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Production of Simvastatin Acid in Saccharomyces cerevisiae


Simvastatin is a semisynthetic cholesterol-lowering medication and one of the top-selling statins in the world. Currently, industrial production of simvastatin acid (SVA) is a multistep process starting from the natural product lovastatin and requires two organisms, Aspergillus terreus and Escherichia coli. For this reason, there is significant interest in direct production of simvastatin from a single microbial host. In this study, six heterologous genes were introduced into Saccharomyces cerevisiae and the acyl-donor dimethylbutyryl-S-methyl mercaptopropionate (DMB-SMMP) was added, resulting in initial production of 0.5 mg/L SVA. Switching the yeast strain from JHY686 to BJ5464-NpgA increased total polyketide production to over 60 mg/L. Conversion from dihydromonacolin L acid to monacolin J acid was increased from 60 to 90% by tuning the copy number of the P450 lovA. Increasing the media pH to 8.7 led to a further 10-fold increase in SVA production. Optimized chemical lysis of the cell walls in situ after maximum MJA production led to 55 mg/L SVA, representing near complete from MJA and a 110-fold increase in titer from the initial SVA production strain. In addition, surface expression and secretion of the acyl-transferase LovD were explored as potential alternatives to cell lysis. MJA was added exogenously and these methods led to significant increases in percent conversion from MJA to SVA above cytosolic expression of LovD. The yeast strains developed in this work can be used as an alternative production method for SVA, and the strategies employed in this work can be broadly applied for heterologous production of other fungal polyketides and semisynthetic compounds in yeast.

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