403:
paradigms. The enediyne PKS, PKSE, from S. globisporusresponsible for the biosynthesis of the C-1027 enediyne is an ACP dependent protein with ketoacylsynthase (KS), acyltransferase (AT), ketoreductase (KR), and dehydratase (DH) domains. PKSE also contains a C-termianal PPTase domain, and the process is terminated by a thioesterase (TE). Starting with acetyl-CoA, PKSE iteratively combines 7 units of malonyl-CoA creating an intermediate heptaene, which is then catalyzed by accessory enzymes into a 9 membered enediyne. There is also a remarkable similarity between the biosynthesis of 9-membered and 10-membered enediynes such as the anticancer drug
Calicheamicin.
26:
82:
424:
458:
373:
441:
74:
407:
474:
219:
InChI=1S/C43H42ClN3O13/c1-21-39(52)46-34-26(17-25(54-6)18-30(34)56-21)40(53)57-31-20-55-33(49)19-28(45)23-15-27(44)37(29(48)16-23)58-32-11-7-9-22(31)12-13-24-10-8-14-43(24,32)60-41-36(51)35(50)38(47(4)5)42(2,3)59-41/h8-10,14-18,28,31-32,35-36,38,41,48,50-51H,1,19-20,45H2,2-6H3,(H,46,52)/b22-9+/t28-,31-,32+,35-,36+,38-,41-,43+/m0/s1
453:
The benzoxazolinate moiety is synthesized from chorismate, which itself is biosynthesized from the shipmate pathway. Chorismate is sequentially acted upon by a 2-amino-2-deoxyisochorismate synthase, and an iron–sulfur FMN-dependent ADIC dehydrogenase to synthesize 3-enolpyruvoylanthranilate (OPA).
436:
The β-amino acid moiety is a non-ribosomal peptide synthesized from tyrosine. The necessary enzymes for its biosynthesis include a phenol hydroxylase (SgcC), a nonribosomal peptide synthetase adenylation enzyme (SgcC1), an NRPS peptidyl–carrier protein (SgcC2), a halogenase (SgcC3), an aminomutase
419:
The deoxy aminosugar found in C-1027 is derived from 5-glucose-1-phosphate. The C-1027 gene cluster contains a thymine diphosphate glucose synthetase (SgcA1), a TDP-glucose 4,6-dehydratase (SgcA2), a TDP-4-keto-6-deoxyglucose epimerase (SgcA2), a C-methyl transferase (SgcA3), an amino transferase
402:
The structure of C-1027 is composed of a nine-membered enediyne complex, a deoxygenated aminosugar, a β-amino acid, and a benzoxazolinate moiety. Enediynes contain a double bond between two triple bonds, and their biosynthesis is distinct from other known polyketide and fatty-acid synthesis
364:
species. C-1027 can induce oxygen-independent interstrand DNA crosslinks in addition to the oxygen-dependent single- and double-stranded DNA breaks typically generated by other enediynes. This unique oxygen-independent mechanism suggests that C-1027 may be effective against
1060:
Alhert J, Shepard E, Lomovskaya N, Zazopoulos E, Staffa A, Bachmann BO, Huang K, Fonstein L, Czisny A, Whitwam RE, Farnet CM, Thorson JS (2002). "The
Calicheamicin Gene Cluster and Its Iterative Type I Enediyne PKS".
388:
in many cancer cells and recent studies have indicated that it induces unusual DNA damage responses to double-strand breaks, including altering cell cycle progression and inducing chromosomal aberrations.
360:. Unlike other enediynes, this molecule contains no triggering mechanism. It is already primed to undergo the cycloaromatization reaction without external activation to produce the toxic 1,4-benzenoid
42:(3R,4R,14R,19S)-22-chloro-4-{oxy}-23-hydroxy-14-(3-hydroxy-7-methoxy-2-methylidene-2H-1,4-benzoxazine-5-carbonyloxy)-17-oxo-2,16-dioxapentacyclopentacosa-1(22),5,7,9,11,13(25),20,23-octaen-19-aminium
420:(SgcA4), an N-methyl transferase (SgcA5), and a glycosyl transferase (SgcA6). These are all the necessary enzymes to synthesize the deoxy aminosugar and attach it to the enediyne core.
761:
Xu YJ, Zhen YS, Goldberg IH (May 1994). "C1027 chromophore, a potent new enediyne antitumor antibiotic, induces sequence-specific double-strand DNA cleavage".
847:"Draft genome sequence of Streptomyces globisporus C-1027, which produces an antitumor antibiotic consisting of a nine-membered enediyne with a chromoprotein"
235:
248:
Aromatized chromophore:: N1C(=O)C(=C)OC2=CC(OC)=CC(C(=O)O3COC(=O)C(C4=CC(O)=C(O5()C6=C(C=C3C=C6)C3=CC=C53O3OC(C)(C)((O)3O)N(C)C)C(Cl)=C4)()())=C12
798:"Improvement of the enediyne antitumor antibiotic C-1027 production by manipulating its biosynthetic pathway regulation in Streptomyces globisporus"
1189:
523:"A new macromolecular antitumor antibiotic, C-1027. I. Discovery, taxonomy of producing organism, fermentation and biological activity"
1289:
644:
Ken-ichiro Y, Minami Y, Azuma R, Saeki M, Otani T (1993). "Structure and cycloaromatization of a novel enediyne, C-1027 chromophore".
