, Aleku, Godwin A, Man, Henry, Sharma, Mahima, Ramsden, Jeremy I, Grogan, Gideon, and Turner, Nicholas J

Published
2017
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8. Cascade processes merging chemical and enzyme catalysis

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, ARAID Foundation, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Ascaso Alegre, Christian, Mangas-Sanchez, Juan, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, ARAID Foundation, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Ascaso Alegre, Christian, and Mangas-Sanchez, Juan

Abstract

Cascade processes are an attractive strategy to rapidly build molecular complexity and circumvent the need to isolate reaction intermediates, providing higher efficiencies into synthetic routes with lower environmental toll. We have recently developed a new method to synthesise chiral 1,4-nitro alcohols by sequentially combining three transformations in the same reaction vessel via asymmetric C–C bond formation using a chiral thiourea catalyst and a bioreduction process as key steps.

Published
2023

15. New trends and future opportunities in the enzymatic formation of C−C, C−N, and C−O bonds

Author

Biotechnology and Biological Sciences Research Council (UK), ARAID Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, European Research Council, Sangster, Jack J., Marshall, James R., Turner, Nicholas J., Mangas-Sanchez, Juan, Biotechnology and Biological Sciences Research Council (UK), ARAID Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, European Research Council, Sangster, Jack J., Marshall, James R., Turner, Nicholas J., and Mangas-Sanchez, Juan

Abstract

Organic chemistry provides society with fundamental products we use daily. Concerns about the impact that the chemical industry has over the environment is propelling major changes in the way we manufacture chemicals. Biocatalysis offers an alternative to other synthetic approaches as it employs enzymes, Nature's catalysts, to carry out chemical transformations. Enzymes are biodegradable, come from renewable sources, operate under mild reaction conditions, and display high selectivities in the processes they catalyse. As a highly multidisciplinary field, biocatalysis benefits from advances in different areas, and developments in the fields of molecular biology, bioinformatics, and chemical engineering have accelerated the extension of the range of available transformations (E. L. Bell et al., Nat. Rev. Meth. Prim. 2021, 1, 1–21). Recently, we surveyed advances in the expansion of the scope of biocatalysis via enzyme discovery and protein engineering (J. R. Marshall et al., Tetrahedron 2021, 82, 131926). Herein, we focus on novel enzymes currently available to the broad synthetic community for the construction of new C−C, C−N and C−O bonds, with the purpose of providing the non-specialist with new and alternative tools for chiral and sustainable chemical synthesis.

Published
2022

16. Construction of chemoenzymatic linear cascades for the synthesis of chiral compounds

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), ARAID Foundation, Ascaso Alegre, Christian, Mangas-Sanchez, Juan, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), ARAID Foundation, Ascaso Alegre, Christian, and Mangas-Sanchez, Juan

Abstract

Inspired by nature, synthetic chemists try to mimic the efficient metabolic networks in living organisms to build complex molecules by combining different types of catalysts in the same reaction vessel. These multistep cascade processes provide many advantages to synthetic procedures, resulting in higher productivities with lower waste generation and cost. However, combining different chemo- and biocatalysts can be challenging as reaction conditions might differ greatly. As a highly multidisciplinary field that benefits from advances in chemical catalysis, molecular biology and reaction engineering, this area of study is rapidly progressing. In this Review, we highlight recent trends and advances in the construction of multistep chemoenzymatic one-pot cascades to access chiral compounds as well as the different strategies to solve current challenges in the field.

Published
2022

21. Application of engineered biocatalysts for the synthesis of active pharmaceutical ingredients (APIs)

Author

Mangas-Sanchez, Juan, Cosgrove, Sebastian C., Turner, Nicholas J., Mangas-Sanchez, Juan, Cosgrove, Sebastian C., and Turner, Nicholas J.

