Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia.
Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia.
Int J Mol Sci. 2022 Feb 8;23(3):1910. doi: 10.3390/ijms23031910.
Histamine levels in the human brain are controlled by rather peculiar metabolic pathways. In the first step, histamine is enzymatically methylated at its imidazole atom, and the produced -methylhistamine undergoes an oxidative deamination catalyzed by monoamine oxidase B (MAO-B), as is common with other monoaminergic neurotransmitters and neuromodulators of the central nervous system. The fact that histamine requires such a conversion prior to oxidative deamination is intriguing since MAO-B is known to be relatively promiscuous towards monoaminergic substrates; its in-vitro oxidation of -methylhistamine is about 10 times faster than that for histamine, yet this rather subtle difference appears to be governing the decomposition pathway. This work clarifies the MAO-B selectivity toward histamine and -methylhistamine by multiscale simulations of the rate-limiting hydride abstraction step for both compounds in the gas phase, in aqueous solution, and in the enzyme, using the established empirical valence bond methodology, assisted by gas-phase density functional theory (DFT) calculations. The computed barriers are in very good agreement with experimental kinetic data, especially for relative trends among systems, thereby reproducing the observed MAO-B selectivity. Simulations clearly demonstrate that solvation effects govern the reactivity, both in aqueous solution as well as in the enzyme although with an opposing effect on the free energy barrier. In the aqueous solution, the transition-state structure involving histamine is better solvated than its methylated analog, leading to a lower barrier for histamine oxidation. In the enzyme, the higher hydrophobicity of -methylhistamine results in a decreased number of water molecules at the active side, leading to decreased dielectric shielding of the preorganized catalytic electrostatic environment provided by the enzyme. This renders the catalytic environment more efficient for -methylhistamine, giving rise to a lower barrier relative to histamine. In addition, the transition state involving -methylhistamine appears to be stabilized by the surrounding nonpolar residues to a larger extent than with unsubstituted histamine, contributing to a lower barrier with the former.
人类大脑中的组胺水平受相当特殊的代谢途径控制。在第一步中，组胺在其咪唑原子上被酶促甲基化，生成的 -甲基组胺在单胺氧化酶 B（MAO-B）的催化下发生氧化脱氨，这与其他单胺能神经递质和中枢神经系统的神经调质相同。组胺在氧化脱氨之前需要这种转化的事实很有趣，因为 MAO-B 被认为对单胺能底物相对混杂；其体外氧化 -甲基组胺的速度比组胺快约 10 倍，但这种相当细微的差异似乎控制着分解途径。这项工作通过在气相、水溶液和酶中对这两种化合物的限速氢化物提取步骤进行多尺度模拟，澄清了 MAO-B 对组胺和 -甲基组胺的选择性，使用了已建立的经验价键方法，并辅以气相密度泛函理论（DFT）计算。计算出的势垒与实验动力学数据非常吻合，尤其是对于系统之间的相对趋势，从而再现了观察到的 MAO-B 选择性。模拟清楚地表明，尽管对自由能势垒有相反的影响，但溶剂化效应既控制着水溶液中的反应性，也控制着酶中的反应性。在水溶液中，涉及组胺的过渡态结构比其甲基化类似物更好地溶剂化，导致组胺氧化的势垒更低。在酶中，-甲基组胺的较高疏水性导致活性侧的水分子数量减少，从而降低了酶提供的预组织催化静电环境的介电屏蔽。这使得催化环境对 -甲基组胺更有效，相对于组胺产生较低的势垒。此外，与未取代的组胺相比，涉及 -甲基组胺的过渡态似乎被周围的非极性残基更大程度地稳定，导致前者的势垒较低。
