9H4F

Structure of Imine Reductase 361 from Micromonospora sp. mutant M125W/I127F/L179V/H250L

Summary for 9H4F

• Entry DOI: 10.2210/pdb9h4f/pdb
• Descriptor: 6-phosphogluconate dehydrogenase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (2 entities in total)
• Functional Keywords: amine, nadp, oxidoreductase
• Biological source: Micromonospora
• Total number of polymer chains: 2
• Total formula weight: 63972.87

Authors

Ho, E.,Domenech, J.,Crossley, A.,Green, A.P.,Grogan, G. (deposition date: 2024-10-18, release date: 2025-08-27)

Primary citation

Hutton, A.E.,Zhao, F.,Ho, E.,Domenech, J.,Harawa, V.,Brown, M.J.B.,Grogan, G.,Clayman, P.D.,Turner, N.J.,Green, A.P.
Engineered Biocatalyst for Enantioselective Hydrazone Reduction.
Angew.Chem.Int.Ed.Engl., 64:e202424350-e202424350, 2025

PubMed Abstract: Enantioselective reduction of hydrazones provides a convergent and versatile route to synthesize hydrazine-containing motifs that are commonly found in pharmaceuticals and agrochemicals. However, current methods require the use of precious metals, costly chiral ligands, and/or forcing reaction conditions. Here, we report the development of a biocatalytic approach for enantioselective hydrazone reduction using engineered imine reductases. Following evaluation of an in-house panel of >400 IRED sequences, we identified a single IR361 I127F L179V variant that promotes reduction of Cbz-protected hydrazones. The introduction of additional two mutations via directed evolution afforded HRED1.1 that is 20-fold more active than the parent template and promotes reduction of a variety of protected hydrazones in high yields and selectivities (>99% e.e.), including in preparative scale biotransformations. Structural analysis of HRED1.1 provides insights into the origins of its unique hydrazone reductase activity. This study offers a powerful biocatalytic route to synthesize valuable chiral hydrazine products and further expands the impressive range of transformations accessible with engineered imine reductases.

PubMed: 40244857
DOI: 10.1002/anie.202424350

Experimental method

X-RAY DIFFRACTION (2.77 Å)