Abstract

Genetic engineering of enzymes has played a significant role in multiple pharmaceutical synthetic processes. The need for selective, robust catalysts that can operate under process chemistry conditions has driven the need for mutagenesis approaches, which have successfully delivered a variety of process-optimized biocatalysts. In this chapter we give an overview of different directed evolution methods that have been applied to pharmaceutical intermediates during the last decade. The exciting progress that has been made since the landmark sitagliptin study in 2010 demonstrates the role that engineered biocatalysts can play in the manufacture of active pharmaceutical ingredients (APIs).

Published
2021

22. Expanding the synthetic scope of biocatalysis by enzyme discovery and protein engineering

Author

Biotechnology and Biological Sciences Research Council (UK), ARAID Foundation, European Commission, European Research Council, Marshall, James R., Mangas-Sanchez, Juan, Turner, Nicholas J., Biotechnology and Biological Sciences Research Council (UK), ARAID Foundation, European Commission, European Research Council, Marshall, James R., Mangas-Sanchez, Juan, and Turner, Nicholas J.

Abstract

Despite the growing impact of enzyme catalysis in industrial chemistry, the full potential of this technology is yet to be unlocked. Accessing new chemistries and expanding the scope of existing reactions is necessary in order to make biocatalysis a pivotal technology in the manufacturing of chemicals across the whole industrial spectrum. This review highlights how the biocatalytic toolbox for synthetic chemistry has recently been expanded by extending the scope of industrially relevant reactions, and the addition of new reactions via enzyme discovery or protein engineering.

Published
2021

24. Screening and characterization of a diverse panel of metagenomic imine reductases for biocatalytic reductive amination

Author

Marshall, James R., primary, Yao, Peiyuan, additional, Montgomery, Sarah L., additional, Finnigan, James D., additional, Thorpe, Thomas W., additional, Palmer, Ryan B., additional, Mangas-Sanchez, Juan, additional, Duncan, Richard A. M., additional, Heath, Rachel S., additional, Graham, Kirsty M., additional, Cook, Darren J., additional, Charnock, Simon J., additional, and Turner, Nicholas J., additional

Published
2020
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26. Engineered Formate Dehydrogenase Fromchaetomium Thermophilum, A Promising Enzymatic Solution For Biotechnical Co(2)Fixation

Author

Cakar, Mehmet M., Ruupunen, Jouni, Mangas-Sanchez, Juan, Birmingham, William R., Yildirim, Deniz, Turunen, Ossi, Turner, Nicholas J., Valjakka, Jarkko, and Binay, Baris

Abstract

Objectives Formate dehydrogenases (FDHs) are NAD(P)H-dependent enzymes that catalyse the reversible oxidation of formate to CO2. The main goal was to use directed evolution to obtain variants of the FDH fromChaetomium thermophilum(CtFDH) with enhanced reduction activity in the conversion of CO(2)into formic acid. Results Four libraries were constructed targeting five residues in the active site. We identified two variants (G93H/I94Y and R259C) with enhanced reduction activity which were characterised in the presence of both aqueous CO(2(g))and HCO3-. The A1 variant (G93H/I94Y) showed a 5.4-fold increase in catalytic efficiency (k(cat)/K-M) compared to that of the wild-type for HCO(3)(-)reduction. The improved biocatalysts were also applied as a coupled cofactor recycling system in the enantioselective oxidation of 4-phenyl-2-propanol catalysed by the alcohol dehydrogenase fromStreptomyces coelicolorA3 (ScADH). Conversions in these reactions increased from 56 to 91% when the A1 variant was used instead of wild-typeCtFDH. Conclusions Two variants presenting up to five-fold increase in catalytic efficiency andk(cat)were obtained and characterised. They constitute a promising enzymatic alternative for CO(2)utilization and will serve as scaffolds to be further developed in order to meet industrial requirements.

Published
2020

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

Author

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

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.

