华法林类似物向二硫化物键形成酶,并暗示和氨酸结合的重要残留物
Dariana Chavez1, Gwendolyn Nita Amarquaye1, Adrian Mejia-Santana1
1Department of Biology, Indiana University, Bloomington, Indiana, USA.
The Journal of biological chemistry
|May 18, 2024
概括
确定了针对参与二硫化键形成的细菌或人体酶的华法林类似物. 这项研究使得使用库马林支架开发新型抗凝剂和抗菌剂成为可能.
科学领域:
- 蛋白质的生物化学 蛋白质的生物化学
- 酶学 是一种酶学.
- 药物发现 药物发现
背景情况:
- 在所有生物体中,二硫化物键的形成对蛋白质折叠至关重要.
- 细菌二硫化键被DsbA和DSbB/VKOR酶催化,DSbA引入键,DSbB/VKOR再生DSbA活动.
- 华法林类似物已被确定为细菌DsbB或VKOR的潜在抑制剂.
研究的目的:
- 调查华法林类似物对细菌和哺乳动物VKOR酶的选择性抑制的结构-活性关系.
- 探索使用细菌选新型抗凝剂的潜力.
- 为了确定关键的氨基酸残留物,参与药物结合和酶活性.
主要方法:
- 在大肠杆菌中表达功能人类VKORc1的表达.
- 对华法林类似物进行结构-活性关系分析.
- 通过突变发生和功能测定来识别关键氨基酸残留物.
主要成果:
- 人类VKORc1在大肠杆菌中成功表达和功能,使抗凝剂的细菌查成为可能.
- 一种华法林类似物抑制了细菌DsbB/VKOR和人类VKORc1,而另一种选择性抑制了人类VKORc1.1.
- 库马林环上的特定替代物和两个关键的氨基酸残留物被确定为药物选择性和酶功能的关键.
结论:
- 这项研究提供了对华法林类似物对细菌和哺乳动物VKOR酶的选择性抑制的见解.
- 这些发现有助于设计基于氨酸的新型抗凝固剂和抗菌剂.
- 在DsbB和VKOR酶中发现了一种对新型二硫化键形成至关重要的保存氨基酸残留物.
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