Hydroxyquinone O-Methylation in Mitomycin Biosynthesis

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• 作者：Sabine Gr&uuml ; schow ; Leng-Chee Chang ; Yingqing Mao ; David H. Sherman
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：May 23, 2007
• 年：2007
• 卷：129
• 期：20
• 页码：6470 - 6476
• 全文大小：110K
• 年卷期：v.129,no.20(May 23, 2007)
• ISSN：1520-5126

文摘

Mitomycins are bioreductively activated DNA-alkylating agents. One member of this family,mitomycin C, is in clinical use as part of combination therapy for certain solid tumors. The cytotoxicitydisplayed by mitomycins is dependent on their electrochemical potential which, in turn, is governed in partby the substituents of the quinone moiety. In this paper we describe studies on the biogenesis of the quinonemethoxy group present in mitomycins A and B. An engineered Streptomyces lavendulae strain in whichthe mmcR methyltransferase gene had been deleted failed to produce the three mitomycins (A, B, and C)that are typically isolated from the wild type organism. Analysis of the culture extracts from the mmcR-deletion mutant strain revealed that two new metabolites, 7-demethylmitomycin A and 7-demethylmitomycinB, had accumulated instead. Production of mitomycins A and C or mitomycin B was selectively restoredupon supplementing the culture medium of a S. lavendulae strain unable to produce the key precursor3-amino-5-hydroxybenzoate with either 7-demethylmitomycin A or 7-demethylmitomycin B, respectively.MmcR methyltransferase obtained by cloning and overexpression of the corresponding mmcR gene wasshown to catalyze the 7-O-methylation of both C9- and C9-configured 7-hydroxymitomycins in vitro.This study provides direct evidence for the catalytic role of MmcR in formation of the 7-OMe group that ischaracteristic of mitomycins A and B and demonstrates the prerequisite of 7-O-methylation for the productionof the clinical agent mitomycin C.