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| ECHA InfoCard | 100.131.541 |
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| Formula | C23H34O5 |
| Molar mass | 390.520 g·mol−1 |
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Mevastatin (compactin,ML-236B) is ahypolipidemic agent that belongs to thestatins class.
It was isolated from the moldPenicillium citrinum byAkira Endo in the 1970s, and he identified it as aHMG-CoA reductase inhibitor,[1] i.e., a statin. Mevastatin might be considered the first statin drug;[2] clinical trials on mevastatin were performed in the late 1970s in Japan, but it was never marketed.[3] The first statin drug available to the general public waslovastatin.
Mevastatin has since been derivatized to the compoundpravastatin, which is a pharmaceutical used in the lowering ofcholesterol and preventingcardiovascular disease.
In vitro, it has antiproliferative properties.[4]
A British group isolated the same compound fromPenicillium brevicompactum, named itcompactin, and published their results in 1976.[5] The British group mentions antifungal properties with no mention of HMG-CoA reductase inhibition.
High doses inhibit growth and proliferation ofmelanoma cells.[6]
Biosynthesis of mevastatin is primarily accomplished via a type 1PKS pathway it proceeds in the PKS pathway as seen in figure 1 until it reaches a hexaketide state where it undergoes aDiels-Alder cyclization. After cyclization it continues via the PKS pathway to a nonaketide after which it is released and undergoes oxidation and dehydration. It is presumed that the oxidations are preformed by a polypeptide that is similar to cytochrome p450 monooxygenase, which is encoded bymlcC within the mevastatin gene. Lastly the biosynthesis is completed by the PKS facilitating the addition of a diketide sidechain and a methylation bySAM.[7] Figure 1 shows mevastatin in its acid form but it can also be in the more commonly seen lactone form. This pathway was first observed inPenicillium cilrinum and was later discovered that another type of fungus,Penicillium brevicompaetum also produced mevastatin via a PKS pathway.
Sustained elevations of cholesterol in the blood increase the risk of cardiovascular disease. Mevastatin acts to lowers hepatic production of cholesterol by competitively inhibitingHMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the cholesterol biosynthesis pathway via the mevalonic acid pathway. When hepatic cholesterol levels are decreased it causes an increased uptake of low density lipoprotein (LDL) cholesterol and reduces cholesterol levels in the circulation.[8] It has also been shown that mevastatin upregulatesendothelial nitric oxide synthase (eNOS) in mice, which is essential for maintaining a healthy cardiovascular system.[9]