Mevastatin (compactin, ML-236B) is a

hypolipidemic agent Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins, such as choleste ...

that belongs to the

statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

s class. It was isolated from the mold ''

Penicillium citrinum ''Penicillium citrinum'' is an anamorph, mesophilic fungus species of the genus of ''Penicillium'' which produces tanzawaic acid A-D, ACC, Mevastatin, Quinocitrinine A, Quinocitrinine B, and nephrotoxic citrinin. ''Penicillium citrinum'' is o ...

'' by Akira Endo in the 1970s, and he identified it as a

HMG-CoA reductase inhibitor Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

, i.e., a statin. Mevastatin might be considered the first statin drug; clinical trials on mevastatin were performed in the late 1970s in Japan, but it was never marketed. The first statin drug available to the general public was

lovastatin Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat high blood cholesterol and reduce the risk of cardiovascular disease. Its use is recommended together with lifestyle changes. It is taken by mouth. ...

. Mevastatin has since been derivatized to the compound

pravastatin Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids. It is suggested to be used together with diet changes, exerc ...

, which is a pharmaceutical used in the lowering of

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

and preventing

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

. ''

In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'', it has antiproliferative properties. A British group isolated the same compound from ''Penicillium brevicompactum'', named it ''compactin'', and published their results in 1976. The British group mentions antifungal properties with no mention of HMG-CoA reductase inhibition. High doses inhibit growth and proliferation of

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

cells.

Biosynthesis

Biosynthesis of mevastatin is primarily accomplished via a type 1 PKS pathway it proceeds in the PKS pathway as seen in figure 1 until it reaches a hexaketide state where it undergoes a Diels-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 by ''mlc''C within the mevastatin gene. Lastly the biosynthesis is completed by the PKS facilitating the addition of a diketide sidechain and a methylation by SAM. 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 in ''Penicillium cilrinum'' and was later discovered that another type of fungus, ''Penicillium brevicompaetum'' also produced mevastatin via a PKS pathway. Mevastatin Structure

Pharmacology

Sustained elevations of cholesterol in the blood increase the risk of cardiovascular disease. Mevastatin acts to lowers hepatic production of cholesterol by competitively inhibiting

HMG-CoA reductase HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-limiting enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other ...

, 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. It has also been shown that mevastatin upregulates endothelial nitric oxide synthase (eNOS) in mice, which is essential for maintaining a healthy cardiovascular system.

References

{{Xenobiotic-sensing receptor modulators Statins Penicillium Delta-lactones Tetrahydropyrans Secondary alcohols

Biosynthesis

Pharmacology

See also

References