Biosynthesis of Simvastatin – a mini-review
Zhongyi Yang, and Chunhui Gan
Zhejiang Hisun Pharmaceutical Co. Ltd, Taizhou 318000, China
Abstract: Simvastatin, a semisynthetic derivertive of lovastatin, is an important drug for the treatment of hypercholesteromia, and is traditionally prepared by direct alkylation of lovastatin. Chemical reaction conditons are very rigid, and the final product is difficult to purify, also the pressure of labor protection and environment protection is very high. Recently, with the devolpement in the research of lovastatin biosynthesis, more and more attention has been paid to simvastatin biosynthesis. This paper compared the chemical and biological routes in simvastatin production. Simvastatin could be produced by direct fermentation with combinational biosynthesis method, and could also be synthesized from monacolin J with acyltransferase LovD.
Keywords: simvastatin, biosynthesis
辛伐他汀(simvastatin)是Merck 公司研制的降血脂药, 商品名Zocor, 其药理作用是作为竞争性抑制剂抑制肝脏细胞内羟甲戊二酰辅酶A 还原酶(HMG-CoA reductase)活力, 限制HMG-CoA 向甲基二羟戊酸的转化, 从而减少内源总胆固醇的生物合成总量[1]。与相同剂量的洛伐他汀(lovastatin)、普伐他汀(pravastatin) 和氟伐他汀(fluvastatin) 等其他HMG-CoA 还原酶抑制剂相比, 辛伐他汀可以更有效地降低血清中的总胆固醇和低密度脂蛋白胆固醇(LDL-cholesterol)[1]。本品自1992 年在美国上市后,多年来一直处于畅销药行列的前三名[2], 随着2006年专利到期, Merck 公司2006 年辛伐他汀的销售额比2005 年下降了36%, 为28 亿美元[3], 辛伐他汀的工艺技术研究和生产成本已成为产品竞争的重要因素。从辛伐他汀和洛伐他汀的分子结构看, 两者仅相差一个甲基, 传统的生产工艺是以洛伐他汀为原料经全化学合成得到辛伐他汀[4,5]。随着分子生物学和代谢工程研究的深入, 辛伐他汀的生物合成逐渐得到学界和产业界的重视
