Skip to main content
SpringerLink
Log in

Recent advances in imine reductase-catalyzed reactions

  • Review
  • Published:
World Journal of Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Imine reductases are nicotinamide-dependent enzymes that catalyze the asymmetric reduction of various imines to the corresponding amine products. Owing to the increasing roles of chiral amines and heterocyclic compounds as intermediates for pharmaceuticals, the demand for novel selective synthesis strategies is vitally important. Recent studies have demonstrated the discovery and structural characterization of a number of stereoselective imine reductase enzymes. Here, we highlight recent progress in applying imine reductases for the formation of chiral amines and heterocycles. It particularly focuses on the utilization of imine reductases in reductive aminations of aldehydes and ketones with various amine nucleophiles, one of the most powerful reactions in the synthesis of chiral amines. Second, we report on the synthesis of saturated substituted N-heterocycles by combining them with further biocatalysts, such as carboxylic acid reductases, oxidases or transaminases. Finally, we summarize the latest applications of imine reductases in the promiscuous asymmetric hydrogenation of a highly reactive carbonyl compound and the engineering of the cofactor specificity from NADPH to NADH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abrahamson MJ, Vázquez-Figueroa E, Woodall NB et al (2012) Development of an amine dehydrogenase for synthesis of chiral amines. Angew Chemie 51:3969–3972

    Article  CAS  Google Scholar 

  • Aleku GA, Man H, France SP et al (2016) Stereoselectivity and structural characterization of an imine reductase (IRED) from Amycolatopsis orientalis. ACS Catal 6:3880–3889

    Article  CAS  Google Scholar 

  • Aleku GA, France SP, Man H et al (2017) A reductive aminase from Aspergillus oryzae. Nat Chem 9:961–969

    Article  CAS  Google Scholar 

  • Alexandre F-R, Pantaleone DP, Taylor PP et al (2002) Amine – boranes : effective reducing agents for the deracemisation of DL-amino acids using L-amino acid oxidase from Proteus myxofaciens. Tetrahedron Lett 43:707–710

    Article  CAS  Google Scholar 

  • Balkenhohl F, Dietrich K, Hauer B, Ladner W (1997) Optisch aktive Amine durch Lipase-katalysierte Methoxyacetylierung. J für Prakt Chemie Chem 339:381–384

    Article  CAS  Google Scholar 

  • Beard TM, Turner NJ (2002) Deracemisation and stereoinversion of α-amino acids using D-amino acid oxidase and hydride reducing agents. Chem Commun 3:246–247

    Article  Google Scholar 

  • Bommarius AS, Drauz K, Hummel W et al (1994) Some new developments in reductive amtnation with cofactor regeneration. Biocatal Biotransformation 10:37–47

    Article  CAS  Google Scholar 

  • Bommarius BR, Schürmann M, Bommarius AS et al. (2014) A novel chimeric amine dehydrogenase shows altered substrate specificity compared to its parent enzymes. Chem Commun 50:14953–14955

    Article  CAS  Google Scholar 

  • Borlinghaus N, Nestl BM (2017) Switching the cofactor specificity of an imine reductase. ChemCatChem. doi:10.1002/cctc.201701194

  • Breuer M, Ditrich K, Habicher T et al (2004) Industrial methods for the production of optically active intermediates. Angew Chem Int Ed 43:788–824

    Article  CAS  Google Scholar 

  • Brien PJO, Herschlag D (1999) Catalytic promiscuity and the evolution of new enzymatic activities. Chem Biol 6:R91–R105

    Article  Google Scholar 

  • Busto E, Gotor-Fernández V, Gotor V (2011) Hydrolases in the Stereoselective synthesis of N-heterocyclic amines and amino acid derivatives. Chem Rev 111:3998–4035

    Article  CAS  Google Scholar 

  • Cahn JKB, Werlang CA, Baumschlager A et al (2017) A general tool for engineering the NAD/NADP cofactor preference of oxidoreductases. ACS Synth Biol 6:326–333

    Article  CAS  Google Scholar 

  • Chen H, Moore J, Lier SJ (2013) Engineerd imine reductases and methods for the reductive amination of ketone and amine compounds. Patent WO2013170050 A1

  • DeSieno M, Du J, Zhao H (2008) Altering enzyme substrate and cofactor specificity via protein engineering. In: Lutz S, Bornscheuer UT (eds) Protein engineering handbook. Wiley, Hoboken, pp 777–796

