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Rapamycin

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Sirolimus was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties.

A 2009 study indicated that rapamycin can prolong the life of mice.[3] If this increase in lifespan were translated to human years, it might allow humans to live more than a hundred years.[4] However, because it strongly suppresses the immune system, the drug cannot be used by humans as a kind of fountain of youth. While the mice in the study were protected in the laboratory, people taking rapamycin are very susceptible to life-threatening infections and cancers, and require constant medical supervision.[5]

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<h2>Mechanism of action</h2>

In a study of Sirolimus as a treatment for TSC, researchers observed a major improvement regarding retardation related to autism. The researchers discovered Sirolimus regulates one of the same proteins that the TSC gene does, but in different parts of the body. They decided to treat mice three to six months old (adulthood in mice life-spans); this increased the autistic mice's intellect to about that of normal mice in as little as three days.[13]

A plaque commemorating the discovery of sirolimus on Easter Island, near Rano Kau.</div>

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Figure 1: Domain organization of PKS of Rapamycin and biosynthetic intermediates.</div>

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Figure 2: Prerapamycin, unbound product of PKS and NRPS.</div>

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Figure 3: Sequence of "tailoring" steps which convert unbound prerapamycin into rapamycin.</div>

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Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which is derived form the shikimate pathway.[14] Interestingly, the cyclohexane ring of the starting unit is reduced during the transfer to module 1. The staring unit is then modified by a series of Claisen condensations with malonyl or methylmalonyl substrates which are attached to an acyl carrier protein (ACP) and extend the polyketide by two carbons each. After each successive condensation, the growing polyketide is further modified according to enzymatic domains which are present to reduce and dehydrate the polyketide thereby introducing the diversity of functionalities observed in rapamycin (See figure 1). Once the linear polyketide is complete, L-pipecolic acid which is synthesized by a lysine cycloamidase from an L-lysine is added to the terminal end of the polyketide by an NRPS. Then the NSPS cyclizes the polyketide giving prerarpmycin, the first enzyme free product. The macrocyclic core is then customized by a series of post-PKS enzymes through methylations by MTases and oxidations by P-450s to yield rapamycin.

Figure 4: Proposed mechanism of lysine cyclodeaminase conversion of L-lysine to L-pipecolic acid.</div>

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Cancer Res. 65 (16): 7052–8. doi:10.1158/0008-5472.CAN-05-0917. PMID 16103051. http://cancerres.aacrjournals.org/cgi/content/full/65/16/7052. Retrieved on 2009-07-08.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Activation+of+Akt+and+eIF4E+survival+pathways+by+rapamycin-mediated+mammalian+target+of+rapamycin+inhibition&rft.jtitle=Cancer+Res.&rft.aulast=Sun+SY%2C+Rosenberg+LM%2C+Wang+X%2C+%27%27et+al.%27%27&rft.au=Sun+SY%2C+Rosenberg+LM%2C+Wang+X%2C+%27%27et+al.%27%27&rft.date=August+2005&rft.volume=65&rft.issue=16&rft.pages=7052%E2%80%938&rft_id=info:doi/10.1158%2F0008-5472.CAN-05-0917&rft_id=info:pmid/16103051&rft_id=http%3A%2F%2Fcancerres.aacrjournals.org%2Fcgi%2Fcontent%2Ffull%2F65%2F16%2F7052&rfr_id=info:sid/en.wikipedia.org:Sirolimus"> </li> <li id="cite_note-Chan-9">^ <cite style="FONT-STYLE: normal" id="CITEREFChan_S2004">Chan S (2004). 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<h2>External links</h2>

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<li><a class="external text" title="http://www.rapamune.com/" rel="nofollow" href="http://www.rapamune.com/~~" rel="nofollow~~">Rapamune official website</a></li>

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