It was isolated from the mold Penicillium citrinum by Akira Endo in the 1970s, and he identified it as a 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.
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 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 mlcC within the mevastatin gene. Lastly the biosynthesis is completed by the PKS facilitating the addition of a diketide sidechain and a methylation by 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.
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]
^Endo A, Kuroda M, Tsujita Y (December 1976). "ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium". The Journal of Antibiotics. 29 (12): 1346–8. doi:10.7164/antibiotics.29.1346. PMID 1010803.
^. Archived from the original on December 21, 2008.
^Endo A (October 2004). "The origin of the statins. 2004". Atherosclerosis. Supplements. 5 (3): 125–30. doi:10.1016/j.atherosclerosissup.2004.08.033. PMID 15531285.
^Wächtershäuser A, Akoglu B, Stein J (July 2001). "HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2". Carcinogenesis. 22 (7): 1061–7. doi:10.1093/carcin/22.7.1061. PMID 11408350.
^Brown AG, Smale TC, King TJ, Hasenkamp R, Thompson RH (1976). "Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum". Journal of the Chemical Society, Perkin Transactions 1 (11): 1165–70. doi:10.1039/P19760001165. PMID 945291.
^Glynn SA, O'Sullivan D, Eustace AJ, Clynes M, O'Donovan N (January 2008). "The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells". BMC Cancer. 8: 9. doi:10.1186/1471-2407-8-9. PMC2253545. PMID 18199328.
^ abAbe Y, Suzuki T, Ono C, Iwamoto K, Hosobuchi M, Yoshikawa H (July 2002). "Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum". Molecular Genetics and Genomics. 267 (5): 636–46. doi:10.1007/s00438-002-0697-y. PMID 12172803. S2CID 24427023.
^"Mevastatin". PubChem. U.S. National Library of Medicine. Retrieved 2016-06-04.
^Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA (April 2001). "Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice". Stroke. 32 (4): 980–6. doi:10.1161/01.STR.32.4.980. PMID 11283400.
October 21, 2023
mevastatin, compactin, 236b, hypolipidemic, agent, that, belongs, statins, class, clinical, dataatc, codenoneidentifiersiupac, name, hydroxy, oxotetrahydro, pyran, ethyl, methyl, hexahydronaphthalen, methylbutanoatecas, number73573, npubchem, cid64715iuphar, b. Mevastatin compactin ML 236B is a hypolipidemic agent that belongs to the statins class MevastatinClinical dataATC codeNoneIdentifiersIUPAC name 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 methylbutanoateCAS Number73573 88 3 NPubChem CID64715IUPHAR BPS3031DrugBankDB06693 YChemSpider58262 YUNII1UQM1K0W9XKEGGC13963 YChEBICHEBI 34848 NChEMBLChEMBL54440 YCompTox Dashboard EPA DTXSID4040684ECHA InfoCard100 131 541Chemical and physical dataFormulaC 23H 34O 5Molar mass390 520 g mol 13D model JSmol Interactive imageSMILES 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 CCInChI 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 YKey AJLFOPYRIVGYMJ INTXDZFKSA N Y N Y what is this verify It was isolated from the mold Penicillium citrinum by Akira Endo in the 1970s and he identified it as a 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 Contents 1 Biosynthesis 2 Pharmacology 3 See also 4 ReferencesBiosynthesis Edit nbsp Biosynthetic pathway 7 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 mlcC within the mevastatin gene Lastly the biosynthesis is completed by the PKS facilitating the addition of a diketide sidechain and a methylation by 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 nbsp Lactone and acid form of mevastatinPharmacology EditSustained 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 EditMedicinal moldsReferences Edit Endo A Kuroda M Tsujita Y December 1976 ML 236A ML 236B and ML 236C new inhibitors of cholesterogenesis produced by Penicillium citrinium The Journal of Antibiotics 29 12 1346 8 doi 10 7164 antibiotics 29 1346 PMID 1010803 The story of statins Archived from the original on December 21 2008 Endo A October 2004 The origin of the statins 2004 Atherosclerosis Supplements 5 3 125 30 doi 10 1016 j atherosclerosissup 2004 08 033 PMID 15531285 Wachtershauser A Akoglu B Stein J July 2001 HMG CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco 2 Carcinogenesis 22 7 1061 7 doi 10 1093 carcin 22 7 1061 PMID 11408350 Brown AG Smale TC King TJ Hasenkamp R Thompson RH 1976 Crystal and molecular structure of compactin a new antifungal metabolite from Penicillium brevicompactum Journal of the Chemical Society Perkin Transactions 1 11 1165 70 doi 10 1039 P19760001165 PMID 945291 Glynn SA O Sullivan D Eustace AJ Clynes M O Donovan N January 2008 The 3 hydroxy 3 methylglutaryl coenzyme A reductase inhibitors simvastatin lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells BMC Cancer 8 9 doi 10 1186 1471 2407 8 9 PMC 2253545 PMID 18199328 a b Abe Y Suzuki T Ono C Iwamoto K Hosobuchi M Yoshikawa H July 2002 Molecular cloning and characterization of an ML 236B compactin biosynthetic gene cluster in Penicillium citrinum Molecular Genetics and Genomics 267 5 636 46 doi 10 1007 s00438 002 0697 y PMID 12172803 S2CID 24427023 Mevastatin PubChem U S National Library of Medicine Retrieved 2016 06 04 Amin Hanjani S Stagliano NE Yamada M Huang PL Liao JK Moskowitz MA April 2001 Mevastatin an HMG CoA reductase inhibitor reduces stroke damage and upregulates endothelial nitric oxide synthase in mice Stroke 32 4 980 6 doi 10 1161 01 STR 32 4 980 PMID 11283400 Retrieved from https en wikipedia org w index php title Mevastatin amp oldid 1171090726, wikipedia, wiki, book, books, library,
