(263g) Novel Biocatalyst for Simvastatin Synthesis

The statins are important drugs for the treatment of high cholestrol levels. Statins inhibit the rate-limiting step of cholestrol biosynthesis by binding to HMG-CoA reductase. The semisynthetic statin, simvastatin (Zocor(R)), is the number two selling drug in the U.S. and has an annual sales of $4.5 billion. Currently, simvastatin is synthesized from the natural product lovastatin in multiple steps, requiring selective protection of reactive functional groups. The complexity and inefficiency of the synthesis have contributed to the high cost of simvastatin to prescribed patients. We present here the identification and characterization of a novel enzyme that is able to convert lovastatin directly to simvastatin in different microorganism hosts, including yeast and E. coli. In this presentation we will cover the following: 1) cloning, expression and in vitro characterization of the newly identified enzyme; 2) substrate specificity of the enzyme towards lovastatin and related statin precursors; 3) in vivo bioconversion of lovastatin to simvastatin; and 4) structural guided mutagenesis of the enzyme to further improve enzyme activity. We believe this enzyme can be used in the biosynthesis of simvastatin and is a significant upgrade over the current synthesis route.