系列甾体药物关键中间体转化菌种构建及智能化生产应用

Construction of strains for bioconversion of steroid key intermediates and intelligent industrial production

摘要:

甾体激素药物是仅次于抗生素的第二大类药物，当前甾体工业的初始原料已经由从黄姜等植物中提取的薯蓣皂素转向植物甾醇。作为食用油工业的副产物，植物甾醇来源广泛，价格低廉，经微生物转化后可生成雄烯二酮(androstenedione, AD)、雄二烯二酮(androstadiendione, ADD)、9α-羟基-雄烯二酮(9α-hydroxy-androstenedione, 9α-OH-AD)等一系列化合物，这些关键中间体可用于甾体药物合成。甾体代谢途径长、副产物多、调控复杂，传统的微生物筛选、诱变育种方法和油水两相转化体系已经不适于当前的工业生产需求。文中以笔者团队与浙江仙居君业药业有限公司联合开发的新一代甾体药物关键中间体的转化菌株构建和智能化生产为例，综述甾体药物中间体菌种改造和转化工艺开发及其在产业化应用中的进展。未来，随着合成生物学技术的发展，有望开发出更适于甾体药物合成的新一代中间体；乃至以葡萄糖等为原料，使用微生物直接合成甾体原料药。这些生物技术(biotechnology, BT)创建的新一代菌株在基于信息化、智能化技术(intelligent technology, IT)建设的现代工厂中的应用，将会形成更高效、更绿色的生产方式，并产生显著的社会效益和经济价值。

Abstract:

Steroidal hormone pharmaceuticals are the second largest class of medicines after antibiotics. At present, the initial materials of the steroidal industry have shifted from sapogenins, which were extracted from plants of the genus Dioscore to phytosterols. As a byproduct of soybean oil production, phytosterols are readily available and of low prices. Androstenedione (AD), androstadiendione (ADD), 9α-hydroxy-androstenedione (9α-OH-AD) and a series of key intermediates used in the synthesis of steroidal pharmaceuticals can be produced from phytosterols by microbial transformation. Nevertheless, due to the long metabolic pathways, the byproducts and the complex regulation, traditional microbial screening, mutagenizing methods and the oil-water biphasic transformation systems are no longer suitable for current industrial production. A new generation strains for the production of key steroidal pharmaceutical intermediates have been constructed and an intelligent production process has been jointly developed by us and Zhejiang Xianju Junye Pharmaceutical Co. Ltd.. Taking these products and processes as an example, this article reviews the improvement of strains for the production of steroidal pharmaceutical intermediates and the development of biotransformation process on an industrial scale. With the development of synthetic biology, it is expected to develop a new generation of intermediates which are more suitable for the synthesis of steroidal medicines. Moreover, de novo biosynthesis the steroidal active pharmaceutical ingredients from glucose is also expected. The application of these new-generation strains constructed by biotechnology (BT) in modern factories based on informatization and intelligent technology (IT) will be more efficient and greener, and create remarkable social and economic values.