Published
2018

30. One-Pot Biocatalytic Cascade Reduction of Cyclic Enimines for the Preparation of Diastereomerically Enriched N-Heterocycles

Author

Thorpe, Thomas W., primary, France, Scott P., additional, Hussain, Shahed, additional, Marshall, James R., additional, Zawodny, Wojciech, additional, Mangas-Sanchez, Juan, additional, Montgomery, Sarah L., additional, Howard, Roger M., additional, Daniels, David S. B., additional, Kumar, Rajesh, additional, Parmeggiani, Fabio, additional, and Turner, Nicholas J., additional

Published
2019
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32. Discovery of a new metal and NAD+-dependent formate dehydrogenase from Clostridium ljungdahlii

Author

M. Mervan Çakar, Mangas-Sanchez, Juan, Birmingham, William R., Turner, Nicholas J., and Barış Binay

Abstract

Over the next decades, with the growing concern of rising atmospheric carbon dioxide (CO2) levels, the importance of investigating new approaches for its reduction becomes crucial. Reclamation of CO2 for conversion into biofuels represents an alternative and attractive production method that has been studied in recent years, now with enzymatic methods gaining more attention. Formate dehydrogenases (FDHs) are NAD(P)H-dependent oxidoreductases that catalyze the conversion of formate into CO2 and have been extensively used for cofactor recycling in chemoenzymatic processes. A new FDH from Clostridium ljungdahlii (ClFDH) has been recently shown to possess activity in the reverse reaction: the mineralization of CO2 into formate. In this study, we show the successful homologous expression of ClFDH in Escherichia coli. Biochemical and kinetic characterization of the enzyme revealed that this homologue also demonstrates activity toward CO2 reduction. Structural analysis of the enzyme through homology modeling is also presented.

Published
2018
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34. Engineered formate dehydrogenase from Chaetomium thermophilum, a promising enzymatic solution for biotechnical CO2 fixation.

Author

Çakar, Mehmet M., Ruupunen, Jouni, Mangas-Sanchez, Juan, Birmingham, William R., Yildirim, Deniz, Turunen, Ossi, Turner, Nicholas J., Valjakka, Jarkko, and Binay, Barış

Subjects
CHAETOMIUM, ALCOHOL dehydrogenase, STREPTOMYCES coelicolor, FORMIC acid, BIOCATALYSIS, DEHYDROGENASES, COFACTORS (Biochemistry)
Abstract

Objectives: Formate dehydrogenases (FDHs) are NAD(P)H-dependent enzymes that catalyse the reversible oxidation of formate to CO2. The main goal was to use directed evolution to obtain variants of the FDH from Chaetomium thermophilum (CtFDH) with enhanced reduction activity in the conversion of CO2 into formic acid. Results: Four libraries were constructed targeting five residues in the active site. We identified two variants (G93H/I94Y and R259C) with enhanced reduction activity which were characterised in the presence of both aqueous CO2(g) and HCO3−. The A1 variant (G93H/I94Y) showed a 5.4-fold increase in catalytic efficiency (kcat/KM) compared to that of the wild-type for HCO3− reduction. The improved biocatalysts were also applied as a coupled cofactor recycling system in the enantioselective oxidation of 4-phenyl-2-propanol catalysed by the alcohol dehydrogenase from Streptomyces coelicolor A3 (ScADH). Conversions in these reactions increased from 56 to 91% when the A1 variant was used instead of wild-type CtFDH. Conclusions: Two variants presenting up to five-fold increase in catalytic efficiency and kcat were obtained and characterised. They constitute a promising enzymatic alternative for CO2 utilization and will serve as scaffolds to be further developed in order to meet industrial requirements. [ABSTRACT FROM AUTHOR]

Published
2020
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37. Chemoenzymatic synthesis of rivastigmine based on lipase-catalyzed processes

Author

Mangas-Sanchez, Juan, Rodriguez-Mata, Maria, Busto, Eduardo, Gotor-Fernandez, Vicente, and Gotor, Vicente

Subjects
Rivastigmine -- Research, Lipase -- Research, Chemical synthesis -- Research, Biological sciences, Chemistry
Abstract

Chemoenzymatic synthesis of enantiomerically pure rivastigmine is carried out with Candida antartica lipase B responsible for the stereoselective acetylation of the corresponding (R)-alcohol or amine. Total chemoenzymatic synthesis of the pharmaceutical is performed in good yield from commercially available 3-methoxyacetophenone.

