Structures of ‘Tyrosine-IRED’ IR91 from Kribbella flavida in Complex with a Reductive Amination Substrate and Product

Imine reductases with an (S)-preference for the reduction of the model substrate 2-methyl pyrroline typically contain tyrosine in the active site (Y-IREDs) instead of the aspartate present within (R)-selective enzymes (D-IREDs). As with D-IREDs, a subset of Y-IREDs is capable of enabling reductive amination reactions between some ketone and amine partners to give optical active amines with high optical purity. However, structures of Y-IREDs in complex with the substrates and products of the reductive amination have not been forthcoming. Here we present structures of the Y-IRED IR91 from Kribbella flavida in complex with 5-methoxy-2-tetralone, a synthetic precursor to the anti-Parkinson’s treatment rotigotine, and also its reductive amination product with methylamine, 5-methoxy-(S)-2-(N-methylamino)-tetralin. The structures, in combination with mutation and kinetic studies, support a role for tryptophan residue W258 in the activity of the enzyme, possibly in binding of the ketone prior to reaction with methylamine.