437:(SgcC4), and an NRPS-condensation enzyme (SgcC5). All of these enzymes are encoded for within the C-1027 biosynthetic gene cluster.
210:
1003:"A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis"
470:
The four building blocks are then combined into C-1027, although the exact mechanisms and order of this is relatively unknown.
1304:
308:
1299:
496:
1114:"Biosynthesis of the enediyne antitumor antibiotic C-1027 involves a new branching point in chorismate metabolism"
243:
CC1(((((O1)O23C=CC=C2C#C/C/4=C\C#C3OC5=C(C=C(C=C5Cl)(CC(=O)OC4OC(=O)C6=CC(=CC7=C6NC(=O)C(=C)O7)OC)N)O)O)O)N(C)C)C
353:
molecules known, due to its induction of a higher ratio of DNA double-strand breaks than single-strand breaks.
950:
Liu W, Christenson S, Standage S, Shen B (2002). "Biosynthesis of the
Enediyne Antitumor Antibiotic C-1027".
1182:
381:
346:
122:
38:
356:
C-1027's chromophore contains a nine-membered enediyne that is responsible for most of the molecule's
1284:
1125:
1070:
1014:
959:
671:
Liang ZX (April 2010). "Complexity and simplicity in the biosynthesis of enediyne natural products".
357:
1258:
564:"A new macromolecular antitumor antibiotic, C-1027. II. Isolation and physico-chemical properties"
1294:
1175:
1094:
983:
1153:
1086:
1042:
975:
925:
876:
827:
778:
740:
688:
626:
585:
544:
142:
1227:
1143:
1133:
1078:
1032:
1022:
967:
915:
907:
866:
858:
817:
809:
770:
730:
722:
711:"Lidamycin shows highly potent cytotoxic to myeloma cells and inhibits tumor growth in mice"
680:
653:
616:
575:
534:
263:
25:
1263:
1129:
1074:
1018:
963:
102:
1148:
1113:
1037:
1002:
920:
895:
871:
846:
822:
797:
735:
710:
302:
1001:
Shen B, Zhiang J, Van Lanen SG, Ju J, Liu W, Dorrestein PC, Li W, Kelleher NL (2008).
657:
1278:
1243:
366:
987:
896:"Enediynes: Exploration of microbial genomics to discover new anticancer drug leads"
423:
196:
188:
1222:
1098:
894:
Shen B, Yan X, Huang T, Ge H, Yang D, Teng Q, Rudolf JD, Lohman JR (January 2015).
457:
1253:
1248:
621:
604:
580:
563:
539:
522:
338:
911:
521:
Hu J, Xue YC, Xie MY, Zhang R, Otani T, Minami Y, Yamada Y, Marunaka T (1988).
440:
372:
1217:
331:
290:
133:
454:
OPA is then further catalyzed into the benzoxazolinate precursor for C-1027.
1138:
1082:
1027:
971:
605:"A new macromolecular antitumor antibiotic, C-1027. III. Antitumor activity"
385:
361:
350:
342:
328:
1157:
1090:
1046:
979:
929:
880:
831:
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692:
782:
630:
589:
548:
406:
1198:
335:
153:
862:
774:
726:
163:
473:
380:
C-1027 shows promise as an anticancer drug and is currently undergoing
175:
813:
684:
113:
301:
Except where otherwise noted, data are given for materials in their
472:
456:
439:
422:
405:
371:
93:
81:
73:
63:
1171:
1167:
603:
Zhen YS, Ming XY, Yu B, Otani T, Saito H, Yamada Y (1989).
845:
Wang L, Wang S, He Q, Yu T, Li Q, Hong B (August 2012).
562:
Otani T, Minami Y, Marunaka T, ZHANG R, Xie MY (1988).
1236:
1205:
1118:Proceedings from the National Academy of Sciences
1007:Proceedings from the National Academy of Sciences
384:in China, with a 30% success rate. It can induce
796:Chen Y, Yin M, Horsman GP, Shen B (March 2011).
195:
187:
1183:
345:. It shows antibiotic activity against most
8:
900:Bioorganic & Medicinal Chemistry Letters
709:Zhen YZ, Lin YJ, Li Y, Zhen YS (July 2009).
704:
702:
1190:
1176:
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939:
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17:
1147:
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821:
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734:
620:
579:
538:
487:
240:
215:
162:
222:Key: DGGZCXUXASNDAC-QQNGCVSVSA-N
121:
101:
7:
1112:Shen B, Van Lanen SG, Lin S (2008).
178:
14:
24:
349:. It is one of the most potent
305:(at 25 °C , 100 kPa).
