酸化对碳酸无水酶的活性,抑制和稳定性的影响
Xiaojing Huang1, Daniel Winter1, Dominic J Glover2
1School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
International journal of molecular sciences
|June 10, 2023
概括
像酸化这样的翻译后修改显著改变碳酸酶 (CA) 活性和药物相互作用. 模仿酸化揭示了对酶效率和抑制剂结合的异形特异性影响,影响了药物开发.
科学领域:
- 生物化学 生物化学
- 酶学 是一种酶学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 碳酸无水酶 (CA) 是关键的金属酶,参与pH稳态和疾病.
- 翻译后修改 (PTMs) 影响CA功能,但它们对酶活性和抑制剂概况的影响尚不清楚.
- 酸化是一种普遍的PTM,影响CA活性和药物相互作用.
研究的目的:
- 调查酸化对人类碳酸酶I (hCAI) 和人类碳酸酶II (hCAII) 的活性和抑制的影响.
- 确定模仿酸化如何影响这些CA异型的催化效率和药物结合亲和力.
- 探索PTM作为CA功能和药物开发的监管机制的潜力.
主要方法:
- 利用局部导向的突变发生 (酸转化为谷氨酸,S > E) 来模仿酸化.
- 对改性CA异型的催化效率的评估变化.
- 对CA异型与已确定的硫胺胺抑制剂 (包括乙醇胺) 的结合亲缘关系的量化改变.
主要成果:
- 在特定位点的相仿性突变 (S > E) 显著改变了hCAI和hCAII的催化效率,以依赖于异构体和位点的方式.
- 在hCAII中Ser50的S > E突变大大降低了800倍以上的对乙醇胺的结合亲和力.
- 酸化对酶活性和小分子抑制剂对碳酸酶的疗效都有显著影响.
结论:
- 酸化CA作为一种影响酶活性的调节机制.
- 酸化会影响碳酸酶抑制剂的结合亲和力和特异性.
- 了解PTM对于开发针对性,"变形特异性"碳酸酶抑制剂用于治疗应用至关重要.
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