View source for Rapamycin

<p><font color="#000000"><strong>Sirolimus</strong> (INN/USAN), also known as <strong>rapamycin</strong>, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, Sirolimus was first discovered as a product of the bacterium <em>Streptomyces hygroscopicus</em> in a soil sample from Easter Island<sup id="cite_ref-Vezi_0-0" class="reference"><font size="2"><span>[</span>1<span>]</span></font></sup> &mdash; an island also known as &quot;Rapa Nui&quot;, hence the name.<sup id="cite_ref-RapamycinOrigin_1-0" class="reference"><font size="2"><span>[</span>2<span>]</span></font></sup> It is marketed under the trade name <strong>Rapamune</strong> by Wyeth.</font></p>
<p><font color="#000000">Sirolimus was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties.</font></p>
<p><font color="#000000">A 2009 study indicated that rapamycin can prolong the life of mice.<sup id="cite_ref-2" class="reference"><font size="2"><span>[</span>3<span>]</span></font></sup> If this increase in lifespan were translated to human years, it might allow humans to live more than a hundred years.<sup id="cite_ref-3" class="reference"><font size="2"><span>[</span>4<span>]</span></font></sup> 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.<sup id="cite_ref-4" class="reference"><font size="2"><span>[</span>5<span>]</span></font></sup></font></p>

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<h2><font color="#000000"><span class="mw-headline">Mechanism of action</span></font></h2>
<p><font color="#000000">Unlike the similarly-named tacrolimus, sirolimus is not a calcineurin inhibitor. However, it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to interleukin-2 (IL-2) and thereby blocks activation of T- and B-cells. In contrast, tacrolimus inhibits the production of IL-2.</font></p>
<p><font color="#000000">The mode of action of Sirolimus is to bind the cytosolic protein <em>FK-binding protein 12</em> (FKBP12) in a manner similar to tacrolimus. However, unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the <em>mammalian target of rapamycin</em> (mTOR) pathway by directly binding the mTOR Complex1 (mTORC1). mTOR is also called FRAP (FKBP-rapamycin associated protein) or RAFT (rapamycin and FKBP target). FRAP and RAFT are actually more accurate names since they reflect the fact that rapamycin must bind FKBP12 first, and only the FKBP12-rapamycin complex can bind FRAP/RAFT/mTOR.</font></p>
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<h2><font color="#000000"><span class="mw-headline">Use in transplant</span></font></h2>
<p><font color="#000000">The chief advantage sirolimus has over calcineurin inhibitors is that it has low toxicity towards kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on October 7 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.</font></p>
<p><font color="#000000">Sirolimus can also be used alone, or in conjunction with calcineurin inhibitors and/or mycophenolate mofetil, so as to provide steroid-free immunosuppression regimes. However, impaired wound healing and thrombocytopenia is a possible side effect of sirolimus; therefore, some transplant centres prefer not to use it immediately after the transplant operation, instead administering it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and is the subject of a number of ongoing clinical trials.</font></p>
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<h2><font color="#000000"><span class="mw-headline">Anti-proliferative effects</span></font></h2>
