Structure-guided semi-rational design of an imine reductase for enantio-complementary synthesis of pyrrolidinamine

Abstract

In this study, engineered imine reductases (IREDs) of IRED M5, originally from Actinoalloteichus hymeniacidonis, were obtained through structure-guided semi-rational design.

Computational design of an imine reductase: mechanism-guided stereoselectivity reversion and interface stabilization

“…PmIR-Re represents an engineered IRED with completely reversed stereoselectivity (>99% ee) achieved through mechanism-guided computational design. In contrast to the previously reported residues W210 in AspRedAm 31 and W234/F260 in IRED-M5, 32 which potentially affect stereoselectivity by steric hindrance of the bulky side chain, the stereoselectivity in PmIR could be controlled by electrostatic interactions between the iminium cation and the acidic amino acids adjacent to the nicotinamide moiety of NADPH. Therefore, the stereoselectivity of IREDs can be tailored through rational reconstruction of electrostatic interactions and reshaping of the binding pocket.…”

Chemoenzymatic total synthesis of rotigotine via IRED-catalyzed reductive amination

“…However, previous studies have indicated that the L200 amino acid site is highly conserved, leading to inactivation in most mutations. 24 The S -selectivity at the F260 site also increased with the introduction of larger side chain amino acid residues. An increase in the ee value was observed when M203 was mutated to leucine, and W234 to alanine and phenylalanine.…”

“…23 In the following year, we developed a semi-rational design approach to identify key residues 260, 200, 149, and 234 that play a crucial role in achieving excellent enantioselectivity. 24,25 In light of these results, we envisaged the opportunity to further explore the potential of this mutant through semi-rational design for the synthesis of ( S )-2-aminotetralin 1a of the rotigotine molecule (Fig. 2B).…”

Chemoenzymatic Synthesis of Selegiline: An Imine Reductase-Catalyzed Approach

“…In our previous research, we successfully developed the IR36-M5 mutant capable of catalyzing reactions involving piperidines and azepane alkylamines while also enhancing and reversing stereocenters [ 37 , 38 ]. Specifically, when utilizing propargylamine a as the donor, both pyrrolidinone and oxo-azepane exhibited outstanding R -stereoselectivity, achieving 98% and 99% ee values, respectively.…”