果糖结合口袋中的残留物是基托赫索基纳酶-A活性所必需的
Juliana C Ferreira1, Adrian J Villanueva1, Samar Fadl1
1Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
The Journal of biological chemistry
|July 6, 2024
概括
过多的果糖摄入量与肥胖和癌症有关. 这项研究揭示了基托赫索金酶-A (KHK) 的结构和突变,确定了KHK作为代谢综合征和癌症转移的潜在治疗标.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 代谢研究研究 代谢研究
背景情况:
- 过度的果糖消费导致全球肥胖,癌症和代谢综合征的增加.
- 果糖分解,由基基酶 (KHK) 启动,是调节不良的.
- KHK与代谢障碍和癌症发展有关.
研究的目的:
- 确定人体凯托赫索金酶-A (KHK-A) 的晶体结构.
- 研究KHK-A果糖结合口袋中关键残留物的功能作用.
- 探索KHK作为代谢疾病和癌症的治疗点的潜力.
主要方法:
- 在1.85 Å的分辨率下测定KHK-A的阿波状态结构的X射线晶体学.
- 位点定向突变发生,以分析果糖结合口袋内的残留功能.
- 酶动力学,分子动力学模拟和蛋白质-蛋白质相互作用组分析.
主要成果:
- 确定了KHK-A的晶体结构.
- 突变D15A,N42A和N45A使KHK-A失活;R141A和K174A降低了活性和稳定性.
- R141A和K174A突变降低了果糖亲和力2-4倍,但没有改变ATP亲和力.
- 模拟提供了有关联体协调和单体状态的见解.
- 相互作用组分析揭示了瘤组织中明显的表达模式和下调.
结论:
- 阐明了KHK-A的结构和功能,提供了关于其在果糖代谢中的作用的见解.
- 特定的残留物对KHK-A活性和果糖结合至关重要.
- 癌症中KHK信号通路的改变表明KHK是预防转移的潜在目标.
- 这些发现支持重新评估KHK在癌症中的作用,并为治疗肥胖,癌症和代谢综合征提供了目标.
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