Analysis of YM-216391 Biosynthetic Gene Cluster and Improvement of the Cyclopeptide Production in a Heterologous Host

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• 作者：Xiao-Hong Jian ; Hai-Xue Pan ; Ting-Ting Ning ; Yuan-Yuan Shi ; Yong-Sheng Chen ; Yan Li ; Xiao-Wei Zeng ; Jian Xu ; Gong-Li Tang
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：April 20, 2012
• 年：2012
• 卷：7
• 期：4
• 页码：646-651
• 全文大小：411K
• 年卷期：v.7,no.4(April 20, 2012)
• ISSN：1554-8937

文摘

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) 尾-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.