Published
2009

40. Biocatalytic Routes to Enantiomerically Enriched Dibenz[c ,e ]azepines

Author

France, Scott P., primary, Aleku, Godwin A., additional, Sharma, Mahima, additional, Mangas-Sanchez, Juan, additional, Howard, Roger M., additional, Steflik, Jeremy, additional, Kumar, Rajesh, additional, Adams, Ralph W., additional, Slabu, Iustina, additional, Crook, Robert, additional, Grogan, Gideon, additional, Wallace, Timothy W., additional, and Turner, Nicholas J., additional

Published
2017
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48. Discovery of a new metal and NAD+-dependent formate dehydrogenase from <italic>Clostridium ljungdahlii</italic>.

Author

Çakar, M. Mervan, Mangas-Sanchez, Juan, Birmingham, William R., Turner, Nicholas J., and Binay, Barış

Subjects
*ATMOSPHERIC carbon dioxide, *BIOMASS energy, *ATMOSPHERIC carbon dioxide & the environment, *DEHYDROGENASES, *ESCHERICHIA coli, *ENZYMES, *PREVENTION
Abstract

Over the next decades, with the growing concern of rising atmospheric carbon dioxide (CO2) levels, the importance of investigating new approaches for its reduction becomes crucial. Reclamation of CO2 for conversion into biofuels represents an alternative and attractive production method that has been studied in recent years, now with enzymatic methods gaining more attention. Formate dehydrogenases (FDHs) are NAD(P)H-dependent oxidoreductases that catalyze the conversion of formate into CO2 and have been extensively used for cofactor recycling in chemoenzymatic processes. A new FDH from Clostridium ljungdahlii (ClFDH) has been recently shown to possess activity in the reverse reaction: the mineralization of CO2 into formate. In this study, we show the successful homologous expression of ClFDH in Escherichia coli. Biochemical and kinetic characterization of the enzyme revealed that this homologue also demonstrates activity toward CO2 reduction. Structural analysis of the enzyme through homology modeling is also presented. [ABSTRACT FROM AUTHOR]

Published
2018
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49. Biocatalytic Routes to Enantiomerically Enriched Dibenz[ c, e]azepines.

Author

France, Scott P., Aleku, Godwin A., Sharma, Mahima, Mangas‐Sanchez, Juan, Howard, Roger M., Steflik, Jeremy, Kumar, Rajesh, Adams, Ralph W., Slabu, Iustina, Crook, Robert, Grogan, Gideon, Wallace, Timothy W., and Turner, Nicholas J.

Subjects
BIOCATALYSIS, ENANTIOMERS, AZEPINES, REDUCTASES, AMINOTRANSFERASES, CRYSTALLOGRAPHY
Abstract

Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the key stereocentres of these molecules. Several enantiocomplementary IREDs were identified for the synthesis of ( R)- and ( S)-5-methyl-6,7-dihydro-5 H-dibenz[c,e]azepine with excellent enantioselectivity, by reduction of the parent imines. Crystallographic evidence suggests that IREDs may be able to bind one conformer of the imine substrate such that, upon reduction, the major product conformer is generated directly. ω-TA biocatalysts were also successfully employed for the production of enantiopure 1-(2-bromophenyl)ethan-1-amine, thus enabling an orthogonal route for the installation of chirality into dibenz[c,e]azepine framework. [ABSTRACT FROM AUTHOR]

Published
2017
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