酶法制备熊去氧胆酸的研究进展

Review of Progress in Enzymatic Production of Ursodeoxycholic Acid

熊去氧胆酸(ursodeoxycholic acid,UDCA)是用于治疗多种肝胆疾病的临床优选药物,对某些癌症及其他疾病也有辅助治疗的作用。然而,UDCA的化学合成普遍存在路线繁琐、反应条件苛刻、对环境不友好,产率低等缺陷,严重限制了其工业化生产与应用。因此,具有合成路线短、产率高、反应条件温和、成本低等优势的绿色生物合成技术逐渐成为UDCA合成的主要研究方向。生物转化法合成UDCA通常是以石胆酸(lithocholic acid,LCA)、鹅去氧胆酸(chenodeoxycholic acid,CDCA)或胆酸(cholic acid,CA)为底物,利用全细胞转化法或酶法合成UDCA,该生物合成的本质主要是利用酶的特异性将底物转化为UDCA。因此,具有特异性辅酶依赖性、高酶活性、高稳定性和高浓度底物耐受性的7α/β-羟基类固醇脱氢酶(7α/β-HSDH)和P450单加氧酶的设计开发成为研究热点。综述UDCA的酶法制备技术,探讨现有酶法合成的优缺点,展望未来发展方向,以期实现UDCA的绿色、高效、安全、可持续的生物制造。

Ursodeoxycholic acid(UDCA)is the clinically preferred drug for treating various hepatobiliary diseases and plays an adjuvant role in some cancers and other diseases.However,the environmental concerns,harsh reaction conditions,low yield,and labor-intensive approaches associated with the chemical synthesis of UDCA often severely restrict its industrial production and utilization.Consequently,the primary area of study for UDCA synthesis has gradually shifted to green biosynthesis technology,which offers the benefits of a quick synthetic pathway,high yield,benign reaction conditions,and low cost.Currently,individuals utilize affordable and easily accessible lithocholic acid(LCA),chenodeoxycholic acid(CDCA),or cholic acid(CA)as substrates for enzymatic synthesis of UDCA or whole-cell transformation synthesis.Since the primary function of enzymes in biosynthesis is to convert substrates to UDCA,the development and design of 7α/β-hydroxysteroid dehydrogenase(7α/β-HSDH)and P450 monooxygenase with specific coenzyme dependence,high enzyme activity,high stability,and high substrate concentration tolerance have emerged as research hotspots.Biosynthesis relies mainly on biological enzymes’specificity to convert substrates into UDCA.Thus,hydroxysteroid dehydrogenase(7α/β-HSDH)and P450 monooxygenase with specific coenzyme dependence,high enzymatic activity,high stability,and high substrate tolerance need to be designed and developed.This study reviews the green synthesis technique of UDCA,discusses the benefits and drawbacks of the current biosynthesis,and looks ahead to future development directions to achieve sustainable,safe,effective,and green biomanufacturing of UDCA.