期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 23, 期 12, 页码 2915-2925出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201605430
关键词
computational chemistry; enzyme selectivity; histamine metabolism; hydride transfer reaction; monoamine oxidase
资金
- Croatian Science Foundation through the Career Development Project for Young Researchers [I-3376-2014]
- European Commission for an individual FP7 Marie Curie Career Integration Grant [PCIG12-GA-2012-334493]
Monoamine oxidase (MAO) enzymes catalyze the degradation of a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, whose imbalance is extensively linked with the biochemical pathology of various neurological disorders. Although sharing around 70% sequence identity, both MAO A and B isoforms differ in substrate affinities and inhibitor sensitivities. Inhibitors that act on MAO A are used to treat depression, due to their ability to raise serotonin concentrations, whereas MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Despite this functional importance, the factors affecting MAO selectivity are poorly understood. Here, we used a combination of molecular dynamics (MD) simulations, molecular mechanics with Poisson-Boltzmann and surface area solvation (MM-PBSA) binding free energy evaluations, and quantum mechanical (QM) cluster calculations to address the unexpected, yet challenging MAO B selectivity for N-methylhistamine (NMH) over histamine (HIS), differing only in a single methyl group distant from the reactive ethylamino center. This study shows that a dominant selectivity contribution is offered by a lower activation free energy for NMH by 2.6 kcal mol(-1), in excellent agreement with the experimental Delta Delta G(EXP)(=) = 1.4 kcal mol(-1), together with a more favorable reaction exergonicity and active-site binding. This study also confirms the hydrophobic nature of the MAO B active site and underlines the important role of Ile199, Leu171, and Leu328 in properly orienting substrates for the reaction.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据