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 an acyltransferase from the lovastatin biosynthetic pathway, LovD, we were able to achieve >99% conversion of monacolin J to simvastatin without the use of any chemical protection steps. The key approaches were 1) use of a membrane permeable substrate that was efficiently utilized by LovD as the acyl donor; 2) metabolic engineering of the E. coli host; and 3) directed evolution of LovD.  The process was scaled up for gram-scale synthesis of simvastatin. Bioconversion using high cell density, fed-batch fermentation was also examined. The whole cell biocatalysis process can therefore be an attractive alternative to the current, multistep semisynthetic transformations.  Furthermore, the three dimensional structure of LovD was elucidated, which shows LovD has an unusual fold as an acyltransferase.