<p><font color="#000000">The anti-proliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus eluting stents when compared to bare metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent is marketed by Cordis, a division of Johnson &amp; Johnson, under the tradename Cypher.<sup id="cite_ref-5" class="reference"><font size="2"><span>[</span>6<span>]</span></font></sup> It has been proposed, however, that such stents may increase the risk of vascular thrombosis.<sup id="cite_ref-Shuchman_6-0" class="reference"><font size="2"><span>[</span>7<span>]</span></font></sup></font></p>
<p><font color="#000000">Additionally sirolimus is currently being assessed as a theraputic option for autosomal dominant polycystic kidney disease (ADPKD). Case reports indicate that sirolimus can reduce kidney volume and delay the loss of renal function in patients with ADPKD.<sup id="cite_ref-peces_7-0" class="reference"><font size="2"><span>[</span>8<span>]</span></font></sup></font></p>
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<h2><font color="#000000"><span class="mw-headline">Tuberous sclerosis complex</span></font></h2>
<p><font color="#000000">Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that leaves sufferers prone to benign tumor growth in the brain, heart, kidneys, skin and other organs. The drug is approved by the USFDA for use in children and adults who develop subependymal giant cell astrocytomas, or SEGAs, a brain tumor that appears in up to 30 percent of TSC patients. Phase III clinical trials have linked the drug to SEGA remission, although the tumors often re-grew once treatment stopped. Sirolimus has also been shown to shrink kidney tumors in adults with TSC. Anecdotal reports that the drug ameliorates TSC symptoms such as facial angiofibromas, ADHD, and autism remain unproven.</font></p>
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<h3><font color="#000000"><span class="mw-headline">Cancer</span></font></h3>
<p><font color="#000000">The anti-proliferative effects of sirolimus may have a role in treating cancer. Recently, it was shown that sirolimus inhibited the progression of dermal Kaposi's sarcoma in patients with renal transplants. Other mTOR inhibitors such as temsirolimus (CCI-779) or everolimus (RAD001) are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.</font></p>
<p><font color="#000000">Combination therapy of doxorubicin and sirolimus has been shown to drive AKT-positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs like doxorubicin or cyclophosphamide. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; nor are eIF4E expressing lymphomas sensitive to sirolimus.<sup id="cite_ref-8" class="reference"><font size="2"><span>[</span>9<span>]</span></font></sup> Rapamycin showed no effect on its own.<sup id="cite_ref-Chan_9-0" class="reference"><font size="2"><span>[</span>10<span>]</span></font></sup><sup id="cite_ref-ScienceDaily_10-0" class="reference"><font size="2"><span>[</span>11<span>]</span></font></sup><sup id="cite_ref-SignalingGateway_11-0" class="reference"><font size="2"><span>[</span>12<span>]</span></font></sup></font></p>
<p><font color="#000000">As with all immunosuppressive medications, rapamycin decreases the body's inherent anti-cancer activity and allows some cancers which would have been naturally destroyed to proliferate. Patients on immunosuppressive medications have a 10- to 100-fold increased risk of cancer compared to the general population. Furthermore, people who currently have or have already been treated for cancer have a higher rate of tumor progression and recurrence than patients with an intact immune system<sup style="WHITE-SPACE: nowrap" class="noprint Template-Fact" title="This claim needs references to reliable sources from January 2008"><font size="2">[<em>citation needed</em>]</font></sup>.</font></p>
