A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis.
The enediynes, unified by their unique molecular architecture and mode of action, represent some of the most potent anticancer drugs ever discovered. The biosynthesis of the enediyne core has been predicted to be initiated by a polyketide synthase (PKS) that is distinct from all known PKSs. Characterization of the enediyne PKS involved in C-1027 (SgcE) and neocarzinostatin (NcsE) biosynthesis has now revealed that (i) the PKSs contain a central acyl carrier protein domain and C-terminal phosphopantetheinyl transferase domain; (ii) the PKSs are functional in heterologous hosts, and coexpression with an enediyne thioesterase gene produces the first isolable compound, 1,3,5,7,9,11,13-pentadecaheptaene, in enediyne core biosynthesis; and (iii) the findings for SgcE and NcsE are likely shared among all nine-membered enediynes, thereby supporting a common mechanism to initiate enediyne biosynthesis.
Zhang
Jian
J
Department of Chemistry, Division of Pharmaceutical Sciences, and University of Wisconsin National Cooperative Drug Discovery Group, University of Wisconsin, Madison, WI 53705, USA.
Van Lanen
Steven G
SG
Ju
Jianhua
J
Liu
Wen
W
Dorrestein
Pieter C
PC
Li
Wenli
W
Kelleher
Neil L
NL
Shen
Ben
B
D000213:Acyl Carrier Protein / Q000737:chemistry* / Q000235:genetics; D000595:Amino Acid Sequence; D000617:Aminoglycosides / Q000096:biosynthesis / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis*; D001665:Binding Sites; D019295:Computational Biology; D053281:Enediynes / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D010205:Pantothenic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D011090:Polyenes / Q000737:chemistry*; D048630:Polyketide Synthases / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary; D009353:Zinostatin / Q000096:biosynthesis / Q000737:chemistry
D000213:Acyl Carrier Protein; D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D011090:Polyenes; C058024:C 1027; D010205:Pantothenic Acid; C011988:phosphopantothenic acid; D048630:Polyketide Synthases; D009353:Zinostatin