With the aging population, the risk factor for cardiovascular disease (CVD) popular trend has obviously raised. CVD has seriously threated the residents' health which death rate is much higher than the other disease, such as tumor. Cholesterol-lowering therapy is an effective method for prevention and treatment of CVD.

Simvastatin (Zocor) is one of the most pharmaceutically significant cholesterol-lowering drugs with annual sales exceeding $3 billion in 2015. Industrial production of simvastatin includes three steps: microbial production of lovastatin through Aspergillus terreus fermentation, alkaline hydrolysis of lovastatin to produce monacolin J, and chemical transformation of monacolin J to simvastatin (Fig. 1).

The Microbial Metabolic Engineering Group at Qingdao Institute of Bioenergy and Bioprocess Technology (QIBEBT), Chinese Academy of Sciences(CAS), cooperated with Hisun Pharm which was the world's largest lovastatin/simvastatin producer, developed a single-step microbial production process for monacolin J by engineering of an industrial lovastatin-producing A. terreus strain (Fig. 1). This technical route was more simple and environment friendly, which made complete bioproduction of simvastatin feasible and promising.

Fig. 1 Overview of the production processes of simvastatin （Image by Huang Xuenian）

In this program, a new lovastatin hydrolase PcEST which cloud cleave the side chain of lovastatin to produce monacolin J was identified from a special fungus. PcEST possessed a nearly 232-fold higher catalytic efficiency.  By genetic engineering technology, approximately 95% of the biosynthesized lovastatin was successfully hydrolyzed to monacolin J. This genetic engineering mutant would be an efficient and practical microbial cell factory to directly produce monacolin J through single-step fermentation, and would be easily applied to industrial production with the existing equipment and fermentation process of lovastatin production(Fig. 2).

 Fig. 2 Construction and characterization of the monacolin J-producing cell factory （Image by Huang Xuenian）

This work has been published on the journal of Metabolic Engineering. It is supported by National Natural Sciences Foundation of China (No. 31400080) and Hisun Pharmaceutical Co., Ltd. in China.

(Text by LU Xuefeng and HUANG Xuenian)

Cotact:

Prof. LU Xuefeng, Ph.D,

Qingdao Institute of BioEnergy and Bioprocess Technology, CAS

Qingdao, Shandong, 266000, China,

Tel: 86-532-80662711

E-mail: lvxf@qibebt.ac.cn