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<h2><font color="#000000"><span class="mw-headline">Potential treatment for autism</span></font></h2>
<p><font color="#000000">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.<sup id="cite_ref-12" class="reference"><font size="2"><span>[</span>13<span>]</span></font></sup></font></p>
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<div style="WIDTH: 302px" class="thumbinner"><font color="#000000"><font size="2"><img class="thumbimage" alt="" width="300" height="200" src="http://upload.wikimedia.org/wikipedia/commons/thumb/9/96/Rapamycin_plaque_on_Easter_Island.JPG/300px-Rapamycin_plaque_on_Easter_Island.JPG" /></font> </font>
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<font color="#000000">A plaque commemorating the discovery of sirolimus on Easter Island, near Rano Kau.</font></div>
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<h2><font color="#000000"><span class="mw-headline">Biosynthesis</span></font></h2>
<p><font color="#000000">Rapamycin is a macrocyclic polyketide isolated from <em>Streptomyces hygroscopicus</em> that has been shown to exhibit antifungal, antitumor, and immunosuppressant properties.<sup id="cite_ref-Vezi_0-1" class="reference"><font size="2"><span>[</span>1<span>]</span></font></sup> The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB and RapC which contain a total of 14 modules (See figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC.<sup id="cite_ref-Rapamycin_domains_and_primary_genes_13-0" class="reference"><font size="2"><span>[</span>14<span>]</span></font></sup> Then the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide and then cyclizes the molecule yielding the unbound product, prerapamycin.<sup id="cite_ref-prerapamycin_14-0" class="reference"><font size="2"><span>[</span>15<span>]</span></font></sup></font></p>
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<div style="OVERFLOW-X: scroll; OVERFLOW-Y: hidden; OVERFLOW: auto"><font color="#000000" size="2"><img alt="Figure 1: Domain organization of PKS of Rapamycin and biosynthetic intermediates." width="1320" height="693" src="http://upload.wikimedia.org/wikipedia/commons/7/71/Domain_organization_of_PKS_of_Rapamycin_and_biosynthetic_intermediates.gif" /></font></div>
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<font color="#000000">Figure 1: Domain organization of PKS of Rapamycin and biosynthetic intermediates.</font></div>
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<div style="WIDTH: 182px" class="thumbinner"><font color="#000000"><img class="thumbimage" alt="" width="180" height="188" src="http://upload.wikimedia.org/wikipedia/commons/0/04/Prerapamycin.gif" /> </font>
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<font color="#000000">Figure 2: Prerapamycin, unbound product of PKS and NRPS.</font></div>
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<p><font color="#000000">The core macrocycle, prerapamycin is then modified (See figure 3) by an additional five enzymes which lead to the final product, rapamycin. First the core macrocycle is modified by RapI, SAM-dependant O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a cytochrome P-450 monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450 installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin.<sup id="cite_ref-Rapamycin_genes_15-0" class="reference"><font size="2"><span>[</span>16<span>]</span></font></sup><br />
