- 硫协调化学驱动B12加载到 metionin合成酶上
bioRxiv : the preprint server for biology
|August 7, 2023
概括
人类蛋白质MMADHC通过利用不稳定的-硫键,促进了维生素B12转移到甲氨酸合成酶. 这种机制解释了MMADHC变种患者的同胞性尿症.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 人体生理学 人体生理学
背景情况:
- 科巴胺 (维生素B12) 是甲氨酸合成酶的一个必不可少的有机金属辅因子.
- 在生物系统中,-硫 (Co-S) 协调化学通常是不稳定且罕见的.
- 有效的细胞内贩运可巴拉明对于其功能至关重要.
研究的目的:
- 为了阐明人类可巴胺贩运蛋白MMADHC将其辅因子卸载到 metionin合成酶的分子机制.
- 研究-硫协调在这种转移过程中的作用.
- 为了将机制与由MMADHC变体引起的同胞性尿症的分子基础相关联.
主要方法:
- 关于MMADHC和科巴拉明之间的相互作用的特征.
- 在辅因子转移过程中对结构变化的分析.
- 调查MMADHC的临床变体,以评估功能影响.
主要成果:
- 在MMADHC中,可利用Co-S键的可变性来进行可巴胺的卸载.
- 在MMADHC上,氨酸-261充当了可巴胺的下轴联结体.
- 复杂的形成与 metionin 合成酶触发连接体交换,形成五坐标的 thiolato-cobalamin.
- 半氨酸-262完成了转移,释放MMADHC作为半氨酸二硫化物.
结论:
- 通过MMADHC介导的可巴胺转移机制依赖于利用Co-S协调的化学可变性.
- 临床的MMADHC变体损害了辅因子结合和脱载,解释了相关的同胞素尿病的发病原因.
- 这项研究揭示了不稳定的Co-S化学在辅因子贩运中的新奇生物学作用.
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