在米托米辛生物合成中的基诺O甲基化
Sabine Grüschow1, Leng-Chee Chang, Yingqing Mao
1Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Journal of the American Chemical Society
|April 28, 2007
概括
该MmcR甲基转移酶对于通过添加甲基基组来产生米托菌素A和B至关重要. 这一甲基化步骤对于关键化疗药物mitomycin C的生物合成至关重要.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 自然产品生物合成 自然产品生物合成
背景情况:
- 线粒素是生物还原活性激活的DNA化剂,用于癌症治疗.
- 线粒素的细胞毒性取决于它们的电化学潜力,受替代物的影响.
- 甲基和乙基中子甲氧基组对于它们的活性至关重要.
研究的目的:
- 调查米托菌素A和B中的金甲氧基组的生物发生.
- 确定mmcR甲基转移酶基因在线粒素生产中的作用.
- 阐明7-O-甲基化对于菌素C生物合成的必要性.
主要方法:
- 基因删除研究:工程化Streptomyces lavendulae菌株与mmcR删除.
- 代谢物分析:分析了来自野生型和突变菌株的培养提取物.
- 酶检测:克隆和过度表达的MmcR甲基转移酶用于体外甲基化研究.
主要成果:
- 删除mmcR取消了A,B和C线粒素的生产.
- 在突变菌株中观察到的7-甲基甲基菌素A和B的积累.
- 在体外,MmcR催化了7-hydroxymitomycins的7-O-甲基化,在提供前体时恢复了mitomycin的产量.
结论:
- 毫米克R甲基转移酶在形成米托基因A和B的7-甲氧基组方面发挥着直接的催化作用.
- 7-O-甲基化是临床药物mitomycin C.生物合成的先决条件.
- 了解mitomycin生物合成为开发新型DNA化剂提供了洞察力.
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