    Google Scholar 

  • France SP, Hussain S, Hill AM et al (2016) One-pot cascade synthesis of mono- and disubstituted piperidines and pyrrolidines using carboxylic acid reductase (CAR), ω-transaminase (ω-TA), and imine reductase (IRED) biocatalysts. ACS Catal 6:3753–3759

    Article  CAS  Google Scholar 

  • France SP, Howard RM, Steflik J, Weise NJ, Mangas-Sanchez J, Montgomery SL, Crook R, Kumar R, Turner NJ (2017a) Identification of novel bacterial members of the imine reductase enzyme family that perform reductive amination. ChemCatChem. doi: 10.1002/cctc.201701408

    Google Scholar 

  • France SP, Hepworth LJ, Turner NJ, Flitsch SL (2017b) Constructing biocatalytic cascades: in vitro and in vivo approaches to de novo multi-enzyme pathways. ACS Catal 7:710–724

    Article  CAS  Google Scholar 

  • Gand M, Müller H, Wardenga R, Höhne M (2014) Characterization of three novel enzymes with imine reductase activity. J Mol Catal B 110:126–132

    Article  CAS  Google Scholar 

  • Gand M, Thöle C, Müller H et al (2016) A NADH-accepting imine reductase variant: immobilization and cofactor regeneration by oxidative deamination. J Biotechnol 230:11–18

    Article  CAS  Google Scholar 

  • Ghislieri D, Turner NJ (2013) Biocatalytic approaches to the synthesis of enantiomerically pure chiral amines. Top Catal 57:284–300

    Article  Google Scholar 

  • Grogan G, Turner NJ (2016) InspIRED by nature: NADPH-dependent imine reductases (ireds) as catalysts for the preparation of chiral amines. Chem A Eur J 22:1900–1907

    Article  CAS  Google Scholar 

  • Heath RS, Pontini M, Hussain S, Turner NJ (2016) Combined imine reductase and amine oxidase catalyzed deracemization of nitrogen heterocycles. ChemCatChem 8:117–120

    Article  CAS  Google Scholar 

  • Hepworth LJ, France SP, Hussain S et al (2017) Enzyme cascades in whole cells for the synthesis of chiral cyclic amines. ACS Catal 7:2920–2925

    Article  CAS  Google Scholar 

  • Hoffmann S, Seayad AM, List B (2005) A powerful Brønsted acid catalyst for the organocatalytic asymmetric transfer hydrogenation of imines. Angew Chem Int Ed 44:7424–7427

    Article  CAS  Google Scholar 

  • Huber T, Schneider L, Präg A et al (2014) Direct reductive amination of ketones: structure and activity of S-selective imine reductases from Streptomyces. ChemCatChem 6:2248–2252

    Article  CAS  Google Scholar 

  • Hussain S, Leipold F, Man H et al (2015) An (R)-Imine reductase biocatalyst for the asymmetric reduction of cyclic imines. ChemCatChem 7:579–583

    Article  CAS  Google Scholar 

  • Ismail H, Lau RM, Van Rantwijk F, Sheldon RA (2008) Fully enzymatic resolution of chiral amines: acylation and deacylation in the presence of Candida antarctica lipase B. Adv Synth Catal 350:1511–1516

    Article  CAS  Google Scholar 

  • Jarvis LM (2016) The year in new drugs. Chem Eng News 94:12–17

    Google Scholar 

  • Jarvis WR, Colbeck JC, Krebber A et al (2010) Biocatalytic asymmetric synthesis of sitagliptin manufacture. Science 329:305–310

    Article  Google Scholar 

  • Johnson NB, Lennon IC, Moran PH, Ramsden JA (2007) Industrial-scale synthesis and applications of asymmetric hydrogenation catalysts. Acc Chem Res 40:1291–1299

    Article  CAS  Google Scholar 

  • Khersonsky O, Tawfik DS (2010) Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biochem 79:471–505

    Article  CAS  Google Scholar 

  • Khersonsky O, Roodveldt C, Tawfik DS (2006) Enzyme promiscuity: evolutionary and mechanistic aspects. Curr Opin Chem Biol 10:498–508

    Article  CAS  Google Scholar 

  • Knaus T, Böhmer W, Mutti FG (2017) Amine dehydrogenases: efficient biocatalysts for the reductive amination of carbonyl compounds. Green Chem 19:453–463

