Cui Li, Zhu Ying, Guan Xiaoqing, Deng Zixin, Bai Linquan, Feng Yan
State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, and Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University , Shanghai 200240, China.
ACS Synth Biol. 2016 Jan 15;5(1):15-20. doi: 10.1021/acssynbio.5b00138. Epub 2015 Oct 13.
The C7N aminocyclitol β-valienamine is a lead compound for the development of new biologically active β-glycosidase inhibitors as chemical chaperone therapeutic agents for lysosomal storage diseases. Its chemical synthesis is challenging due to the presence of multichiral centers in the structure. Herein, we took advantage of a heterogeneous aminotransferase with stereospecificity and designed a novel pathway for producing β-valienamine in Streptomyces hygroscopicus 5008, a validamycin producer. The aminotransferase BtrR from Bacillus circulans was able to convert valienone to β-valienamine with an optical purity of up to >99.9% enantiomeric excess value in vitro. When the aminotransferase gene was introduced into a mutant of S. hygroscopicus 5008 accumulating valienone, 20 mg/L of β-valienamine was produced after 96 h cultivation in shaking flasks. This work provides a powerful alternative for preparing the chiral intermediates for pharmaceutical development.
C7N氨基环醇β-缬氨胺是开发新型生物活性β-糖苷酶抑制剂的先导化合物，可作为溶酶体贮积病的化学伴侣治疗剂。由于其结构中存在多个手性中心，其化学合成具有挑战性。在此，我们利用具有立体特异性的非均相转氨酶，设计了一条在有效霉素产生菌吸水链霉菌5008中生产β-缬氨胺的新途径。来自环状芽孢杆菌的转氨酶BtrR能够在体外将缬氨酮转化为β-缬氨胺，对映体过量值的光学纯度高达>99.9%。当将转氨酶基因导入积累缬氨酮的吸水链霉菌5008突变体中时，在摇瓶中培养96小时后产生了20 mg/L的β-缬氨胺。这项工作为制备用于药物开发的手性中间体提供了一种有力的替代方法。
