Document Detail


Efficient synthesis of simvastatin by use of whole-cell biocatalysis.
MedLine Citation:
PMID:  17277201     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Simvastatin is a semisynthetic derivative of the fungal polyketide lovastatin and is an important drug for lowering cholesterol levels in adults. We have developed a one-step, whole-cell biocatalytic process for the synthesis of simvastatin from monacolin J. By using an Escherichia coli strain overexpressing the previously discovered acyltransferase LovD (X. Xie, K. Watanabe, W. A. Wojcicki, C. C. Wang, and Y. Tang, Chem. Biol. 13:1161-1169, 2006), 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, alpha-dimethylbutyryl-S-methyl-mercaptopropionate, 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 high-performance liquid chromatography. Bioconversion using high-cell-density, fed-batch fermentation was also examined. The whole-cell biocatalysis can therefore be an attractive alternative to currently used multistep semisynthetic transformations.
Authors:
Xinkai Xie; Yi Tang
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-02-02
Journal Detail:
Title:  Applied and environmental microbiology     Volume:  73     ISSN:  0099-2240     ISO Abbreviation:  Appl. Environ. Microbiol.     Publication Date:  2007 Apr 
Date Detail:
Created Date:  2007-04-03     Completed Date:  2007-05-29     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  7605801     Medline TA:  Appl Environ Microbiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2054-60     Citation Subset:  IM    
Affiliation:
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, USA.
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MeSH Terms
Descriptor/Qualifier:
Acyltransferases / metabolism
Catalysis
Chromatography, High Pressure Liquid
Escherichia coli / metabolism
Fermentation
Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemical synthesis*
Naphthalenes / metabolism
Simvastatin / chemical synthesis*
Chemical
Reg. No./Substance:
0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Naphthalenes; 76343-78-7/monacolin J; 79902-63-9/Simvastatin; EC 2.3.-/Acyltransferases
Comments/Corrections

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