    Article  CAS  Google Scholar 

  • Kohls H, Steffen-Munsberg F, Höhne M (2014) Recent achievements in developing the biocatalytic toolbox for chiral amine synthesis. Curr Opin Chem Biol 19:180–192

    Article  CAS  Google Scholar 

  • Koszelewski D, Tauber K, Faber K, Kroutil W (2010) ω-Transaminases for the synthesis of non-racemic α-chiral primary amines. Trends Biotechnol 28:324–332

    Article  CAS  Google Scholar 

  • Leipold F, Hussain S, Ghislieri D, Turner NJ (2013) Asymmetric reduction of cyclic imines catalyzed by a whole-cell biocatalyst containing an (S)-imine reductase. ChemCatChem 5:3505–3508

    Article  CAS  Google Scholar 

  • Lenz M, Meisner J, Quertinmont L et al (2017) Asymmetric ketone reduction by imine reductases. ChemBioChem 18:253–256

    Article  CAS  Google Scholar 

  • Li H, Luan Z-J, Zheng G-W, Xu J-H (2015) Efficient synthesis of chiral indolines using an imine reductase from Paenibacillus lactis. Adv Synth Catal 357:1692–1696

    Article  CAS  Google Scholar 

  • Li H, Zhang GX, Li LM et al (2016) A Novel (R)-imine reductase from Paenibacillus lactis for asymmetric reduction of 3H-indoles. ChemCatChem 8:724–727

    Article  CAS  Google Scholar 

  • Lundquist R, Olivera BM (1971) Pyridine nucleotide metabolism in Escherichia coli. J Biol Chem 246:1107–1116

    CAS  Google Scholar 

  • Man H, Wells E, Hussain S et al (2015) Structure, activity and stereoselectivity of NADPH-dependent oxidoreductases catalysing the S-selective reduction of the imine substrate 2-methylpyrroline. ChemBioChem 16:1052–1059

    Article  CAS  Google Scholar 

  • Mangas-Sanchez J, France SP, Montgomery SL et al (2017) Imine reductases (IREDs). Curr Opin Chem Biol 37:19–25

    Article  CAS  Google Scholar 

  • Matzel P, Gand M, Höhne M (2017) One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases. Green Chem 19:385–389

    Article  CAS  Google Scholar 

  • Maugeri Z, Rother D (2016) Application of imine reductases (IREDs) in micro-aqueous reaction systems. Adv Synth Catal 358:2745–2750

    Article  CAS  Google Scholar 

  • Maugeri Z, Rother D (2017) Reductive amination of ketones catalyzed by whole cell biocatalysts containing imine reductases (IREDs). J Biotechnol 258:167–170

    Article  CAS  Google Scholar 

  • Mitsukura K, Suzuki M, Shinoda S et al (2011) Purification and characterization of a novel (R)-imine reductase from Streptomyces sp. GF3587. Biosci Biotechnol Biochem 75:1778–1782

    Article  CAS  Google Scholar 

  • Mitsukura K, Kuramoto T, Yoshida T et al (2013) A NADPH-dependent (S)-imine reductase (SIR) from Streptomyces sp. GF3546 for asymmetric synthesis of optically active amines: purification, characterization, gene cloning, and expression. Appl Microbiol Biotechnol 97:8079–8086

    Article  CAS  Google Scholar 

  • Muschiol J, Peters C, Oberleitner N et al (2015) Cascade catalysis–strategies and challenges en route to preparative synthetic biology. Chem Commun 51:5798–5811

    Article  CAS  Google Scholar 

  • Nugent TC, El-Shazly M (2010) Chiral amine synthesis: recent developments and trends for enamide reduction, reductive amination, and imine reduction. Adv Synth Catal 352:753–819

    Article  CAS  Google Scholar 

  • Ratzka J, Lauterbach L, Lenz O, Ansorge-Schumacher MB (2011) Systematic evaluation of the dihydrogen-oxidising and NAD+-reducing soluble [NiFe]-hydrogenase from Ralstonia eutropha H16 as a cofactor regeneration catalyst. Biocatal Biotransform 29:246–252

    Article  CAS  Google Scholar 

  • Rodríguez-Mata M, Frank A, Wells E et al (2013) Structure and activity of NADPH-dependent reductase Q1EQE0 from Streptomyces kanamyceticus, which catalyses the R-selective reduction of an imine substrate. ChemBioChem 14:1372–1379

