Organization of the biosynthetic gene cluster for the polyketide antitumor macrolide, pladienolide, in Streptomyces platensis Mer-11107.
Pladienolides are novel 12-membered macrolides produced by Streptomyces platensis Mer-11107. They show strong antitumor activity and are a potential lead in the search for novel antitumor agents. We sequenced the 65-kb region covering the biosynthetic gene cluster, and found four polyketide synthase genes (pldAI-pldAIV) composed of 11 modules, three genes involved in post-modifications (pldB-D), and a luxR-family regulatory gene (pldR). The thioesterase domain of pldAIV was more dissimilar to that of polyketide synthase systems synthesizing 12/14-membered macrolide polyketides than to that of systems synthesizing other cyclic polyketides. The pldB gene was identified as a 6-hydroxylase belonging to a cytochrome P450 of the CYP107 family. This was clarified by a disruption experiment on pldB, in which the disruptant produced 6-dehydroxy pladienolide B. Two genes located downstream of pldB, designated pldC and pldD, are thought to be a probable genes for 7-O-acetylase and 18, 19-epoxydase respectively.
Machida
Kazuhiro
K
Bioresource Laboratories, Mercian Corporation, Shizuoka, Japan.
Arisawa
Akira
A
Takeda
Susumu
S
Tsuchida
Toshio
T
Aritoku
Yasuhide
Y
Yoshida
Masashi
M
Ikeda
Haruo
H
D000970:Antineoplastic Agents / Q000032:analysis / Q000378:metabolism*; D003001:Cloning, Molecular; D004852:Epoxy Compounds / Q000032:analysis / Q000378:metabolism*; D018942:Macrolides / Q000032:analysis / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D013302:Streptomyces / Q000145:classification / Q000235:genetics* / Q000378:metabolism*
D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D018942:Macrolides; C522342:pladienolide B