It was the first statin approved by the FDA.Lovastatin is also naturally produced by certain higher fungi, such as Pleurotus ostreatus (oyster mushroom) and closely related Pleurotus spp. Research into the effect of oyster mushroom and its extracts on the cholesterol levels of laboratory animals has been extensive, although the effect has been demonstrated in a very limited number of human subjects.In 1998, the FDA placed a ban on the sale of dietary supplements derived from red yeast rice, which naturally contains lovastatin, arguing that products containing prescription agents require drug approval. Judge Dale A. Kimball of the United States District Court for the District of Utah, granted a motion by Cholestins manufacturer, Pharmanex, that the agencys ban was illegal under the 1994 Dietary Supplement Health and Education Act because the product was marketed as a dietary supplement, not a drug. The objective is to decrease excess levels of cholesterol to an amount consistent with maintenance of normal body function. Cholesterol is biosynthesized in a series of more than 25 separate enzymatic reactions that initially involves three successive condensations of acetyl-CoA units to form the six-carbon compound 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). This is reduced to mevalonate and then converted in a series of reactions to the isoprenes that are building-blocks of squalene, the immediate precursor to sterols, which cyclizes to lanosterol (a methylated sterol) and further metabolized to cholesterol. A number of early attempts to block the synthesis of cholesterol resulted in agents that inhibited late in the biosynthetic pathway between lanosterol and cholesterol.
Dihydromonacolin L, (J), then undergoes oxidation and dehydration via a cytochrome P450 oxygenase encoded by LovA to obtain monacolin J, (L). The MT domain from lovB is active in the conversion of (B) to (C) when it transfers a methyl group from S-adenosyl-L-methionine (SAM) to the tetraketide (C) . Owing to the fact that LovB contains an inactive ER domain, LovC is required at specific steps to obtain fully reduced products. The domain organization of LovB, LovC, LovG and LovF is shown in Figure 2. The inactive ER domain of lovB is shown with an oval and where LovC acts in trans to LovB is shown with a red box. In a parallel pathway, the diketide side chain of lovastatin is synthesized by another highly reducing type I polyketide synthase enzyme encoded by LovF . Lastly, the side chain, 2-methylbutyrate (M) is covalently attached to C-8 hydroxy group of monacolin J (L) by a transesterase encoded by LovD to form lovastatin. Total synthesis
A major bulk of work in the synthesis of lovastatin was done by M. Hirama in the 1980s. Hirama synthesized compactin and used one of the intermediates to follow a different path to get to lovastatin. The synthetic sequence is shown in the schemes below. The γ-lactone was synthesized using Yamada methodology starting with glutamic acid. Lactone opening was done using lithium methoxide in methanol and then silylation to give a separable mixture of the starting lactone and the silyl ether. The silyl ether on hydrogenolysis followed by Collins oxidation gave the aldehyde.