What a Difference a Methyl Group Makes: The Selectivity of Monoamine Oxidase B Towards Histamine and N‐Methylhistamine

Abstract

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 , in excellent agreement with the experimental ΔΔG =1.4 kcal mol , 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.

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…Thus, the results demonstrated the molecular interpretation and identification of structural determinants for the substrate specificity of the MAO‐B enzyme. The study also confirmed the hydrophobic nature of the MAO‐B active site and substantiated the crucial function of residues Ile199, Leu171, and Leu328 in properly orienting substrates for the reaction …”

“…Per‐residue interaction energy decomposition analysis depicted that the residue Ile197 was found to contribute the most toward deprenyl binding to MAO‐B. In contrast, Tyr396 and Tyr433 contributed greater and improved binding of compound 258 to MAO‐B …”

Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration

“…The effect of the rest of the protein environment was considered with the CPCM implicit solvation model using a dielectric constant of ε = 4.0, as suggested by Himo and co-workers [28], and a dielectric constant of ε = 78.4 for the aqueous solution, all in line with our previous reports [13], where we also demonstrated that a potential increase in the former dielectric constant to ε = 20.0 lowers the accuracy of the obtained results and even predicts wrong trends among ligands. Additionally, in our experience, such a truncated cluster-continuum model of the entire protein turned very useful in rationalizing various aspects of the catalytic activity [29], selectivity [30] and inhibition [31] of the monoamine oxidase family of enzymes, and is broadly used by different groups to decipher various biological phenomena [32][33][34][35][36], which justifies its use here. We note in passing that, despite its practical usefulness, the proposed value of ε = 4 is, in some cases, apparently too small to prevent the proton transfer from protonated to anionic residues, which then occurred spontaneously during the geometry optimization, provided the involved pair is in close vicinity.…”

The Metal Effect on Self-Assembling of Oxalamide Gelators Explored by Mass Spectrometry and DFT Calculations

“…In this way all of the reported computational data correspond to the gas-phase Gibbs free energies at a temperature of 298.15 K and a pressure of 1 atm. The choice of such a computational setup was prompted by our recent success in modeling the properties of gelator molecules [23] and metal binding affinities [24], as well as correctly reproducing thermodynamic and kinetic parameters of organic [25,26] and enzymatic [27] reactions. In order to circumvent problems with the flexibility of the investigated systems, we tried many different conformations in each studied case and report here the results corresponding to the most stable structures.…”