Imine reductase
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).
Function[edit]
Imine reduction[edit]
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]
Reductive amination[edit]
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[edit]
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[edit]
References[edit]
- ^ a b c Mangas-Sanchez, Juan; France, Scott P; Montgomery, Sarah L; Aleku, Godwin A; Man, Henry; Sharma, Mahima; Ramsden, Jeremy I; Grogan, Gideon; Turner, Nicholas J (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, Maike; Borlinghaus, Niels; Weinmann, Leonie; Nestl, Bettina M. (2017). "Recent advances in imine reductase-catalyzed reactions". World Journal of Microbiology and Biotechnology. 33 (11): 199. doi:10.1007/s11274-017-2365-8. ISSN 0959-3993. PMID 29022156. S2CID 255141416.
- ^ a b Gilio, Amelia K.; Thorpe, Thomas W.; Turner, Nicholas; Grogan, Gideon (2022). "Reductive aminations by imine reductases: from milligrams to tons". Chemical Science. 13 (17): 4697–4713. doi:10.1039/D2SC00124A. ISSN 2041-6520. PMC 9067572. PMID 35655886.
- ^ Mitsukura, Koichi; Suzuki, Mai; Tada, Kazuhiro; Yoshida, Toyokazu; Nagasawa, Toru (2010-08-12). "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. ISSN 1477-0520. PMID 20820664.
- ^ Mitsukura, Koichi; Suzuki, Mai; Shinoda, Sho; Kuramoto, Tatsuya; Yoshida, Toyokazu; Nagasawa, Toru (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. ISSN 0916-8451. PMID 21897027.
- ^ Scheller, Philipp N.; Fademrecht, Silvia; Hofelzer, Sebastian; Pleiss, Jürgen; Leipold, Friedemann; Turner, Nicholas J.; Nestl, Bettina M.; Hauer, Bernhard (2014-10-13). "Enzyme Toolbox: Novel Enantiocomplementary Imine Reductases". ChemBioChem. 15 (15): 2201–2204. doi:10.1002/cbic.201402213. ISSN 1439-4227. PMID 25163890. S2CID 42316871.
- ^ Fademrecht, Silvia; Scheller, Philipp N.; Nestl, Bettina M.; Hauer, Bernhard; Pleiss, Jürgen (2016). "Identification of imine reductase-specific sequence motifs". Proteins: Structure, Function, and Bioinformatics. 84 (5): 600–610. doi:10.1002/prot.25008. ISSN 0887-3585. PMID 26857686. S2CID 10149699.
- ^ Aleku, Godwin A.; France, Scott P.; Man, Henry; Mangas-Sanchez, Juan; Montgomery, Sarah L.; Sharma, Mahima; Leipold, Friedemann; Hussain, Shahed; Grogan, Gideon; Turner, Nicholas J. (2017). "A reductive aminase from Aspergillus oryzae". Nature Chemistry. 9 (10): 961–969. Bibcode:2017NatCh...9..961A. doi:10.1038/nchem.2782. ISSN 1755-4330. PMID 28937665. S2CID 33498137.
- ^ Schober, Markus; MacDermaid, Chris; Ollis, Anne A.; Chang, Sandy; Khan, Diluar; Hosford, Joseph; Latham, Jonathan; Ihnken, Leigh Anne F.; Brown, Murray J. B.; Fuerst, Douglas; Sanganee, Mahesh J.; Roiban, Gheorghe-Doru (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, Rajesh; Karmilowicz, Michael J.; Burke, Dylan; Burns, Michael P.; Clark, Leslie A.; Connor, Christina G.; Cordi, Eric; Do, Nga M.; Doyle, Kevin M.; Hoagland, Steve; Lewis, Chad A.; Mangan, David; Martinez, Carlos A.; McInturff, Emma L.; Meldrum, Kevin (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, María; Frank, Annika; Wells, Elizabeth; Leipold, Friedemann; Turner, Nicholas J.; Hart, Sam; Turkenburg, Johan P.; Grogan, Gideon (2013-07-22). "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. ISSN 1439-4227. PMID 23813853. S2CID 205557837.
- ^ Lenz, Maike; Fademrecht, Silvia; Sharma, Mahima; Pleiss, Jürgen; Grogan, Gideon; Nestl, Bettina M (2018-04-01). "New imine-reducing enzymes from β -hydroxyacid dehydrogenases by single amino acid substitutions". Protein Engineering, Design and Selection. 31 (4): 109–120. doi:10.1093/protein/gzy006. ISSN 1741-0126. PMID 29733377.