Efficient biosynthesis of (R)-1-(3-(trifluoromethyl)phenyl)ethanol using a novel reductase AxSDR from Algoriella xinjiangensis

(R)-1-(3-(trifluoromethyl)phenyl)ethanol ((R)-1b) is a crucial chiral intermediate for synthesizing neuroprotective drugs, such as (R)-3-(1-(3-(trifluoromethyl)phenyl)ethoxy) azetidine-1-carboxamide. In this study, through gene mining strategies, a novel short-chain dehydrogenase/reductase from Algoriella xinjiangensis (AxSDR) was discovered. Reductase AxSDR exhibits outstanding reduction capabilities, and was successfully expressed in Escherichia coli BL21(DE3). The recombinant E. coli expressing AxSDR demonstrated differential catalytic activities toward prochiral aromatic ketones. Notably, AxSDR have strong preference for ketones substituted at the meta- or para-positions, as opposed to their ortho-substituted counterparts. Homology modeling and molecular docking were performed to elucidate the molecular basis of AxSDR's substrate selectivity. Furthermore, by optimizing reactions parameters, a highly efficient asymmetric bioreduction process was established for converting 3′-(trifluoromethyl)acetophenone (1a) to (R)-1b Using recombinant E. coli whole cells expressing AxSDR as biocatalysts, 1500 mmol·L^-1 1a was converted to (R)-1b, achieving a yield of 99.4 %, an enantiomeric excess of 99.8 % and a space-time yield (STY) of 523 g·L^-1·d^-1 under optimized conditions. These results represent the highest substrate loading and STY reported to date for (R)-1b production. Significantly, the AxSDR is the first reductase with reducing activity reported from A. xinjiangensis, and its exceptional performance highlights its potential as a promising biocatalyst for the industrial-scale preparation of (R)-1b