Mevastatin

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Mevastatin
Clinical data
ATC code
  • None
Identifiers
  • (1S,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate
JSmol)
  • O=C(O[C@@H]1[C@H]3C(=C/CC1)\C=C/[C@@H]([C@@H]3CC[C@H]2OC(=O)C[C@H](O)C2)C)[C@@H](C)CC
  • InChI=1S/C23H34O5/c1-4-14(2)23(26)28-20-7-5-6-16-9-8-15(3)19(22(16)20)11-10-18-12-17(24)13-21(25)27-18/h6,8-9,14-15,17-20,22,24H,4-5,7,10-13H2,1-3H3/t14-,15-,17+,18+,19-,20-,22-/m0/s1 checkY
  • Key:AJLFOPYRIVGYMJ-INTXDZFKSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Mevastatin (compactin, ML-236B) is a

hypolipidemic agent that belongs to the statins
class.

It was isolated from the mold

HMG-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 was lovastatin
.

Mevastatin has since been derivatized to the compound pravastatin, which is a pharmaceutical used in the lowering of cholesterol and preventing cardiovascular disease.

In vitro, it has antiproliferative properties.[4]

A British group isolated the same compound from Penicillium brevicompactum, named it compactin, 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 of melanoma cells.[6]

Biosynthesis

Biosynthetic pathway[7]

Biosynthesis of mevastatin is primarily accomplished via a type 1

SAM.[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 in Penicillium cilrinum and was later discovered that another type of fungus, Penicillium brevicompaetum also produced mevastatin via a PKS pathway.

Lactone
and acid form of mevastatin

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, 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 upregulates endothelial nitric oxide synthase (eNOS) in mice, which is essential for maintaining a healthy cardiovascular system.[9]

See also

  • Medicinal molds

References

  1. PMID 1010803
    .
  2. ^ "The story of statins". Archived from the original on December 21, 2008.
  3. PMID 15531285
    .
  4. PMID 11408350
    .
  5. PMID 945291
    .
  6. PMID 18199328
    .
  7. ^
    S2CID 24427023
    .
  8. ^ "Mevastatin". PubChem. U.S. National Library of Medicine. Retrieved 2016-06-04.
  9. PMID 11283400
    .
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