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

TY - JOUR

T1 - Structures of ‘Tyrosine-IRED’ IR91 from Kribbella flavida in Complex with a Reductive Amination Substrate and Product

AU - Srinivas, Krishnan

AU - Gilio, Amelia

AU - Sharma, Mahima

AU - Green, Lawrence

AU - Ascham, Alexander

AU - Domenech, Jack

AU - Pogranyi, Balazs

AU - Li, Jason

AU - France, Scott P.

AU - Lewis, Russell

AU - Unsworth, William Paul

AU - Grogan, Gideon James

N1 - © 2025 Wiley-VCH GmbH. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2025/9/17

Y1 - 2025/9/17

N2 - 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.

AB - 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.

U2 - 10.1002/cbic.202500450

DO - 10.1002/cbic.202500450

M3 - Article

SN - 1439-4227

VL - 26

JO - Chembiochem

JF - Chembiochem

IS - 17

M1 - e202500450

ER -