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| verifiedrevid = 400323562 |
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| Reference = <ref>{{cite journal|journal=]|volume=71|issue=2|pages=636–644|year=2006|doi= 10.1021/jo052031o+S0022-3263(05)02031-1|title=Formal Total Synthesis of Neocarzinostatin Chromophore|author=Shoji Kobayashi, Makiko Hori, Guang Xing Wang, and Masahiro Hirama|pmid=16408974}} </ref> |
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|verifiedrevid = 441386715 |
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| Name = Neocarzinostatin chromophore |
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|Reference = <ref>{{cite journal|journal=]|volume=71|issue=2|pages=636–644|year=2006|doi= 10.1021/JO052031O|title=Formal Total Synthesis of Neocarzinostatin Chromophore|author1=Shoji Kobayashi |author2=Makiko Hori |author3=Guang Xing Wang |author4=Masahiro Hirama |name-list-style=amp |pmid=16408974}}</ref> |
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| ImageFile = Neocarzinostatin.png |
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|Name = Neocarzinostatin chromophore |
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| ImageSize = 200px |
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|ImageFile = Neocarzinostatin.png |
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| IUPACName = <small>(1a''S'',5''R'',6''R'',6a''E'')-6-{oxy}-1a-(2-oxo-1,3-dioxolan-4-yl)-2,3,8,9-tetradehydro-1a,5,6,9a-tetrahydrocyclopentacyclononaoxiren-5-yl 2-hydroxy-7-methoxy-5-methyl-1-naphthoate</small> |
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|ImageAlt = Structural formula of neocarzinostatin |
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| OtherNames = |
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|ImageFile1 = Neocarzinostatin 3D spacefill.png |
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| Section1 = {{Chembox Identifiers |
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|ImageAlt1 = Space-filling model of the neocarzinostatin molecule |
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| InChI = 1/C35H35NO12/c1-16-12-19(42-4)14-22-20(16)8-9-23(37)27(22)32(40)45-24-13-18-10-11-35(26-15-43-34(41)46-26)25(48-35)7-5-6-21(18)31(24)47-33-28(36-3)30(39)29(38)17(2)44-33/h8-9,12-14,17,21,24-26,28-31,33,36-39H,6,15H2,1-4H3/t17-,21?,24-,25?,26?,28-,29+,30-,31-,33-,35+/m1/s1 |
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|IUPACName = <small>(1a''S'',5''R'',6''R'',6a''E'')-6-{oxy}-1a-(2-oxo-1,3-dioxolan-4-yl)-2,3,8,9-tetradehydro-1a,5,6,9a-tetrahydrocyclopentacyclononaoxiren-5-yl 2-hydroxy-7-methoxy-5-methyl-1-naphthoate</small> |
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| InChIKey = BLXZMHNVKCEIJX-LTZUVELHBD |
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|Section1={{Chembox Identifiers |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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|PubChem = 447545 |
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| StdInChI = 1S/C35H35NO12/c1-16-12-19(42-4)14-22-20(16)8-9-23(37)27(22)32(40)45-24-13-18-10-11-35(26-15-43-34(41)46-26)25(48-35)7-5-6-21(18)31(24)47-33-28(36-3)30(39)29(38)17(2)44-33/h8-9,12-14,17,21,24-26,28-31,33,36-39H,6,15H2,1-4H3/t17-,21?,24-,25?,26?,28-,29+,30-,31-,33-,35+/m1/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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|ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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|ChemSpiderID = 394601 |
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| StdInChIKey = BLXZMHNVKCEIJX-LTZUVELHSA-N |
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|SMILES = Cc1cc(cc2c1ccc(c2C(=O)O3C=C/4C#C5((O5)C#C/C=C4/3O6((((O6)C)O)O)NC)7COC(=O)O7)O)OC |
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|InChI = 1/C35H33NO12/c1-16-12-19(42-4)14-22-20(16)8-9-23(37)27(22)32(40)45-24-13-18-10-11-35(26-15-43-34(41)46-26)25(48-35)7-5-6-21(18)31(24)47-33-28(36-3)30(39)29(38)17(2)44-33/h6,8-9,12-14,17,24-26,28-31,33,36-39H,15H2,1-4H3/b21-6+/t17-,24-,25-,26-,28-,29+,30-,31-,33-,35+/m1/s1 |
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| CASOther = Neocarzinostatin chromophore<br>, Neocarzinostatin |