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The biosynthetic genes responsible for rapamycin synthesis have been identified. As expected, three extremely large open reading frames (OFRs) designated as <em>rapA</em>, <em>rapB</em> and <em>rapC</em> encode for three extremely large and complex multienzymes, RapA, RapB, and RapC respectively.<sup id="cite_ref-Rapamycin_domains_and_primary_genes_13-1" class="reference"><font size="2"><span>[</span>14<span>]</span></font></sup> The gene <em>rapL</em> has been established to code for a NAD+ dependant lysine cycloamidase which converts L-lysine to L-pipecolic acid (See figure 4) for incorporation at the end of the polyketide.<sup id="cite_ref-rapamycin_report_16-0" class="reference"><font size="2"><span>[</span>17<span>]</span></font></sup> A gene <em>rapP</em>, which is embedded between the PKS genes and translationally coupled to <em>rapC</em> encodes for an additional enzyme, a NPRS responsible for incorporating L-pipecolic acid, chain termination and cyclization of prerapamycin. Additionally genes <em>rapI</em>, <em>rapJ</em>, <em>rapM</em>, <em>rapN</em>, <em>rapO</em>, and <em>rapQ</em> have been identified as coding for &quot;tailoring&quot; enzymes which modify the marcrcyclic core to give rapamycin (See figure 3). Finally, <em>rapG</em> and <em>rapH</em> have been identified to code for enzymes which have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression.<sup id="cite_ref-rapG_rapH_17-0" class="reference"><font size="2"><span>[</span>18<span>]</span></font></sup><br />
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<font color="#000000">Figure 3: Sequence of &quot;tailoring&quot; steps which convert unbound prerapamycin into rapamycin.</font></div>
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<p><font color="#000000">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.<sup id="cite_ref-Rapamycin_domains_and_primary_genes_13-2" class="reference"><font size="2"><span>[</span>14<span>]</span></font></sup> 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.</font></p>
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<font color="#000000">Figure 4: Proposed mechanism of lysine cyclodeaminase conversion of L-lysine to L-pipecolic acid.</font></div>
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<h2><font color="#000000"><span class="mw-headline">References</span></font></h2>
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<ol class="references">
    <li id="cite_note-Vezi-0"><font color="#000000">^ <sup><em><strong><font size="2">a</font></strong></em></sup> <sup><em><strong><font size="2">b</font></strong></em></sup> <cite style="FONT-STYLE: normal" id="CITEREFV.C3.A9zina_C.2C_Kudelski_A.2C_Sehgal_SN1975">V&eacute;zina C, Kudelski A, Sehgal SN (October 1975). &quot;Rapamycin (AY-22,989), a new antifungal antibiotic.&quot;. <em>J. Antibiot.</em> <strong>28</strong> (10): 721&ndash;6. PMID 1102508.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Rapamycin+%28AY-22%2C989%29%2C+a+new+antifungal+antibiotic.&amp;rft.jtitle=J.+Antibiot.&amp;rft.aulast=V%C3%A9zina+C%2C+Kudelski+A%2C+Sehgal+SN&amp;rft.au=V%C3%A9zina+C%2C+Kudelski+A%2C+Sehgal+SN&amp;rft.date=October+1975&amp;rft.volume=28&amp;rft.issue=10&amp;rft.pages=721%E2%80%936&amp;rft_id=info:pmid/1102508&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-RapamycinOrigin-1"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFPritchard_DI2005">Pritchard DI (2005). &quot;Sourcing a chemical succession for cyclosporin from parasites and human pathogens&quot;. <em>Drug Discovery Today</em> <strong>10</strong> (10): 688&ndash;691. doi:<span class="neverexpand">10.1016/S1359-6446(05)03395-7</span>. PMID 15896681.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Sourcing+a+chemical+succession+for+cyclosporin+from+parasites+and+human+pathogens&amp;rft.jtitle=Drug+Discovery+Today&amp;rft.aulast=Pritchard+DI&amp;rft.au=Pritchard+DI&amp;rft.date=2005&amp;rft.volume=10&amp;rft.issue=10&amp;rft.pages=688%E2%80%93691&amp;rft_id=info:doi/10.1016%2FS1359-6446%2805%2903395-7&amp;rft_id=info:pmid/15896681&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-2"><font color="#000000"><strong>^</strong> BBC, retrieved 10 July 2009</font> </li>
