title: Unveiling the post-PKS redox tailoring steps in biosynthesis of the type II polyketide antitumor antibiotic xantholipin.
abstract: Xantholipin from Streptomyces flavogriseus is a curved hexacyclic aromatic polyketide antitumor antibiotic. The entire 52 kb xantholipin (xan) biosynthetic gene cluster was sequenced, and bioinformatic analysis revealed open reading frames encoding type II polyketide synthases, regulators, and polyketide tailoring enzymes. Individual in-frame mutagenesis of five tailoring enzymes lead to the production of nine xantholipin analogs, revealing that the xanthone scaffold formation was catalyzed by the FAD binding monooxygenase XanO4, the δ-lactam formation by the asparagine synthetase homolog XanA, the methylenedioxy bridge generation by the P450 monooxygenase XanO2 and the hydroxylation of the carbon backbone by the FAD binding monooxygenase XanO5. These findings may also apply to other polycyclic xanthone antibiotics, and they form the basis for genetic engineering of the xantholipin and similar biosynthetic gene clusters for the generation of compounds with improved antitumor activities.
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China.
authors.forename: Weike
authors.initials: W
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Lingxin
authors.initials: L
authors.lastname: Kong
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Chu
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
authors.forename: Delin
authors.initials: D
authors.lastname: You
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000145:classification / Q000235:genetics; D045744:Cell Line, Tumor; D018922:HL-60 Cells; D006801:Humans; D007769:Lactams / Q000378:metabolism; D005810:Multigene Family; D010084:Oxidation-Reduction; D010802:Phylogeny; D061065:Polyketides / Q000737:chemistry / Q000378:metabolism*; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D007769:Lactams; D061065:Polyketides; C573547:xantholipin