    Article  Google Scholar 

  • Roiban G-D, Kern M, Liu Z et al (2017) Efficient biocatalytic reductive aminations by extending the imine reductase toolbox. ChemCatChem. doi:10.1002/cctc.201701379

    Google Scholar 

  • Scheller PN, Nestl BM (2016) The biochemical characterization of three imine-reducing enzymes from Streptosporangium roseum DSM43021, Streptomyces turgidiscabies and Paenibacillus elgii. Appl Microbiol Biotechnol 100:10509–10520

    Article  CAS  Google Scholar 

  • Scheller PN, Fademrecht S, Hofelzer S et al (2014) Enzyme toolbox: novel enantiocomplementary imine reductases. ChemBioChem 15:2201–2204

    Article  CAS  Google Scholar 

  • Scheller PN, Lenz M, Hammer SC et al (2015) Imine reductase-catalyzed intermolecular reductive amination of aldehydes and ketones. ChemCatChem 7:3239–3242

    Article  CAS  Google Scholar 

  • Schrittwieser JH, Velikogne S, Kroutil W (2015) Biocatalytic imine reduction and reductive amination of ketones. Adv Synth Catal 357:1655–1685

    Article  CAS  Google Scholar 

  • Schrittwieser JH, Velikogne S, Hall M, Kroutil W (2017) Artificial biocatalytic linear cascades for preparation of organic molecules. Chem Rev. doi: 10.1021/acs.chemrev.7b00033

    Google Scholar 

  • Shaked Z, Whitesides GM (1980) Enzyme-catalyzed organic synthesis: NADH regeneration by using formate dehydrogenase. J Am Chem Soc 102:7104–7105

    Article  CAS  Google Scholar 

  • Slabu I, Galman JL, Weise NJ et al (2016) Putrescine transaminases for the synthesis of saturated nitrogen heterocycles from polyamines. ChemCatChem 8:1038–1042

    Article  CAS  Google Scholar 

  • van der Donk WA, Zhao H (2003) Recent developments in pyridine nucleotide regeneration. Curr Opin Biotechnol 14:421–426

    Article  Google Scholar 

  • Vrtis JM, White AK, Metcalf WW, van der Donk WA (2002) Phosphite dehydrogenase: a versatile cofactor-regeneration enzyme. Angew Chemie Int Ed 41:3257–3259

    Article  CAS  Google Scholar 

  • Wang C, Xiao J (2014) Asymmetric reductive amination. In: Li W, Zhang X (eds) Stereoselective formation of amines. Springer, New York pp 261–282

    Google Scholar 

  • Wetzl D, Berrera M, Sandon N et al (2015) Expanding the imine reductase toolbox by exploring the bacterial protein sequence space. ChemBioChem 16:1749–1756

    Article  CAS  Google Scholar 

  • Wetzl D, Gand M, Ross A et al (2016) Asymmetric reductive amination of ketones catalyzed by imine reductases. ChemCatChem 8:2023–2026

    Article  CAS  Google Scholar 

  • Zhu J, Tan H, Yang L et al (2017) Enantioselective synthesis of 1-aryl-substituted tetrahydroisoquinolines employing imine reductase. ACS Catal 7:7003–7007

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the European Union and EFPIA companies in kind contribution for the Innovative Medicine Initiative under Grant Agreement No. 115360 (Chemical manufacturing methods for the twenty-first century pharmaceutical industries, CHEM21) and the DFG (Deutsche Forschungsgemeinschaft).

Author information

Authors and Affiliations

  1. Institute of Biochemistry and Technical Biochemistry, Universitaet Stuttgart, Allmandring 31, 70569, Stuttgart, Germany

    Maike Lenz, Niels Borlinghaus, Leonie Weinmann & Bettina M. Nestl

Authors
  1. Maike Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Niels Borlinghaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leonie Weinmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bettina M. Nestl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bettina M. Nestl.

Ethics declarations

Conflict of interest

All the authors approved the manuscript and have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lenz, M., Borlinghaus, N., Weinmann, L. et al. Recent advances in imine reductase-catalyzed reactions. World J Microbiol Biotechnol 33, 199 (2017). https://doi.org/10.1007/s11274-017-2365-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11274-017-2365-8

Keywords

Search

Navigation