尿素敏感查识别了demethoxy-coenzyme Q和NUDT5作为核酸合成的调节者
Abigail Strefeler1, Zakery N Baker2, Sylvain Chollet1
1Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
Nature metabolism
|November 13, 2025
概括
研究人员发现,NUDT5通过抑制氨酸合成来调节核酸平衡,这对于保护氨酸合成和提高癌症药物疗效至关重要.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 核酸代谢对于快速分裂的细胞至关重要,是癌症,自身炎症性疾病和病毒感染的关键治疗点.
- 核酸代谢的精确调节,特别是新兴胺合成,尚未完全理解.
- 了解这些调节机制对于开发更有效的疗法至关重要.
研究的目的:
- 为了识别新的新型胺合成的新型调节剂.
- 阐明NUDT5在核酸代谢中的作用及其对治疗抗性的影响.
- 为了研究控制氨酸和胺氨酸合成的复杂的调节网络.
主要方法:
- 进行了尿素敏感的CRISPR-Cas9查,以确定关键的调节者.
- 利用生物化学分析来研究酶动力学和蛋白质与蛋白质相互作用.
- 研究了代谢产物对酶活性的全调节.
主要成果:
- 同酶Q (CoQ) 在存在脱氧-CoQ中间体时,对胺合成不必要.
- ADP-ribose pyrophosphatase NUDT5直接结合并抑制基酸酸盐 (PRPP) 合成酶 (PPAT),这是 purin 合成中的速度限制酶.
- NUDT5 缺乏导致过度的 purin 合成,耗尽 PRPP 池,损害 pyrimidine 合成,并赋予对核基模拟药物的耐药性.
- 在PRPP中,它以全分泌方式调节了NUDT5-PPAT相互作用.
结论:
- 通过控制PRPP池,NUDT5充当核酸平衡的关键调节者.
- NUDT5-PPAT相互作用是核酸代谢中的关键调节节点.
- NUDT5是调节核酸代谢和克服癌症和其他疾病中耐药性的潜在治疗标.
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