| 新型醛酮还原酶不对称转化制备(S)-N,N-二甲基-3-羟基-
3-(2-噻吩)-1-丙胺 |
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| 引用本文： | 郭荣云,聂尧,穆晓清,徐岩,肖荣.新型醛酮还原酶不对称转化制备(S)-N,N-二甲基-3-羟基-
3-(2-噻吩)-1-丙胺[J].化工进展,2014,33(9):2344-2349. |
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| 作者姓名： | 郭荣云 聂尧 穆晓清 徐岩 肖荣 |
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| 作者单位： | 1.江南大学生物工程学院工业生物技术教育部重点实验室，江苏 无锡 214122；2江南大学食品生物技术国家重点实验室，江苏 无锡 214122；3罗格斯大学高级生物技术与医学中心，新泽西州 08854，美国 |
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| 基金项目： | 国家重点基础研究发展计划(2011CB710800);国家高技术研究发展计划(2011AA02A209、2011AA02A210);国家自然科学基金(21376107、21336009);高等学校学科创新引智计划(111计划)(111-2-06);高端外国专家项目(GDW20133200113);江苏高校优势学科建设工程项目 |
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| 摘 要： | 生物催化具有反应条件温和、绿色环保、高立体选择性等优点，已成为制备光学活性度洛西汀的重要方式和途径，但仍存在有效的生物催化剂数量有限和反应效率低等问题，基因组数据库的发展为新型立体选择性生物催化剂的开发提供了有效的途径和平台。本研究通过基因组信息挖掘，从Candida parapsilosis CCTCCM 203011中发现了8个新型的醛酮还原酶，分析研究不同的醛酮还原酶对N,N-二甲基-3-酮-3-(2-噻吩)-1-丙胺(DKTP)的催化还原能力，发现CPAR4能够高立体选择性地催化还原DKTP生成度洛西汀中间体(S)-N,N-二甲基-3-羟 基-3-(2-噻吩)-1-丙胺(DHTP)。通过粗酶体系反应参数的优化，CPAR4催化还原底物浓度在3g/L时，产率达到94.5%，光学纯度大于99.9%ee；当底物浓度为5g/L 时，产率仍达到70%以上。该重组菌粗酶液能够高立体选择性地生物还原DKTP生成度洛西汀中间体 (S)-DHTP，具有一定的应用潜力。
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| 关 键 词： | 醛酮还原酶 生物催化 选择催化还原 (S)-N N-二甲基-3-羟基-3-(2-噻吩)-1-丙胺 粗酶体系 |
A novel aldo-keto reductase for the biocatalytic synthesis of (S)-N,N- dimethyl-3-hydroxy-3-(2-thienyl)-1-propanamine |
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| GUO Rongyun;NIE Yao;MU Xiaoqing;XU Yan;XIAO Rong.A novel aldo-keto reductase for the biocatalytic synthesis of (S)-N,N- dimethyl-3-hydroxy-3-(2-thienyl)-1-propanamine[J].Chemical Industry and Engineering Progress,2014,33(9):2344-2349. |
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| Authors: | GUO Rongyun;NIE Yao;MU Xiaoqing;XU Yan;XIAO Rong |
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| Affiliation: | 1 School of Biotechnology and Key Laboratory of Industrial Biotechnology，Ministry of Education，Jiangnan University，Wuxi 214122，Jiangsu，China；2State Key Laboratory of Food Science and Technology，Jiangnan University，Wuxi 214122，Jiangsu，China；3 The Center for Advanced Biotechnology and Medicine，Rutgers University，New Jersey 08854，USA |
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| Abstract: | Biocatalytic synthesis of chiral Duloxetine and its intermediate is one of the greatest technologies due to its high chemo-，regio- and stereo-selectivity；while the amount of available biocatalyst is yet limited and the conversion efficiency needs to be improved. In recent years，the availability of microbial genome sequences allows scientists to discover novel enzymes with potential applications. Based on the genome sequence of Candida parapsilosis，eight aldo-keto reductases were discovered and evaluated for the synthesis of N,N-dimethyl-3-keto-3-(2-thienyl)-1- propanamine (DKTP). Among them，CPAR4 showed higher catalytic ability for asymmetric reduction of N,N-dimethyl-3-keto-3-(2-thienyl)-1-propanamine (DKTP) to (S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)- 1-propanamine (DHTP)，a key intermediate of chiral Duloxetine. Then the biomediated reaction conditions using the cell-free system involving the expressed CPAR4 were optimized and (S)-DHTP (>99.9%ee) was produced with the yield of 94.5% at the initial substrate concentration of 3g/L，and even when the substrate concentration was increased to 5g/L，the enantiopure product can also be obtained with the yield over 70%. Therefore，the newly identified enzyme and its cell-free system would be promising for highly stereo specific bioreduction of prochiral pharmaceutical intermediates. |
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| Keywords: | aldo-keto reductase biocatalysis SCR (S)-N N-dimethyl-3-hydroxy-3-(2-thienyl)- 1-propanamine cell-free system |
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