正常和异常的甲基转移酶活动为Dynemicin A生物合成的最后步骤提供了洞察力
Paramita Pal1, Serena M L Wessely1, Craig A Townsend1
1Department of Chemistry, The Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, United States.
Journal of the American Chemical Society
|June 5, 2023
概括
研究人员发现了Dynemicin A (DYN) 生物合成中的关键基因, 删除一个基因DynA5揭示了它在DYN产生中的意想不到的作用,
科学领域:
- 自然产品化学
- 分子生物学
- 生物化学
背景情况:
- 在癌症化疗中具有很强的DNA分裂能力.
- 动力素A (DYN) 是一种关键的化基因,其基因和基因分量均来自常见的C15-heptaene前体.
- DYN的生物合成涉及两个不同的中间体的异构化.
研究的目的:
- 研究两个S-腺甲胺 (SAM) 依赖的甲基转移酶基因DynO6和DynA5在Dynemicin A (DYN) 生物合成中的作用.
- 阐明DynA5在DYN形成的异体化后阶段的功能.
- 提出DYN生物合成下游步骤的生物遗传学理由.
主要方法:
- 在Micromonospora chersina中进行基因删除实验,以创建ΔdynO6和ΔdynA5菌株.
- 在淘汰菌株中分析DYN生产标位和共同代谢物形成.
- 将实验数据与现有文献整合,以提出生物合成途径.
主要成果:
- 删除DynO6证实了它在DYN生物合成中的O-甲基转移酶作用.
- 删除DynA5虽然没有阻止DYN的合成,但导致了位的降低和不寻常的共同代谢物的产生.
- 该DdynA5菌株的代谢概况为DYN的下游加工提供了关键的见解.
结论:
- 在DYN生物合成的后期阶段,DynA5发挥了意想不到的作用,影响了产品产量和代谢物概况.
- 这项研究提出了DYN形成的新生物遗传途径,包括关键环氧化物形成的模型反应.
- 了解这些生物合成步骤对于潜在的DYN类似物用于癌症化疗至关重要.
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