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Partitioning of Catechol Derivatives in Lipid Membranes: Implications for Substrate Specificity to Catechol-O-methyltransferase.
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2020-02-26 , DOI: 10.1021/acschemneuro.0c00049
Petteri Parkkila , Tapani Viitala

We have utilized multi-parametric surface plasmon resonance and impendance-based quartz crystal microbalance instruments to study the distribution coefficients of catechol derivatives in cell model membranes. Our findings verify that the octanol-water partitioning coefficient is a poor descriptor of the total lipid affinity for small molecules which show limited lipophilicity in the octanol-water system. Notably, 3-methoxytyramine, the methylated derivative of the neurotransmitter dopamine, showed substantial affinity to the lipids despite its non-lipophilic nature predicted by octanol-water partitioning. The average ratio of distribution coefficients between 3-methoxytyramine and dopamine was 8.0. We also found that the interactions between the catechols and the membranes modeling the cell membrane outer leaflet are very weak, suggesting other than membrane-mediated mechanism of action for the neurotransmitters at the post-synaptic site. The average distribution coefficient for these membranes was one-third of the average value for pure phosphatidylcholine membranes, calculated using all compounds. In the context of our previous work, we further theorize that membrane-bound enzymes can utilize membrane headgroup partitioning to find their substrates. This could explain the differences in enzyme affinity between soluble and membrane-bound isoforms of catechol-O-methyltransferase, an essential enzyme in catechol metabolism.

中文翻译:

脂膜中邻苯二酚衍生物的分区:对邻苯二酚-O-甲基转移酶的底物特异性的影响。

我们已经利用多参数表面等离子体激元共振和基于阻抗的石英晶体微量天平仪器来研究儿茶酚衍生物在细胞模型膜中的分布系数。我们的发现证实,辛醇-水分配系数不能很好地描述对小分子的总脂质亲和力,这些小分子在辛醇-水系统中显示出有限的亲脂性。值得注意的是,神经递质多巴胺的甲基化衍生物3-甲氧基酪胺尽管对辛醇-水分配有预测的非亲脂性,但对脂质表现出显着的亲和力。3-甲氧基酪胺和多巴胺之间的平均分配系数比为8.0。我们还发现儿茶酚和模拟细胞膜外部小叶的膜之间的相互作用非常弱,提示除了膜介导的突触后位点神经递质的作用机制。这些膜的平均分配系数是使用所有化合物计算的纯磷脂酰胆碱膜平均值的三分之一。在我们之前的工作中,我们进一步推论出膜结合酶可以利用膜头基分配来寻找其底物。这可以解释儿茶酚-O-甲基转移酶的可溶性和膜结合同工型之间的酶亲和力差异,后者是儿茶酚代谢中的必需酶。使用所有化合物计算。在我们之前的工作中,我们进一步推论出膜结合酶可以利用膜头基分配来寻找其底物。这可以解释儿茶酚-O-甲基转移酶的可溶性和膜结合同工型之间的酶亲和力差异,后者是儿茶酚代谢中的必需酶。使用所有化合物计算。在我们之前的工作中,我们进一步推论出膜结合酶可以利用膜头基分配来寻找其底物。这可以解释儿茶酚-O-甲基转移酶的可溶性和膜结合同工型之间的酶亲和力差异,这是儿茶酚代谢中的必需酶。
更新日期:2020-03-05
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