334:consisting of a complex of an
194:Aromatized chromophore::
161:Aromatized chromophore::
80:Aromatized chromophore::
1:
658:10.1016/S0040-4039(00)77644-1
427:Deoxy Aminosugar Biosynthesis
295:844.267 g·mol−1
461:Benzoxazolinate Biosynthesis
802:Journal of Natural Products
622:10.7164/antibiotics.42.1294
581:10.7164/antibiotics.41.1580
540:10.7164/antibiotics.41.1575
1321:
912:10.1016/j.bmcl.2014.11.019
715:Acta Pharmacologica Sinica
609:The Journal of Antibiotics
568:The Journal of Antibiotics
527:The Journal of Antibiotics
1290:Experimental cancer drugs
444:B-Amino Acid Biosynthesis
299:
256:
231:
206:
55:
47:
37:
32:
23:
501:pubchem.ncbi.nlm.nih.gov
382:phase II clinical trials
1139:10.1073/pnas.0708750105
1083:10.1126/science.1072105
1028:10.1073/pnas.0711625105
972:10.1126/science.1072110
851:Journal of Bacteriology
673:Natural Product Reports
478:
462:
445:
428:
411:
377:
347:Gram-positive bacteria
476:
460:
443:
426:
410:Enediyne Biosynthesis
409:
375:
50:Lidamycin chromophore
1305:Vinylidene compounds
1300:Nine-membered rings
1130:2008PNAS..105..494V
1075:2002Sci...297.1173A
1069:(5584): 1173–1176.
1019:2008PNAS..105.1460Z
964:2002Sci...297.1170L
958:(5584): 1170–1173.
863:10.1128/JB.00797-12
775:10.1021/bi00185a036
727:10.1038/aps.2009.75
477:C-1027 Biosynthesis
367:hypoxic tumor cells
358:biological activity
20:
19:C-1027 chromophore
479:
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429:
412:
378:
309:Infobox references
18:
1272:
1271:
1237:10 membered rings
814:10.1021/np100825y
652:(16): 2637–2640.
574:(11): 1580–1585.
533:(11): 1575–1579.
317:Chemical compound
315:
314:
83:Interactive image
75:Interactive image
1312:
1228:Neocarzinostatin
1206:9 membered rings
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1013:(5): 1460–1465.
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685:10.1039/b908165h
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646:Tetrahedron Lett
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615:(8): 1294–1298.
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415:Deoxy Aminosugar
376:C-1027 Mechanism
264:Chemical formula
199:
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1315:
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1264:Shishijimicin A
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769:(19): 5947–54.
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1124:(2): 494–499.
1104:
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993:
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837:
788:
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721:(7): 1025–32.
698:
679:(4): 499–528.
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1244:Calicheamicin
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1259:Golfomycin A
1223:Maduropeptin
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1107:
1066:
1062:
1055:
1010:
1006:
996:
955:
951:
903:
899:
889:
857:(15): 4144.
854:
850:
840:
808:(3): 420–4.
805:
801:
791:
766:
763:Biochemistry
762:
718:
714:
676:
672:
666:
649:
645:
639:
612:
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598:
571:
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557:
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516:
504:. Retrieved
500:
490:
469:
452:
435:
432:β-Amino Acid
418:
401:
393:Biosynthesis
379:
355:
324:
320:
319:
123:ChEMBL506048
56:Identifiers
48:Other names
15:
1285:Antibiotics
1254:Esperamicin
1249:Dynemicin A
906:(1): 9–15.
497:"Lidamycin"
339:chromophore
257:Properties
103:CHEBI:68320
1279:Categories
1218:Kedarcidin
482:References
343:apoprotein
332:antibiotic
291:Molar mass
134:ChemSpider
62:3D model (
39:IUPAC name
1295:Enediynes
1199:Enediynes
495:Pubchem.
386:apoptosis
362:diradical
351:cytotoxic
329:antitumor
325:lidamycin
1158:18182490
1091:12183629
1047:18223152
988:52817812
980:12183628
930:25434000
881:22815456
832:21250756
745:19575006
693:20336235
398:Enediyne
336:enediyne
154:DrugBank
1149:2206564
1126:Bibcode
1099:8227050
1071:Bibcode
1063:Science
1038:2234166
1015:Bibcode
960:Bibcode
952:Science
921:4480864
872:3416545
823:3064734
783:8180224
736:4006655
631:2759910
590:3198492
549:3198491
341:and an
285:
197:5289301
189:9962646
176:PubChem
164:DB03933
143:8138248
1213:C-1027
1156:
1146:
1097:
1089:
1045:
1035:
986:
978:
928:
918:
879:
869:
830:
820:
781:
743:
733:
691:
629:
588:
547:
466:C-1027
327:is an
321:C-1027
236:SMILES
114:ChEMBL
33:Names
1095:S2CID
984:S2CID
506:5 May
211:InChI
94:ChEBI
64:JSmol
1154:PMID
1087:PMID
1043:PMID
976:PMID
926:PMID
877:PMID
828:PMID
779:PMID
741:PMID
689:PMID
627:PMID
586:PMID
545:PMID
508:2018
1144:PMC
1134:doi
1122:105
1079:doi
1067:297
1033:PMC
1023:doi
1011:105
968:doi
956:297
916:PMC
908:doi
867:PMC
859:doi
855:194
818:PMC
810:doi
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