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|InChIKey = QZGIWPZCWHMVQL-UIYAJPBUBN |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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|StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| ChemSpiderID=21106457 |
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|StdInChI = 1S/C35H33NO12/c1-16-12-19(42-4)14-22-20(16)8-9-23(37)27(22)32(40)45-24-13-18-10-11-35(26-15-43-34(41)46-26)25(48-35)7-5-6-21(18)31(24)47-33-28(36-3)30(39)29(38)17(2)44-33/h6,8-9,12-14,17,24-26,28-31,33,36-39H,15H2,1-4H3/b21-6+/t17-,24-,25-,26-,28-,29+,30-,31-,33-,35+/m1/s1 |
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| PubChem = |
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|StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| SMILES = COc7cc1c(ccc(O)c1C(=O)O3\C=C4\C#C5(OC5C#CCC43O2O(C)(O)(O)2NC)C6COC(=O)O6)c(C)c7 |
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|StdInChIKey = QZGIWPZCWHMVQL-UIYAJPBUSA-N |
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|CASNo_Ref = {{cascite|correct|CAS}} |
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|CASNo = 79633-18-4 |
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|CASNo_Comment = Neocarzinostatin chromophore |
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|CASNo2_Ref = {{cascite|correct|CAS}} |
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|CASNo2 = 9014-02-2 |
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|CASNo2_Comment = Neocarzinostatin |
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|UNII_Ref = {{fdacite|correct|FDA}} |
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|UNII = 2SJ8J82D90 |
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|UNII_Comment = Neocarzinostatin chromophore |
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|UNII2_Ref = {{fdacite|correct|FDA}} |
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|UNII2 = PP082U6W1L |
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|UNII2_Comment = Neocarzinostatin |
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}} |
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|Section2={{Chembox Properties |
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|Formula = C<sub>35</sub>H<sub>33</sub>NO<sub>12</sub> |
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|MolarMass = 659.64 g/mol |
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|Section5={{Chembox Pharmacology |
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|Excretion = Renal |
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| Section2 = {{Chembox Properties |
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| Formula = C<sub>35</sub>H<sub>33</sub>NO<sub>12</sub> |
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| MolarMass = 659.64 g/mol |
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| Section3 = {{Chembox Hazards |
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| Section5 = {{Chembox Pharmacology |
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| Excretion = Renal |
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'''Neocarzinostatin''' is a ] ] ] ] with anti-]al activity secreted by ''Streptomyces macromomyceticus''. |
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'''Neocarzinostatin''' (NCS) is a ] ] ] ] secreted by ''] macromomyceticus''. |
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It consists of two parts, a labile ] (bicyclic dienediyne structure shown at right) and a 113 amino acid ]{{Disambiguation needed|date=July 2011}} to which the chromophore is tightly and non-] with high affinity (K<sub>d</sub> ~ 10<sup>-10</sup> M). The chromophore is a very potent ]-damaging agent; it is very labile and the role of the apoprotein is to protect it and release it to the target DNA. Opening of the epoxide under reductive conditions present in cells creates favorable conditions for a ], leading to a diradical intermediate and eventually double DNA strand cleavage. Other members of the neocarzinostatin group of antibiotics are ], ], ] and ]. |
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It consists of two parts, a labile ] (the non-protein molecular entity shown at right) and a 113 amino acid ] to which the chromophore is tightly and non-] with high affinity (K<sub>d</sub> ~ 10<sup>−10</sup> M). The non-protein component is a very potent ]-damaging agent; However it is extremely unstable and the role of the protein is to protect it and release it to the target DNA. Opening of the epoxide under reductive conditions present in cells creates favorable conditions for a ], leading to formation of ], followed by DNA strand cleavage. Another important member of the ] group of ]s is ]. |
