The natural product lovastatin and its semisynthetic, more effective derivative simvastatin are important drugs for the treatment of hypercholesterolemia. Here we report the biochemical characterization of a dedicated acyltransferase, LovD, encoded in the lovastatin biosynthetic pathway. We demonstrate that LovD has broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. LovD can efficiently catalyze the acyl transfer from CoA thioesters or N-acetylcysteamine (SNAC) thioesters to monacolin J. When a-dimethylbutyryl-SNAC is used as the acyl donor, LovD was able to convert monacolin J and 6-hydroxyl-6-desmethylmonacolin J into simvastatin and huvastatin, respectively. Using the E. coli LovD overexpression strain as a whole-cell biocatalyst, preparative amounts of simvastatin were synthesized in a single fermentation step. Our results demonstrate LovD is an attractive enzyme for engineered biosynthesis of pharmaceutically important cholesterol lowering drugs.

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