    <li id="cite_note-3"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFHarrison_DE.2C_Strong_R.2C_Sharp_ZD.2C_.27.27et_al..27.272009">Harrison DE, Strong R, Sharp ZD, <em>et al.</em> (8 July 2009). &quot;Rapamycin fed late in life extends lifespan in genetically heterogeneous mice&quot;. <em>Nature</em>. doi:<span class="neverexpand">10.1038/nature08221</span>. Lay summary&nbsp;&ndash;&nbsp;<em>London Times</em> (2009-07-08).</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Rapamycin+fed+late+in+life+extends+lifespan+in+genetically+heterogeneous+mice&amp;rft.jtitle=Nature&amp;rft.aulast=Harrison+DE%2C+Strong+R%2C+Sharp+ZD%2C+%27%27et+al.%27%27&amp;rft.au=Harrison+DE%2C+Strong+R%2C+Sharp+ZD%2C+%27%27et+al.%27%27&amp;rft.date=8+July+2009&amp;rft_id=info:doi/10.1038%2Fnature08221&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-4"><font color="#000000"><strong>^</strong> [<cite style="FONT-STYLE: normal" id="CITEREFJocelyn_Rice2009">Jocelyn Rice (8 July 2009). &quot;First Drug Shown to Extend Life Span in Mammals&quot;. <em>Technology Review</em> (Massachusetts Institute of Technology): 1-2<span class="printonly">. http://www.technologyreview.com/biomedicine/22974/page1/</span><span class="reference-accessdate">. Retrieved on 2009-07-09</span>.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=First+Drug+Shown+to+Extend+Life+Span+in+Mammals&amp;rft.jtitle=Technology+Review&amp;rft.aulast=Jocelyn+Rice&amp;rft.au=Jocelyn+Rice&amp;rft.date=8+July+2009&amp;rft.pages=1-2&amp;rft.pub=Massachusetts+Institute+of+Technology&amp;rft_id=http%3A%2F%2Fwww.technologyreview.com%2Fbiomedicine%2F22974%2Fpage1%2F&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-5"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" class="web">&quot;Cypher Sirolimus-eluting Coronary Stent&quot;. Cypher Stent<span class="printonly">. http://www.cypherusa.com/</span><span class="reference-accessdate">. Retrieved on 2008-04-01</span>.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=bookitem&amp;rft.btitle=Cypher+Sirolimus-eluting+Coronary+Stent&amp;rft.atitle=&amp;rft.pub=%5B%5BCypher+Stent%5D%5D&amp;rft_id=http%3A%2F%2Fwww.cypherusa.com%2F&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-Shuchman-6"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFShuchman_M2006">Shuchman M (2006). &quot;Trading restenosis for thrombosis? New questions about drug-eluting stents&quot;. <em>N Engl J Med</em> <strong>355</strong> (19): 1949&ndash;52. doi:<span class="neverexpand">10.1056/NEJMp068234</span>. PMID 17093244.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Trading+restenosis+for+thrombosis%3F+New+questions+about+drug-eluting+stents&amp;rft.jtitle=%5B%5BNew+England+Journal+of+Medicine%7CN+Engl+J+Med%5D%5D&amp;rft.aulast=Shuchman+M&amp;rft.au=Shuchman+M&amp;rft.date=2006&amp;rft.volume=355&amp;rft.issue=19&amp;rft.pages=1949%E2%80%9352&amp;rft_id=info:doi/10.1056%2FNEJMp068234&amp;rft_id=info:pmid/17093244&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-peces-7"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFPeces_R.2C_Peces_C.2C_P.C3.A9rez-Due.C3.B1as_V.2C_.27.27et_al..27.272009">Peces R, Peces C, P&eacute;rez-Due&ntilde;as V, <em>et al.</em> (16 January 2009). &quot;Rapamycin reduces kidney volume and delays the loss of renal function in a patient with autosomal-dominant polycystic kidney disease&quot;. <em>NDT Plus</em> (Oxford Journals) <strong>2</strong> (2): 133-135. doi:<span class="neverexpand">10.1093/ndtplus/sfn210</span>. ISSN 1753-0792.