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As a medicine it is among the most potent, and in Japan only it has been used against ] clinically. |
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As a medicine it is among the most potent, and in Japan only it has been used against ] clinically. {{clarify|date=September 2015}} |
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__TOC__ |
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==Biosynthesis of NCS Chromophore== |
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The biosynthesis of neocarzinostatin takes place through a convergence of the activities of a gene cluster, which includes two separate iterative type I ] (PKS) and ] biosynthetic pathways. The first type I PKS gene, NcsE, codes for the ] moiety. The second type I PKS gene, NcsB, codes for the naphthoic acid moiety. Additionally, a cluster of ''NcsC'' genes are responsible for coding enzymes for the synthesis of the deoxyamino sugar moiety of NCS chromophore.<ref>{{cite journal| journal=Chem. Biol. |date=25 Mar 2005| volume=12| pages=293–302 | title=The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type I polyketide synthases |pmid= 15797213| doi=10.1016/j.chembiol.2004.12.013| last1=Liu| first1=W| last2=Nonaka| first2=K| last3=Christenson| first3=SD| last4=Shen| first4=B|issue=3| doi-access=free}}</ref> The biosynthesis can be divided into three preliminary steps with a final convergence of the three moieties: |
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'''1. Synthesis of deoxyaminosugar moiety:''' This part is carried out by the enzymes encoded by a cluster of seven genes, named ''NcsC'' through ''Ncs6''. Since, these enzymes have similarity to dNDP-D-mannose synthases, it has been proposed that, the synthesis starts from D-]. Since the C-2 hydroxyl group (-OH) is ultimately eliminated, the possibility of having D-] cannot also be ruled out. However, additional studies indicate that, D-mannose-1-phosphate is the more likely starting point. |
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'''2. Synthesis of naphthoic acid moiety:''' ''NcsB'', ''NcsB1'', ''NcsB2'' and ''NcsB3'' are enzymes responsible for the synthesis of the naphthoic acid moiety. This is similar to other enediyne natural products, the genes involved in construction of the aromatic moiety are an iterative type I PKS rather than a type II PKS system.<ref>{{cite journal| journal=Proc Natl Acad Sci U S A |date=Jun 22, 2010| volume=107| issue=25|pages=11331–5 | title=Polyketide synthase chemistry does not direct biosynthetic divergence between 9- and 10-membered enediynes|pmid= 20534556| doi=10.1073/pnas.1003442107| last1=Horsman| first1=GP| last2=Chen| first2=Y| last3=Thorson| first3=JS| last4=Shen| first4=B| pmc=2895059|doi-access=free|bibcode=2010PNAS..10711331H }}</ref> The methyl group on the phenol group is added by ]. |
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'''3. Synthesis of enediyne moiety and convergent assembly:''' The enediyne is synthesized by 14 enzymes encoded by ''NcsE'' to ''NcsE11'' plus ''NcsF1'' and ''NcsF2''. ''NcsE'' to ''NcsE11'' constitute another iterative type I PKS, while ''NcsF1'' and ''NcsF2'' have epoxide hydrolase activity. |
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Finally, the building blocks are assembled in a convergent fashion. Ncs6 glycosyltransferase catalyzes the coupling between the enediyne core and the dNDP-deoxyaminosugar. The naphthoyl group is attached to the enediyne core by the enzyme NcsB2 CoA ligase. There is an additional carbonate functionality added, probably originating from CO<sub>2</sub> (or bicarbonate), however, it remains to be determined whether this step is truly enzymatic. |
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==References== |
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==References== |
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{{Enediynes}} |
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