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Imine reductase

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SkIRED
Streptomyces kanamyceticus R-selective imine reductase PDB: 3ZHB
Identifiers
EC no.1.5.1.48
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
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Gene OntologyAmiGO / QuickGO
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An imine reductase (IRED) is an enzyme that reduces imines to amines.[1][2] This family of enzymes is employed in the industrial production of amine-containing pharmaceuticals.[3] The IRED enzymes that are found to catalyze both imine formation and imine reduction are called reductive aminases (RedAms).

Discovery

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IREDs were originally discovered in 2010 by screening bacterial strains for reducing activity on 2-methyl-1-pyrroline (2-MPN).[4][5] Based on each member's ability to reduce 2-MPN to (R)- or (S)-2-methylpyrrolidine they are designated as R-selective or S-selective, respectively.[6][7]

Applications

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IREDs have been employed to reduce imines formed from ketone-amine mixtures.[1][2] The conversion is not a genuine reductive amination as only the second half of the two-part reaction is catalyzed. In 2017 an IRED was discovered that catalyzed both steps of reductive amination of a wide scope of ketone-amine pairs.[8] These are dubbed reductive aminases (RedAms).[1][2] Engineered RedAms have been employed in industrial processes to support production of pharmaceuticals for clinical trials and commercial manufacturing.[9][10]

Structure

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IREDs are dimeric enzymes with each protomer having an N-terminal Rossmann nucleotide-binding domain and a C-terminal dimerization domain joined by a long interdomain α-helix.[3][11] Each protomer's α-helical dimerization domain wraps around the interdomain helix of its dimer partner forming the substrate-binding cleft above the NAD(P)H cofactor binding site in the Rossmann domain. 3-Hydroxybutyrate dehydrogenases have similar N-terminal nucleotide-binding and C-terminal dimerization domains, but do not share the extensive dimerization interface of IREDs.[12]

See also

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References

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  1. ^ a b c Mangas-Sanchez J, France SP, Montgomery SL, Aleku GA, Man H, Sharma M, et al. (April 2017). "Imine reductases (IREDs)". Current Opinion in Chemical Biology. 37: 19–25. doi:10.1016/j.cbpa.2016.11.022. PMID 28038349.
  2. ^ a b c Lenz M, Borlinghaus N, Weinmann L, Nestl BM (October 2017). "Recent advances in imine reductase-catalyzed reactions". World Journal of Microbiology & Biotechnology. 33 (11): 199. doi:10.1007/s11274-017-2365-8. PMID 29022156. S2CID 255141416.
  3. ^ a b Gilio AK, Thorpe TW, Turner N, Grogan G (May 2022). "Reductive aminations by imine reductases: from milligrams to tons". Chemical Science. 13 (17): 4697–4713. doi:10.1039/D2SC00124A. PMC 9067572. PMID 35655886.
  4. ^ Mitsukura K, Suzuki M, Tada K, Yoshida T, Nagasawa T (October 2010). "Asymmetric synthesis of chiral cyclic amine from cyclic imine by bacterial whole-cell catalyst of enantioselective imine reductase". Organic & Biomolecular Chemistry. 8 (20): 4533–4535. doi:10.1039/C0OB00353K. PMID 20820664.
  5. ^ Mitsukura K, Suzuki M, Shinoda S, Kuramoto T, Yoshida T, Nagasawa T (2011-09-23). "Purification and characterization of a novel (R)-imine reductase from Streptomyces sp. GF3587". Bioscience, Biotechnology, and Biochemistry. 75 (9): 1778–1782. doi:10.1271/bbb.110303. PMID 21897027.
  6. ^ Scheller PN, Fademrecht S, Hofelzer S, Pleiss J, Leipold F, Turner NJ, et al. (October 2014). "Enzyme toolbox: novel enantiocomplementary imine reductases". ChemBioChem. 15 (15): 2201–2204. doi:10.1002/cbic.201402213. PMID 25163890. S2CID 42316871.
  7. ^ Fademrecht S, Scheller PN, Nestl BM, Hauer B, Pleiss J (May 2016). "Identification of imine reductase-specific sequence motifs". Proteins. 84 (5): 600–610. doi:10.1002/prot.25008. PMID 26857686. S2CID 10149699.
  8. ^ Aleku GA, France SP, Man H, Mangas-Sanchez J, Montgomery SL, Sharma M, et al. (October 2017). "A reductive aminase from Aspergillus oryzae". Nature Chemistry. 9 (10): 961–969. Bibcode:2017NatCh...9..961A. doi:10.1038/nchem.2782. PMID 28937665. S2CID 33498137.
  9. ^ Schober M, MacDermaid C, Ollis AA, Chang S, Khan D, Hosford J, et al. (2019-09-16). "Chiral synthesis of LSD1 inhibitor GSK2879552 enabled by directed evolution of an imine reductase". Nature Catalysis. 2 (10): 909–915. doi:10.1038/s41929-019-0341-4. ISSN 2520-1158. S2CID 202580808.
  10. ^ Kumar R, Karmilowicz MJ, Burke D, Burns MP, Clark LA, Connor CG, et al. (2021-09-21). "Biocatalytic reductive amination from discovery to commercial manufacturing applied to abrocitinib JAK1 inhibitor". Nature Catalysis. 4 (9): 775–782. doi:10.1038/s41929-021-00671-5. ISSN 2520-1158. S2CID 237588372.
  11. ^ Rodríguez-Mata M, Frank A, Wells E, Leipold F, Turner NJ, Hart S, et al. (July 2013). "Structure and activity of NADPH-dependent reductase Q1EQE0 from Streptomyces kanamyceticus, which catalyses the R-selective reduction of an imine substrate". ChemBioChem. 14 (11): 1372–1379. doi:10.1002/cbic.201300321. PMID 23813853. S2CID 205557837.
  12. ^ Lenz M, Fademrecht S, Sharma M, Pleiss J, Grogan G, Nestl BM (April 2018). "New imine-reducing enzymes from β-hydroxyacid dehydrogenases by single amino acid substitutions". Protein Engineering, Design & Selection. 31 (4): 109–120. doi:10.1093/protein/gzy006. PMID 29733377.