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| 微生物转化法合成甾药中间体研究进展 |
| Research Progress on Steroid-Drug Intermediates Synthesis by Microbial Transformation |
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| DOI：doi:10.3969/j.issn.1005-7021.2026.02.009 |
| 中文关键词: 分枝杆菌 甾体药物 甾药中间体 生物转化 菌株改造 |
| 英文关键词: Mycobacterium sp. steroid drugs steroid-drug intermediates biotransformation strain modification |
| 基金项目:河南省高等学校重点科研项目计划项目（22A180011）；河南省重点研发与推广专项（科技攻关）（222102320151）；河南省中央引导地方科技发展资金项目（Z20231811004）；大学生创新创业训练计划项目（2024cxcy677） |
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| 摘要点击次数: 39 |
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| 中文摘要: |
| 甾体类药物是仅次于抗生素的第二大类临床用药，具有抗炎、抗病毒、抗肿瘤、抗高血压等生理功能，市场需求量大。目前，利用微生物降解植物甾醇合成甾药中间体（甾药前体），再对其进行化学修饰的微生物半合成法是甾体药物工业化生产的主流方法。本文聚焦于合成甾药中间体的代表性菌株分枝杆菌（Mycobacterium sp.），对分枝杆菌中甾体化合物代谢途径的各环节（甾醇摄取、母核初步氧化、侧链降解、母核氧化、母核断裂）及其所涉及的关键酶进行综述，并总结了适用于分枝杆菌的基因过表达、敲除和敲低遗传改造系统。然而，鉴定并解析甾醇侧链降解过程的复杂酶系仍是当前研究的重难点，也是制约新型甾药中间体开发的关键瓶颈。因此，借助高通量测序、生物信息学分析和定点饱和突变等手段，加速甾醇代谢途径解析，对分枝杆菌细胞工厂的理性设计及新型甾药中间体高产菌株的构建至关重要。 |
| 英文摘要: |
| Steroids are the second-largest category of clinical drugs following antibiotics, with significant physiological functions such as anti-inflammatory, antiviral, antitumor, and antihypertensive effects, bearing a huge market demand. Currently, the mainstream industrial approach for steroid drugs production is microbial semi-synthesis, which involves microbial degradation of phytosterols into steroid-drug intermediates (precursors) followed by chemical modification. This review focuses on Mycobacterium sp., a representative strain used for synthesizing steroid-drug intermediates, and outlines the key steps in its steroid metabolic pathway, including sterol uptake, initial oxidation of sterol nucleus, side chain degradation, further oxidation of sterol nucleus, and nucleus cleavage, along with the key enzymes involved. Furthermore, the genetic modification systems of gene overexpression, knockout and knockdown applicable to Mycobacterium are summarized. However, the identification and characterization of complex enzyme systems in the degradation process of sterol side chain remains a major challenge in current research and a key bottleneck restricting the development of novel steroid-drug intermediates. Therefore, accelerating the analysis of sterol metabolic pathways by high-throughput sequencing, bioinformatics analysis and site-directed saturation mutagenesis is essential for the rational design of mycobacterial cell factories and for the construction of strains with high-yield of new steroid intermediates. |
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