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== Biosynthesis ==
== Biosynthesis ==
Biosynthesis of mevastatin is primarily accomplished via the [[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 cyclization. After cyclization it continues via the PKS pathway to a nonaketide after which it is released and undergoes oxidation and dehydration. Lastly the biosynthesis is completed by the PKS and a methylation by [[S-adenosylmethionine synthetase enzyme|SAM]].<ref name=":0">{{Cite journal|last=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=http://link.springer.com/article/10.1007/s00438-002-0697-y|journal=Molecular Genetics and Genomics|language=en|volume=267|issue=5|pages=636–646|doi=10.1007/s00438-002-0697-y|issn=1617-4615}}</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. 
Biosynthesis of mevastatin is primarily accomplished via the [[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. 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">{{Cite journal|last=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=http://link.springer.com/article/10.1007/s00438-002-0697-y|journal=Molecular Genetics and Genomics|language=en|volume=267|issue=5|pages=636–646|doi=10.1007/s00438-002-0697-y|issn=1617-4615}}</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|Lactone and Acid form of Mevastatin]]

[[File:Mevastatin Biosynthesis Corrected.svg|512x512px]]<ref name=":0" />
[[File:Mevastatin Biosynthesis Corrected.svg|512x512px]]<ref name=":0" />


Revision as of 06:01, 4 June 2016

Mevastatin
Clinical data
ATC code
  • none
Identifiers
  • (1S,7R,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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.131.541 Edit this at Wikidata
Chemical and physical data
FormulaC23H34O5
Molar mass390.513 g/mol g·mol−1
3D model (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 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.

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

Biosynthesis of mevastatin is primarily accomplished via the 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. 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. 

Lactone and Acid form of Mevastatin

[7]

Figure 1. Biosynthesis Pathway of Mevastatin

See also

References

  1. ^ Endo, Akira; Kuroda M.; Tsujita Y. (December 1976). "ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium". Journal of Antibiotics (Tokyo). 29 (12): 1346–8. doi:10.7164/antibiotics.29.1346. PMID 1010803.
  2. ^ "The story of statins". Archived from the original on December 21, 2008. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  3. ^ Endo, Akira (Oct 2004). "The origin of the statins". Atheroscler. Suppl. 5 (3): 125–30. doi:10.1016/j.atherosclerosissup.2004.08.033. PMID 15531285.
  4. ^ Wachtershauser, A.; Akoglu, B; Stein, J (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.
  5. ^ Brown, Allan G.; Smale, Terry C.; King, Trevor J.; Hasenkamp, Rainer; Thompson, Ronald H. (1976). "Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum". J. Chem. Soc., Perkin Trans. 1 (11): 1165–1170. doi:10.1039/P19760001165. PMID 945291.
  6. ^ Glynn, Sharon A; O'Sullivan, Dermot; Eustace, Alex J; Clynes, Martin; O'Donovan, Norma (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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ a b Abe, Y.; Suzuki, T.; Ono, C.; Iwamoto, K.; Hosobuchi, M.; Yoshikawa, H. (2002-07-01). "Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum". Molecular Genetics and Genomics. 267 (5): 636–646. doi:10.1007/s00438-002-0697-y. ISSN 1617-4615.
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