化学
磷酸西他列汀
酮
基质(水族馆)
动力学分辨率
生物催化
胺气处理
催化作用
不对称氢化
对映选择合成
有机化学
烯胺
组合化学
反应机理
生物技术
生物
胰岛素
地质学
海洋学
二甲双胍
作者
Christopher K. Savile,Jacob M. Janey,Emily C. Mundorff,Jeffrey C. Moore,Sarena Tam,William R. Jarvis,Jeffrey C. Colbeck,Anke Krebber,Fred J. Fleitz,Jos Brands,Paul N. Devine,Gjalt W. Huisman,Gregory Hughes
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2010-07-16
卷期号:329 (5989): 305-309
被引量:1384
标识
DOI:10.1126/science.1188934
摘要
Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.
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