Lovastatin polyketide derivatives

Lovastatin is an inhibitor of the enzyme (35)-hydrooxymethylglutaryl-CoA (HMG-CoA) reductase tliat catalyzes the reduction of HMG-CoA to mevalonate, a key step in cholesterol biosynthesis. Tliis activity confers on lovastatin its medically important anti-hyperchoilesterolemic activity and other potentially important uses. It is a secondary metabolite from the filamentous fungus Aspergillus terreus and has been shown to be derived from acetate via a polyketide pathway. 

ML-236B is thought to be derived from polyketide chains, one 18-carbon and one 4-carbon, formed from acetate units in the ncntnal head-to-cail frshion. This putative biosynthetic route is similar to the route reported for lovastatin biosynthesis (Figure 3) (14). 

The discovery of these early statins paved the way for the worldwide development of other drugs based on the statin chemical structure (Figure 8.2). Sankyo and Merck directed their later efforts at manufacturing synthetic analogs. Many different statins are currently available for therapeutic use, but lovastatin and mevastatin remain the only fermentation-derived statins. The lovastatin biosynthetic pathway in A. terreus is well understood. This pathway was the first example of a polyketide synthetic pathway in which two fungal type I polyketide synthases work in combination to produce a product (Hendrickson et al., 1999 Kennedy et al., 1999). Since then several statins, including simvastatin, pravastatin, fluvastatin and atorvastatin, have been approved in many countries and are currently used by millions. 

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