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Rapamycin+reduces+kidney+volume+and+delays+the+loss+of+renal+function+in+a+patient+with+autosomal-dominant+polycystic+kidney+disease&amp;rft.jtitle=NDT+Plus&amp;rft.aulast=Peces+R%2C+Peces+C%2C+P%C3%A9rez-Due%C3%B1as+V%2C+%27%27et+al.%27%27&amp;rft.au=Peces+R%2C+Peces+C%2C+P%C3%A9rez-Due%C3%B1as+V%2C+%27%27et+al.%27%27&amp;rft.date=16+January+2009&amp;rft.volume=2&amp;rft.issue=2&amp;rft.pages=133-135&amp;rft.pub=Oxford+Journals&amp;rft_id=info:doi/10.1093%2Fndtplus%2Fsfn210&amp;rft.issn=1753-0792&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-8"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFSun_SY.2C_Rosenberg_LM.2C_Wang_X.2C_.27.27et_al..27.272005">Sun SY, Rosenberg LM, Wang X, <em>et al.</em> (August 2005). &quot;Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition&quot;. <em>Cancer Res.</em> <strong>65</strong> (16): 7052&ndash;8. doi:<span class="neverexpand">10.1158/0008-5472.CAN-05-0917</span>. PMID 16103051<span class="printonly">. http://cancerres.aacrjournals.org/cgi/content/full/65/16/7052</span><span class="reference-accessdate">. Retrieved on 2009-07-08</span>.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Activation+of+Akt+and+eIF4E+survival+pathways+by+rapamycin-mediated+mammalian+target+of+rapamycin+inhibition&amp;rft.jtitle=Cancer+Res.&amp;rft.aulast=Sun+SY%2C+Rosenberg+LM%2C+Wang+X%2C+%27%27et+al.%27%27&amp;rft.au=Sun+SY%2C+Rosenberg+LM%2C+Wang+X%2C+%27%27et+al.%27%27&amp;rft.date=August+2005&amp;rft.volume=65&amp;rft.issue=16&amp;rft.pages=7052%E2%80%938&amp;rft_id=info:doi/10.1158%2F0008-5472.CAN-05-0917&amp;rft_id=info:pmid/16103051&amp;rft_id=http%3A%2F%2Fcancerres.aacrjournals.org%2Fcgi%2Fcontent%2Ffull%2F65%2F16%2F7052&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-Chan-9"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFChan_S2004">Chan S (2004). &quot;Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer&quot;. <em>Br J Cancer</em> <strong>91</strong> (8): 1420&ndash;4. doi:<span class="neverexpand">10.1038/sj.bjc.6602162</span>. PMID 15365568.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Targeting+the+mammalian+target+of+rapamycin+%28mTOR%29%3A+a+new+approach+to+treating+cancer&amp;rft.jtitle=Br+J+Cancer&amp;rft.aulast=Chan+S&amp;rft.au=Chan+S&amp;rft.date=2004&amp;rft.volume=91&amp;rft.issue=8&amp;rft.pages=1420%E2%80%934&amp;rft_id=info:doi/10.1038%2Fsj.bjc.6602162&amp;rft_id=info:pmid/15365568&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-ScienceDaily-10"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFWendel_HG.2C_De_Stanchina_E.2C_Fridman_JS.2C_.27.27et_al..27.272004">Wendel HG, De Stanchina E, Fridman JS, <em>et al.</em> (March 2004). &quot;Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy&quot;. <em>Nature</em> <strong>428</strong> (6980): 332&ndash;7. doi:<span class="neverexpand">10.1038/nature02369</span>. PMID 15029198. Lay summary&nbsp;&ndash;&nbsp;<em>ScienceDaily</em> (2004-03-18).</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Survival+signalling+by+Akt+and+eIF4E+in+oncogenesis+and+cancer+therapy&amp;rft.jtitle=Nature&amp;rft.aulast=Wendel+HG%2C+De+Stanchina+E%2C+Fridman+JS%2C+%27%27et+al.%27%27&amp;rft.au=Wendel+HG%2C+De+Stanchina+E%2C+Fridman+JS%2C+%27%27et+al.