甾体微生物转化:糖皮质激素氢化可的松生物转化的鲁棒性及其研究应用

Microbial transformation of steroids:biological robustness of bioconversion for the production of glucocorticoid hydrocortisone and its research application

结合作者所在实验室半个世纪从事的甾体微生物转化研究,聚焦国内外仅次于抗生素制药的甾体激素药物中的糖皮质激素药物氢化可的松(hydrokotisone,HC)生物转化研发过程,应用工业微生物鲁棒性理论,结合国内外HC半合成路线,评述工业生物转化产生HC的研究进展,特别是该过程所使用的2株具有较高鲁棒性、可以直接实现向甾体底物Reichstein’s化合物S(RS/RSA)引入C11β-羟基的丝状真菌,新月弯孢霉(Curvularia lunata)AS 3.4381和蓝色犁头霉(Absidia orchidis)AS 3.65的研究情况.本实验室近20年的研究重现了新月弯孢霉60%的HC得率的国外报道水平,具有在国内替换低效率蓝色犁头霉AS3.65工艺路线的可行性;8个研发案例充分说明提高我国糖皮质激素HC工业生产水平,无论是改良菌株,还是改进生物转化工艺的开发应用,实现微生物甾体转化工业的经济性鲁棒性是可行的.

In this review,the author,who has a professional experience in the field of microbial transformation of steroids in the laboratory for semi-era,focused on the glucocorticoid drugs,locus below antibiotics,and hydrocortisone for research and development progress and tried to use the theory of biological robustness in industrial microbiology for investigating two strains from mycelial fungi,Absidia coerulea AS 3.65 and Curvularea lunata AS 3.4381,possessing high robustness in the biotransformation of steroids.The organisms were able to introduce a C11β-hydroxyl group into the substrate Reichsteian’s S(RS/RSA)directly for the production of hydrocortisone.In addition,the experimental results in this laboratory have shown that for the past 20 years and more,a high yield of hydrocortisone-bioconverted RS was reproduced with 60%(g/L,m/V)by C.lunata AS 3.4381.This balances the low efficiency of hydrocortisone-conversion process at home by using A.coerulea AS 3.65 with 45%of RSA(g/L,m/V).Until date,eight research cases have been summarized in the review,which demonstrate that either breeding of strains or improving the biotransformation process to lift a level of industrial production of glucocorticoid hydrocortisone at home,can be used for performance of the robustness in industrial economy in the field of microbial transformation of steroids.