Imine reductase
Industrially relevant enzyme
| SkIRED | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Streptomyces kanamyceticus R-selective imine reductase PDB: 3ZHB | |||||||||
| Identifiers | |||||||||
| EC no. | 1.5.1.48 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
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
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
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
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
References
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
