Imine reductase

An imine reductase (IRED) is an enzyme that reduces imines to amines. This family of enzymes is employed in the industrial production of amine-containing pharmaceuticals. The IRED enzymes that are found to catalyze both imine formation and imine reduction are called reductive aminases (RedAms).

Imine reduction
IREDs were originally discovered in 2010 by screening bacterial strains for reducing activity on 2-methyl-1-pyrroline (2-MPN). 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.

Reductive amination
IREDs have been employed to reduce imines formed from ketone-amine mixtures. 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. These are dubbed reductive aminases (RedAms). Engineered RedAms have been employed in industrial processes to support production of pharmaceuticals for clinical trials and commercial manufacturing.

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. 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.