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Carbonyl reductase identification and development of whole-cell biotransformation for highly efficient synthesis of (R)-3,5-bis(trifluoromethyl)phenyl ethanol
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Carbonyl reductase identification and development of whole-cell biotransformation for highly efficient synthesis of (R)-3,5-bis(trifluoromethyl)phenyl ethanol
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Journal Article
Carbonyl reductase identification and development of whole-cell biotransformation for highly efficient synthesis of (R)-3,5-bis(trifluoromethyl)phenyl ethanol
2016
Overview
Background
(
R
)-[3,5-bis(trifluoromethyl)phenyl] ethanol [(
R
)-3,5-BTPE] is a valuable chiral intermediate for Aprepitant (Emend) and Fosaprepitant (Ivemend). Biocatalyzed asymmetric reduction is a preferred approach to synthesize highly optically active (
R
)-3,5-BTPE. However, the product concentration and productivity of reported (
R
)-3,5-BTPE synthetic processes remain unsatisfied.
Results
A NADPH-dependent carbonyl reductase from
Lactobacillus kefir
(
Lk
CR) was discovered by genome mining for reduction of 3,5-bis(trifluoromethyl) acetophenone (3,5-BTAP) into (
R
)-3,5-BTPE with excellent enantioselectivity. In order to synthesize (
R
)-3,5-BTPE efficiently,
Lk
CR was coexpressed with glucose dehydrogenase from
Bacillus subtilis
(
Bs
GDH) for NADPH regeneration in
Escherichia coli
BL21 (DE3) cells, and the optimal recombinant strain produced 250.3 g/L (
R
)-3,5-BTPE with 99.9%
ee
but an unsatisfied productivity of 5.21 g/(L h). Then, four different linker peptides were used for the fusion expression of
Lk
CR and
Bs
GDH in
E. coli
to regulate catalytic efficiency of the enzymes and improved NADPH-recycling efficiency. Using the best strain (
E. coli
/pET-
Bs
GDH-ER/K(10 nm)-
Lk
CR), up to 297.3 g/L (
R
)-3,5-BTPE with enantiopurity >99.9%
ee
was produced via reduction of as much as 1.2 M of substrate with a 96.7% yield and productivity of 29.7 g/(L h).
Conclusions
Recombinant
E. coli
/pET-
Bs
GDH-ER/K(10 nm)-
Lk
CR was developed for the bioreduction of 3,5-BTAP to (
R
)-3,5-BTPE, offered the best results in terms of high product concentration and productivity, demonstrating its great potential in industrial manufacturing of (
R
)-3,5-BTPE.
Publisher
BioMed Central,Springer Nature B.V
Subject
/ Aldehyde Reductase - metabolism
/ Chemistry and Materials Science
/ E coli
/ Electrophoresis, Polyacrylamide Gel - methods
/ Ethanol
/ Glucose 1-Dehydrogenase - genetics
/ Glucose 1-Dehydrogenase - metabolism
/ Microbial Genetics and Genomics
/ Peptides
/ Phenylethyl Alcohol - analogs & derivatives