%27%27&amp;rft.date=March+2004&amp;rft.volume=428&amp;rft.issue=6980&amp;rft.pages=332%E2%80%937&amp;rft_id=info:doi/10.1038%2Fnature02369&amp;rft_id=info:pmid/15029198&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-SignalingGateway-11"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFNovak2004">Novak, Kristine (May 2004). &quot;Therapeutics: Means to an end&quot;. <em>Nature Reviews Cancer</em> <strong>4</strong>: 332. doi:<span class="neverexpand">10.1038/nrc1349</span><span class="printonly">. http://www.signaling-gateway.org/update/updates/200405/nrc1349.html</span><span class="reference-accessdate">. Retrieved on 2009-07-08</span>.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Therapeutics%3A+Means+to+an+end&amp;rft.jtitle=Nature+Reviews+Cancer&amp;rft.aulast=Novak&amp;rft.aufirst=Kristine&amp;rft.au=Novak%2C+Kristine&amp;rft.date=May+2004&amp;rft.volume=4&amp;rft.pages=332&amp;rft_id=info:doi/10.1038%2Fnrc1349&amp;rft_id=http%3A%2F%2Fwww.signaling-gateway.org%2Fupdate%2Fupdates%2F200405%2Fnrc1349.html&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-12"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFEhninger_D.2C_Han_S.2C_Shilyansky_C.2C_.27.27et_al..27.272008">Ehninger D, Han S, Shilyansky C, <em>et al.</em> (August 2008). &quot;Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis&quot;. <em>Nat. Med.</em> <strong>14</strong> (8): 843&ndash;8. doi:<span class="neverexpand">10.1038/nm1788</span>. PMID 18568033. Lay summary&nbsp;&ndash;&nbsp;<em>Scientific American</em> (2008-06-25).</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Reversal+of+learning+deficits+in+a+Tsc2%2B%2F-+mouse+model+of+tuberous+sclerosis&amp;rft.jtitle=Nat.+Med.&amp;rft.aulast=Ehninger+D%2C+Han+S%2C+Shilyansky+C%2C+%27%27et+al.%27%27&amp;rft.au=Ehninger+D%2C+Han+S%2C+Shilyansky+C%2C+%27%27et+al.%27%27&amp;rft.date=August+2008&amp;rft.volume=14&amp;rft.issue=8&amp;rft.pages=843%E2%80%938&amp;rft_id=info:doi/10.1038%2Fnm1788&amp;rft_id=info:pmid/18568033&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-Rapamycin_domains_and_primary_genes-13"><font color="#000000">^ <sup><em><strong><font size="2">a</font></strong></em></sup> <sup><em><strong><font size="2">b</font></strong></em></sup> <sup><em><strong><font size="2">c</font></strong></em></sup> <cite style="FONT-STYLE: normal" id="CITEREFSchwecke_T.2C_Aparicio_JF.2C_Moln.C3.A1r_I.2C_.27.27et_al..27.271995">Schwecke T, Aparicio JF, Moln&aacute;r I, <em>et al.</em> (August 1995). &quot;The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin&quot;. <em>Proc. Natl. Acad. Sci. U.S.A.</em> <strong>92</strong> (17): 7839&ndash;43. doi:<span class="neverexpand">10.1073/pnas.92.17.7839</span>. PMID 7644502.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=The+biosynthetic+gene+cluster+for+the+polyketide+immunosuppressant+rapamycin&amp;rft.jtitle=Proc.+Natl.+Acad.+Sci.+U.S.A.&amp;rft.aulast=Schwecke+T%2C+Aparicio+JF%2C+Moln%C3%A1r+I%2C+%27%27et+al.%27%27&amp;rft.au=Schwecke+T%2C+Aparicio+JF%2C+Moln%C3%A1r+I%2C+%27%27et+al.%27%27&amp;rft.date=August+1995&amp;rft.volume=92&amp;rft.issue=17&amp;rft.pages=7839%E2%80%9343&amp;rft_id=info:doi/10.1073%2Fpnas.92.17.7839&amp;rft_id=info:pmid/7644502&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-prerapamycin-14"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFGregory_MA.2C_Gaisser_S.2C_Lill_RE.2C_.27.27et_al..27.272004">Gregory MA, Gaisser S, Lill RE, <em>et al.</em> (May 2004). &quot;Isolation and characterization of pre-rapamycin, the first macrocyclic intermediate in the biosynthesis of the immunosuppressant rapamycin by S. hygroscopicus&quot;. <em>Angew. Chem. Int. Ed. Engl.</em> <strong>43</strong> (19): 2551&ndash;3. doi:<span class="neverexpand">10.1002/anie.200453764</span>. PMID 15127450.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Isolation+and+characterization+of+pre-rapamycin%2C+the+first+macrocyclic+intermediate+in+the+biosynthesis+of+the+immunosuppressant+rapamycin+by+S.