Mevastatin: Difference between revisions

| IUPAC_name = (1''S'',7''RS'',8''S'',8a''R'')-8-{2-[(2''R'',4''R'')-4-Hydroxy-6-oxotetrahydro-2''H''-pyran-2-yl]ethyl}-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2''S'')-2-methylbutanoate

It was isolated from the mold ''[[Penicillium citrinum]]'' by [[Akira Endo (biochemist)|Akira Endo]] in the 1970s, and he identified it as a [[HMG-CoA reductase inhibitor]],<ref>{{cite journal |first=Akira|last vauthors = Endo|author2= A, Kuroda M., |author3=Tsujita Y. | title = ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium | journal = The Journal of Antibiotics (Tokyo)|date=December 1976|volume = 29 | issue = 12 | pages = 1346–8 | date = December 1976 | pmid = 1010803 | doi = 10.7164/antibiotics.29.1346 | doi-access = free }}</ref> i.e., a statin. Mevastatin might be considered the first statin drug;<ref>{{cite web|url=http://www.world-of-fungi.org/Mostly_Medical/Mark_Gilson/Mark_Gilson.htm |title=The story of statins |deadurlurl-status=yesdead |archiveurlarchive-url=https://web.archive.org/web/20081221221223/http://www.world-of-fungi.org/Mostly_Medical/Mark_Gilson/Mark_Gilson.htm |archivedatearchive-date=December 21, 2008 }}</ref> clinical trials on mevastatin were performed in the late 1970s in Japan, but it was never marketed.<ref>{{cite journal|first= Akira|last vauthors = Endo A | title = The origin of the statins. 2004 | journal = AtherosclerAtherosclerosis. Suppl.Supplements |date=Oct 2004|volume = 5 | issue = 3 | pages = 125–30 | date = October 2004 | pmid = 15531285 | doi = 10.1016/j.atherosclerosissup.2004.08.033 }}</ref> The first statin drug available to the general public was [[lovastatin]].

''[[In vitro]]'', it has antiproliferative properties.<ref>{{cite journal | doivauthors = 10.1093/carcin/22.7.1061|Wächtershäuser pmidA, =Akoglu B, Stein J 11408350| title = HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2 | journal = Carcinogenesis | volume = 22 | issue = 7 | pages = 1061–7 | yeardate = July 2001 | last1pmid = Wachtershauser11408350 | first1doi = A10.|1093/carcin/22.7.1061 last2 = Akoglu| first2doi-access = B|free last3 = Stein| first3 = J}}</ref>

A British group isolated the same compound from ''Penicillium brevicompactum'', named it ''compactin'', and published their results in 1976.<ref>{{cite journal |last1 vauthors = Brown|first1=Allan G.|last2=AG, Smale|first2=Terry C.|last3=TC, King|first3=Trevor J.|last4=TJ, Hasenkamp|first4=Rainer|last5= R, Thompson|first5=Ronald H.RH | title = Crystal and molecular structure of compactin, a new antifungal metabolite from ''Penicillium brevicompactum''. | journal =J. Chem.Journal Soc.of the Chemical Society, Perkin Trans.Transactions 1 |date=1976| issue = 11 | pages =1165–1170 1165–70 | date = 1976 | pmid = 945291 | doi = 10.1039/P19760001165|pmid=945291 }}</ref> The British group mentions antifungal properties with no mention of HMG-CoA reductase inhibition.

High doses inhibit growth and proliferation of [[melanoma]] cells.<ref>{{cite journal | doivauthors = 10.1186/1471-2407-8-9|Glynn pmidSA, =O'Sullivan 18199328|D, pmcEustace =AJ, Clynes M, O'Donovan N 2253545| title = The 3-hydroxy-3-methylglutaryl-coenzyme aA reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells | journal = BMC Cancer | volume = 8 | pages = 9| year = 2008| last1date = Glynn|January first12008 = Sharon A| last2pmid = O'Sullivan| first2 =18199328 Dermot| last3pmc = Eustace| first3 = Alex2253545 J| last4doi = Clynes|10.1186/1471-2407-8-9 first4 = Martin| last5doi-access = O'Donovan| first5 =free Norma}}</ref>

Biosynthesis of mevastatin is primarily accomplished via a type 1 [[Polyketide synthase|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 reaction|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 [[S-adenosylmethionine synthetase enzyme|SAM]].<ref name=":0">{{Citecite journal |last vauthors = Abe|first= Y.|last2=, Suzuki|first2= T.|last3=, Ono|first3= C.|last4=, Iwamoto|first4= K.|last5=, Hosobuchi|first5= M.|last6=, Yoshikawa|first6= H.|date=2002-07-01 | title = Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum |url=https://link.springer.com/article/10.1007/s00438-002-0697-y| journal = Molecular Genetics and Genomics |language=en| volume = 267 | issue = 5 | pages =636–646 636–46 | date = July 2002 | pmid = 12172803 | doi = 10.1007/s00438-002-0697-y |issn s2cid =1617-4615 24427023 }}</ref> 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.[[File:Mevastatin Structure.svg|thumb|260px|[[Lactone]] and acid form of mevastatin]]

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.<ref>{{Cite web |url= https://pubchem.ncbi.nlm.nih.gov/compound/Mevastatin#section=Pharmacology-and-Biochemistry |title=Mevastatin {{!}}| C23H34O5work -= PubChem |last publisher =Pubchem|website=pubchem U.ncbiS.nlm.nih.gov National Library of Medicine |access-date=2016-06-04}}</ref> It has also been shown that mevastatin upregulates [[Endothelial NOS|endothelial nitric oxide synthase]] (eNOS) in mice, which is essential for maintaining a healthy cardiovascular system.<ref>{{Citecite journal |last vauthors = Amin-Hanjani|first=Sepideh|last2= S, Stagliano|first2=Nancy E.|last3=NE, Yamada|first3=Masaru|last4= M, Huang|first4=Paul L.|last5=PL, Liao|first5=James K.|last6=JK, Moskowitz|first6=Michael A.|date=2001-04-01MA | title = Mevastatin, an HMG-CoA Reductasereductase Inhibitorinhibitor, Reducesreduces Strokestroke Damagedamage and Upregulatesupregulates Endothelialendothelial Nitricnitric Oxideoxide Synthasesynthase in Mice|url=http://stroke.ahajournals.org/content/32/4/980mice | journal = Stroke |language=en| volume = 32 | issue = 4 | pages =980–986 980–6 | date = April 2001 | pmid = 11283400 | doi = 10.1161/01.STR.32.4.980 |issn url =0039-2499 http://stroke.ahajournals.org/content/32/4/980 |pmid doi-access =11283400 }}</ref>

== See also ==

== References ==

[[Category:PenicilliumSecondary alcohols]]