甲基转移酶,INMT和TPMT,在排毒和分泌中的基质识别的不同分子机制
Yasunori Fukumoto1, Rin Kyono1, Yuka Shibukawa1
1Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
(Se) 转化为三甲基离子 (TMSe) 的排毒需要乙胺N-甲基转移酶 (INMT) 和氨酸S-甲基转移酶 (TPMT). 这项研究揭示了INMT与中性基质结合,而TPMT与充电基质结合,解释了它们在代谢中的顺序作用.
科学领域:
- 生物化学 生物化学
- 毒理学 毒理学 毒理学
- 酶学 是一种酶学.
背景情况:
- 饮食中的 (Se) 摄入量接近有毒水平,需要有效的解毒途径.
- 以三甲基离子 (TMSe) 的形式分泌,这一过程需要特定的甲基转移酶.
- 之前的工作在TMSe生产中确定了乙烯胺N-甲基转移酶 (INMT) 和氨酸S-甲基转移酶 (TPMT).
研究的目的:
- 阐明甲基化中INMT和TPMT的基质识别机制.
- 了解这些酶如何顺序地促进过量的排毒.
主要方法:
- 酶活性测定比较INMT,TPMT及其同类物与基质.
- 分子动力学模拟以分析活性位点的基质结合.
- 碎片分子轨道计算以确定关键的结合残留物.
- 位点定向突变发生 (INMT-L164R,TPMT-R152) 以评估功能影响.
主要成果:
- 只有INMT,而不是其类型,显示出显著的Se-methyltransferase活性.
- 分子动力学证实了二甲基化物与INMT的活性中心的优先结合.
- 在INMT的活性部位的疏水性残留物被确定为二甲基化物结合的关键.
- 突变INMT-L164R和TPMT-R152损害了Se-甲基转移酶的活性.
- TPMT似乎与负电荷的基质结合,而INMT则与中性基质结合.
结论:
- INMT和TPMT具有不同的基板识别特性,INMT偏好中性基板,TPMT偏好带电基板.
- 这些基质特异性的差异解释了INMT和TPMT在TMSe形成中的顺序作用.
- 了解这些机制对于管理毒性和优化其代谢途径至关重要.
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