+hygroscopicus&amp;rft.jtitle=Angew.+Chem.+Int.+Ed.+Engl.&amp;rft.aulast=Gregory+MA%2C+Gaisser+S%2C+Lill+RE%2C+%27%27et+al.%27%27&amp;rft.au=Gregory+MA%2C+Gaisser+S%2C+Lill+RE%2C+%27%27et+al.%27%27&amp;rft.date=May+2004&amp;rft.volume=43&amp;rft.issue=19&amp;rft.pages=2551%E2%80%933&amp;rft_id=info:doi/10.1002%2Fanie.200453764&amp;rft_id=info:pmid/15127450&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-Rapamycin_genes-15"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFGregory_MA.2C_Hong_H.2C_Lill_RE.2C_.27.27et_al..27.272006">Gregory MA, Hong H, Lill RE, <em>et al.</em> (October 2006). &quot;Rapamycin biosynthesis: Elucidation of gene product function&quot;. <em>Org. Biomol. Chem.</em> <strong>4</strong> (19): 3565&ndash;8. doi:<span class="neverexpand">10.1039/b608813a</span>. PMID 16990929.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Rapamycin+biosynthesis%3A+Elucidation+of+gene+product+function&amp;rft.jtitle=Org.+Biomol.+Chem.&amp;rft.aulast=Gregory+MA%2C+Hong+H%2C+Lill+RE%2C+%27%27et+al.%27%27&amp;rft.au=Gregory+MA%2C+Hong+H%2C+Lill+RE%2C+%27%27et+al.%27%27&amp;rft.date=October+2006&amp;rft.volume=4&amp;rft.issue=19&amp;rft.pages=3565%E2%80%938&amp;rft_id=info:doi/10.1039%2Fb608813a&amp;rft_id=info:pmid/16990929&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-rapamycin_report-16"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFGraziani_EI2009">Graziani EI (May 2009). &quot;Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs&quot;. <em>Nat Prod Rep</em> <strong>26</strong> (5): 602&ndash;9. doi:<span class="neverexpand">10.1039/b804602f</span>. PMID 19387497.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Recent+advances+in+the+chemistry%2C+biosynthesis+and+pharmacology+of+rapamycin+analogs&amp;rft.jtitle=Nat+Prod+Rep&amp;rft.aulast=Graziani+EI&amp;rft.au=Graziani+EI&amp;rft.date=May+2009&amp;rft.volume=26&amp;rft.issue=5&amp;rft.pages=602%E2%80%939&amp;rft_id=info:doi/10.1039%2Fb804602f&amp;rft_id=info:pmid/19387497&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
    <li id="cite_note-rapG_rapH-17"><font color="#000000"><strong>^</strong> <cite style="FONT-STYLE: normal" id="CITEREFAparicio_JF.2C_Moln.C3.A1r_I.2C_Schwecke_T.2C_.27.27et_al..27.271996">Aparicio JF, Moln&aacute;r I, Schwecke T, <em>et al.</em> (February 1996). &quot;Organization of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of the enzymatic domains in the modular polyketide synthase&quot;. <em>Gene</em> <strong>169</strong> (1): 9&ndash;16. doi:<span class="neverexpand">10.1016/0378-1119(95)00800-4</span>. PMID 8635756.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Organization+of+the+biosynthetic+gene+cluster+for+rapamycin+in+Streptomyces+hygroscopicus%3A+analysis+of+the+enzymatic+domains+in+the+modular+polyketide+synthase&amp;rft.jtitle=Gene&amp;rft.aulast=Aparicio+JF%2C+Moln%C3%A1r+I%2C+Schwecke+T%2C+%27%27et+al.%27%27&amp;rft.au=Aparicio+JF%2C+Moln%C3%A1r+I%2C+Schwecke+T%2C+%27%27et+al.%27%27&amp;rft.date=February+1996&amp;rft.volume=169&amp;rft.issue=1&amp;rft.pages=9%E2%80%9316&amp;rft_id=info:doi/10.1016%2F0378-1119%2895%2900800-4&amp;rft_id=info:pmid/8635756&amp;rfr_id=info:sid/en.wikipedia.org:Sirolimus"><span style="DISPLAY: none">&nbsp;</span></span></font> </li>
</ol>
</div>
<p><a id="External_links" name="External_links"><font color="#000000"></font></a></p>
<h2><span class="mw-headline"><font color="#000000">External links</font></span></h2>
<ul>
    <li><a class="external text" title="http://www.rapamune.com/" rel="nofollow" href="http://www.rapamune.com/"><font color="#0066cc">Rapamune official website</font></a> </li>
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