硫化坐标的葡萄糖代谢切换通过破坏稳定的四基酸激酶M2进行切换
Rong-Hsuan Wang1, Pin-Ru Chen2, Yue-Ting Chen2
1Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
Nature communications
|August 28, 2024
概括
硫化 (H2S) 通过硫化使酸盐激酶M2 (PKM2) 失活,促进癌症的生长. 抑制PKM2硫化可能是一种针对癌症代谢的新疗法策略.
科学领域:
- 生物化学 生物化学
- 癌症生物学 癌症生物学
- 代谢途径 代谢途径
背景情况:
- 癌细胞表现出改变的葡萄糖代谢,有利于有氧糖解而不是氧化酸化.
- 酸盐激酶M2 (PKM2) 活性在癌症中降低,转移代谢物向宏分子合成进行扩散.
研究的目的:
- 研究硫化 (H2S) 在调节PKM2活性中的作用及其对癌症代谢的影响.
- 探索将PKM2硫化作为癌症治疗的潜在目标.
主要方法:
- 研究了H2S对PKM2四聚合物稳定性和酶活性的影响.
- 利用位点定向突变发生 (C326S) 来阻止PKM2硫化.
- 确定了PKM2-C326S突变体的晶体结构.
- 评估了PKM2-C326S对葡萄糖代谢和癌细胞瘤生长的影响.
主要成果:
- 在氨酸残留物中,H2S通过硫化使PKM2四分体不稳定为单体/二分体,特别是C326.
- 硫化PKM2降低了酶活性,并增强了PKM2介导的转录激活.
- 阻断C326硫化稳定PKM2四分体并将癌细胞代谢转向线粒体呼吸.
- 在PKM2-C326S突变显著抑制瘤生长.
结论:
- 通过H2S对PKM2进行硫化,通过改变癌症代谢来促进瘤发生.
- 抑制PKM2硫化是一种针对癌症代谢的潜在治疗策略.
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