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甾体类药物是销售额仅次于抗生素的世界第二大类药物,不同的甾体药物分子结构均由甾体激素中间体衍生而来。甾体激素中间体的传统生产方法包括植物提取皂素法和化学全合成法,其对环境有害,反应产物结构不唯一且成本较高,不利于工业化生产。目前主要的生产工艺是利用微生物对特殊原料进行转化的半合成法,但会遇到微生物酶转化率低、发酵周期长等问题。合成生物学的出现为构建利用糖为唯一碳源生产甾体激素中间体的人工细胞提供了理论上的可行性和可靠的技术支持。重点综述了合成生物技术在甾体激素中间体生产中的应用,以有利于工业发酵的酿酒酵母、分枝杆菌等为底盘细胞,通过引入外源合成功能模块,实现胆甾醇、雄烯二酮等甾体激素中间体的生物合成,并对合成生物技术在医药生产方式转变中的应用进行了展望,以期推动甾体类药物生物制造技术的进步。
Steroids are the second-largest category of drugs in the world with sales after antibiotics, and different steroid drug molecular structures are derived from steroid hormone intermediates. The traditional production methods of steroid hormone intermediates include plant extract saponin and chemical synthesis, which are harmful to the environment, the structure of the reaction product is not unique and the cost is high, which is not good for industrialized production. At present the main production process is the use of micro-organisms on the transformation of special raw materials semi-synthetic method, but will encounter microbial conversion rate is low, fermentation cycle and other issues. The emergence of synthetic biology provides theoretical feasibility and reliable technical support for the construction of artificial cells producing steroid hormone intermediates using sugar as the sole carbon source. This review focuses on the application of synthetic biotechnology in the production of steroid hormone intermediates. In order to facilitate the industrial fermentation of Saccharomyces cerevisiae, mycobacteria and other cells for the chassis, through the introduction of exogenous synthesis of functional modules to achieve cholesterol, androstenedione And other steroid hormone intermediates biosynthesis, and synthetic biotechnology in the transformation of the mode of production of pharmaceutical applications are prospected in order to promote the progress of steroid drug bio-manufacturing technology.