title: Analysis of YM-216391 biosynthetic gene cluster and improvement of the cyclopeptide production in a heterologous host.
abstract: YM-216391, an antitumor natural product, represents a new class of cyclic peptides containing a polyoxazole-thiazole moiety. Herein we describe its gene cluster encoding the biosynthetic paradigm featuring a ribosomally synthesizing precursor peptide followed by a series of novel posttranslational modifications, which include (i) cleavage of both N-terminal leader peptide and C-terminal extension peptide and cyclization in a head-to-tail fashion, (ii) conversion of an L-Ile to D-allo-Ile, and (iii) β-hydroxylation of Phe by a P450 monooxygenase followed by further heterocyclization and oxidation to form a phenyloxazole moiety. The cluster was heterologously expressed in Streptomyces lividans to bypass difficult genetic manipulation. Deletion of the ymR3 gene, encoding a putative transcriptional regulator, increased the YM-216391 yield about 20-fold higher than the original yields for the heterologous expression of wild-type cluster, which set the stage for further combinatorial biosynthesis.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Jian
authors.forename: Hai-Xue
authors.initials: HX
authors.lastname: Pan
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Ning
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Shi
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Zeng
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Gong-Li
authors.initials: GL
authors.lastname: Tang
mesh_terms: D000970:Antineoplastic Agents; D001688:Biological Products; D003001:Cloning, Molecular / Q000379:methods*; D005798:Genes, Bacterial; D005810:Multigene Family; D010080:Oxazoles; D010456:Peptides, Cyclic / Q000096:biosynthesis* / Q000235:genetics; D015202:Protein Engineering / Q000379:methods*; D013302:Streptomyces / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D010080:Oxazoles; D010456:Peptides, Cyclic; C499972:YM 216391