通过结构指导识别一种抑制人类肠道细菌无氧胆代谢的小分子
Marina Orman1, Smaranda Bodea1, Michael A Funk
1Department of Chemistry and Chemical Biology , Harvard University , 12 Oxford Street , Cambridge , Massachusetts 02138 , United States.
Journal of the American Chemical Society
|December 18, 2018
概括
发现贝他因可以抑制肠道微生物从胆中产生的三甲基胺 (TMA). 这一发现为开发针对肠道微生物胆代谢的疗法提供了新的策略.
科学领域:
- 微生物学
- 生物化学
- 人类健康
背景情况:
- 肠道微生物在人类的健康和疾病中起着至关重要的作用.
- 无氧肠道细菌将胆转化为三甲基胺 (TMA),这是一种与各种人类疾病有关的化合物.
- 现有的这种途径的抑制剂具有局限性或未经证实的有效性.
研究的目的:
- 确定肠道微生物转化胆为TMA的新型抑制剂.
- 描述新发现的抑制剂的作用机制.
- 建立针对肠道微生物胆代谢的治疗候选药物的框架.
主要方法:
- 使用细菌分离物和复杂的肠道社区,选化学化合物以抑制胆的TMA产生.
- 在体外酶测试以确认酶标.
- 晶体结构分析以阐明抑制剂-酶相互作用.
- 与之前报告的抑制剂进行比较.
主要成果:
- 甲乙被确定为从胆中产生TMA的强有力的抑制剂.
- 乙乙被证明可以向肠道微生物的胆酶TMA- lyase (CutC).
- 之前报告的抑制剂3,3-二甲基布坦醇 (DMB) 在该系统中没有活性.
结论:
- 在肠道微生物群中,贝他因是一种有前途的胆-TMA路径抑制剂.
- 贝他因的发现为与TMA产生相关的疾病提供了新的治疗途径.
- 已建立的工作流程可以加速未来肠道微生物代谢的抑制剂的开发.
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