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Appl. Environ. Microbiol. doi:10.1128/AEM.02820-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Efficient Synthesis of Simvastatin Using Whole-Cell Biocatalysis

Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095

^* To whom correspondence should be addressed. Email: yitang{at}ucla.edu.

	Abstract

Simvastatin is a semisynthetic derivative of the fungal polyketide lovastatin and is an important drug for lowering the cholesterol levels in adults. We have developed an one-step, whole cell biocatalytic process for the synthesis of simvastatin from monacolin J. Using an Escherichia coli strain overexpressing the previously discovered acyltransferase, LovD (Ref 18), we were able to achieve >99% conversion of monacolin J to simvastatin without the use of any chemical protection steps. The key finding was a membrane permeable substrate, -dimethylbutyryl-S-methyl-mercaptopropionate (DMB-S-MMP), that was efficiently utilized by LovD as the acyl donor. The process was scaled up for gram-scale synthesis of simvastatin. We also demonstrated that simvastatin synthesized via this method can be readily purified from the fermentation broth with >90% recovery and >98% purity as determined by HPLC. Bioconversion using high cell density, fed-batch fermentation was also examined. The whole cell biocatalysis can therefore be an attractive alternative to the current, multistep semisynthetic transformations.