A novel method of producing the key intermediate ASI-2 of ranirestat using a porcine liver esterase (PLE) substitute enzyme
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Published:2019-06-03
Issue:6
Volume:83
Page:1124-1135
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ISSN:0916-8451
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Container-title:Bioscience, Biotechnology, and Biochemistry
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language:en
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Short-container-title:
Author:
Yamamura Ei-Tora1, Tsuzaki Kazuya1, Kita Shinji1
Affiliation:
1. Technical Department, Kyowa Pharma Chemical Co., Ltd., Takaoka, Japan
Abstract
ABSTRACT
(R)-2-amino-2-ethoxycarbonylsuccinimide (ASI-2) is a key intermediate used in the pharmaceutical industry and is valuable for the industrial synthesis of ranirestat, which is a potent aldose reductase inhibitor. ASI-2 was synthesized in a process combining chemical synthesis and bioconversion. Bioconversion in this study is a key reaction, since optically active carboxylic acid derivative ((R)-1-ethyl hydrogen 3-benzyloxycarbonylamino-3-ethoxycarbonylsuccinate, Z-MME-AE) is synthesized from a prochiral ester, diethyl 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinate, Z-MDE-AE, at a theoretical yield of 100%. Upon screening for microorganisms that asymmetrically hydrolyze Z-MDE-AE, Bacillus thuringiensis NBRC13866 was found. A novel esterase EstBT that produces Z-MME-AE was purified from Bacillus thuringiensis NBRC13866 and was stably produced in Escherichia coli JM109 cells. Using EstBT rather than porcine liver esterase (PLE), ASI-2 was synthesized with a 17% higher total yield by a novel method, suggesting that the esterase EstBT is a PLE substitute enzyme and therefore, may be of interest for future industrial applications.
Funder
Kyowa Pharma Chemical Co., Ltd
Publisher
Oxford University Press (OUP)
Subject
Organic Chemistry,Molecular Biology,Applied Microbiology and Biotechnology,General Medicine,Biochemistry,Analytical Chemistry,Biotechnology
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