title: Identification of the post-polyketide synthase modification enzymes for fostriecin biosynthesis in Streptomyces pulveraceus.
abstract: Fostriecin (FST, 1) is a natural product with promising antitumor activity produced by Streptomyces pulveraceus. Its antitumor activity is associated with the selective inhibition of protein phosphatase activities. The biosynthetic gene cluster for FST has recently been cloned and sequenced. To better understand the post-polyketide synthase (PKS) modification steps in the biosynthetic pathway of FST, we constructed and characterized three post-PKS modification gene mutants of fosG, fosK, and fosM by knockout inactivation in S. pulveraceus. As a result, we determined that a fosK-encoded cytochrome P450 monooxygenase is responsible for C-18 hydroxylation, formation of an unsaturated lactone is dependent upon FosM, and the fosG gene product is involved in hydroxylation at C-4 after the action of FosM to yield PD 113,271 from FST. The accumulated analogues from the ΔfosK and ΔfosM mutant strains possessed a malonyl ester moiety that suggested that all the post-PKS modification steps in FST biosynthesis occur with the polyketide chain bearing a malonyl ester at the C-3 position, with formation of the unsaturated six-membered lactone as the last step in FST biosynthesis.
authors.affiliation: Research Center for Molecular Medicine, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, People's Republic of China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Liu
authors.forename: Ri-Xiang
authors.initials: RX
authors.lastname: Kong
authors.forename: Ming-Shan
authors.initials: MS
authors.lastname: Niu
authors.forename: Rong-Guo
authors.initials: RG
authors.lastname: Qiu
authors.forename: Li
authors.initials: L
authors.lastname: Tang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D015394:Molecular Structure; D005810:Multigene Family; D019906:Nuclear Magnetic Resonance, Biomolecular; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011090:Polyenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D048630:Polyketide Synthases / Q000378:metabolism*; D011753:Pyrones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013302:Streptomyces / Q000737:chemistry / Q000201:enzymology / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D011090:Polyenes; D011753:Pyrones; D048630:Polyketide Synthases; D010749:Phosphoprotein Phosphatases; C040313:fostriecin