Construction of an Efficient and Robust <i>Aspergillus terreus</i> Cell Factory for Monacolin J Production

Abstract

Monacolin J is a key precursor for the synthesis of the cholesterol-lowering drug simvastatin. Industrially, monacolin J is manufactured through the alkaline hydrolysis of the fungal polyketide lovastatin, which is relatively complex and environmentally unfriendly. A cell factory for monacolin J production was created by heterologously introducing lovastatin hydrolase into Aspergillus terreus in our previous study. However, residual lovastatin remained a problem for the downstream product purification. In this study, we used combined metabolic engineering strategies to create a more efficient and robust monacolin J-producing cell factory that completely lacks lovastatin residue. The complete deletion of the key gene lovF blocked the biosynthesis of lovastatin and led to a large accumulation of monacolin J without any lovastatin residue. Additionally, the overexpression of the specific transcription factor lovE under the P gpdAt promoter further increased the titer of monacolin J by 52.5% to 5.5 g L^-1. Interestingly, the fermentation robustness was also significantly improved by the expression of lovE. This improvement not only avoids the process of alkaline hydrolysis but also simplifies the downstream separation process.