Journal ArticleDOI
Identification of imine reductase‐specific sequence motifs
TLDR
The results indicate a preference toward NADPH for all IREDs and explain why, despite their sequence similarity to β‐hydroxyacid dehydrogenases (β‐HADs), no conversion of β‐Hydroxyacids has been observed.Abstract:
Chiral amines are valuable building blocks for the production of a variety of pharmaceuticals, agrochemicals and other specialty chemicals. Only recently, imine reductases (IREDs) were discovered which catalyze the stereoselective reduction of imines to chiral amines. Although several IREDs were biochemically characterized in the last few years, knowledge of the reaction mechanism and the molecular basis of substrate specificity and stereoselectivity is limited. To gain further insights into the sequence-function relationships, the Imine Reductase Engineering Database (www.IRED.BioCatNet.de) was established and a systematic analysis of 530 putative IREDs was performed. A standard numbering scheme based on R-IRED-Sk was introduced to facilitate the identification and communication of structurally equivalent positions in different proteins. A conservation analysis revealed a highly conserved cofactor binding region and a predominantly hydrophobic substrate binding cleft. Two IRED-specific motifs were identified, the cofactor binding motif GLGxMGx(5 )[ATS]x(4) Gx(4) [VIL]WNR[TS]x(2) [KR] and the active site motif Gx[DE]x[GDA]x[APS]x(3){K}x[ASL]x[LMVIAG]. Our results indicate a preference toward NADPH for all IREDs and explain why, despite their sequence similarity to β-hydroxyacid dehydrogenases (β-HADs), no conversion of β-hydroxyacids has been observed. Superfamily-specific conservations were investigated to explore the molecular basis of their stereopreference. Based on our analysis and previous experimental results on IRED mutants, an exclusive role of standard position 187 for stereoselectivity is excluded. Alternatively, two standard positions 139 and 194 were identified which are superfamily-specifically conserved and differ in R- and S-selective enzymes.read more
Citations
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Journal ArticleDOI
Imine reductases (IREDs)
Juan Mangas-Sanchez,Sarah L. Montgomery,Godwin A. Aleku,Henry Man,Mahima Sharma,Jeremy I. Ramsden,Gideon Grogan,Nicholas J. Turner +7 more
TL;DR: The latest developments in the structural and mechanistic aspects of IREDs are described, together with synthetic applications of these enzymes, and ongoing and future challenges in the field are identified.
Journal ArticleDOI
Biocatalysis: A Pharma Perspective
Joseph P. Adams,Murray J. B. Brown,Alba Diaz-Rodriguez,Richard C. Lloyd,Gheorghe-Doru Roiban +4 more
Journal ArticleDOI
Oxidoreductase-Catalyzed Synthesis of Chiral Amines
TL;DR: The recent progress achieved and current perspectives in the enzymatic synthesis of chiral amines using four important enzymes, i.e., imine reductases, amine dehydrogenases, monoamine oxidases, and cytochrome P450s are reported.
Journal ArticleDOI
One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases
TL;DR: This work synthesized the pharmaceutically relevant (R)-rasagiline in high yields and good enantiomeric excess from the ketone precursor and demonstrates for the first time that tertiary amines also can be accessed by this route, which provides new opportunities for eco-friendly enzymatic asymmetric syntheses of these important molecules.
Journal ArticleDOI
Efficient Biocatalytic Reductive Aminations by Extending the Imine Reductase Toolbox
Gheorghe-Doru Roiban,Marcelo Kern,Zhi Liu,Julia F. Hyslop,Julia F. Hyslop,Pei Lyn Tey,Matthew S. Levine,Lydia Sanchez Jordan,Kristin K. Brown,Timin Hadi,Leigh Anne F. Ihnken,Murray J. B. Brown +11 more
TL;DR: The use of cell lysates expressing imine reductases operating at 1:1 stoichiometry for a variety of amines and carbonyls is reported.
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