Why Monoamine Oxidase B Preferably Metabolizes N-Methylhistamine over Histamine: Evidence from the Multiscale Simulation of the Rate-Limiting Step

Abstract

Histamine levels in the human brain are controlled by rather peculiar metabolic pathways. In the first step, histamine is enzymatically methylated at its imidazole Nτ atom, and the produced N-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 N-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 N-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 N-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 N-methylhistamine, giving rise to a lower barrier relative to histamine. In addition, the transition state involving N-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.

Oxidation of Flavin by Molecular Oxygen: Computational Insights into a Possible Radical Mechanism

“…26 In addition, our experience with DFT modeling of (enzymatic) reactions involving flavin is exclusively positive. 4,53,56 We are aware that the present investigations of higher spin states should be taken with caution, but at the same time, we stress that full engagement of superior post-Hartree− Fock electronic structure techniques to the presently studied system (35 atoms and 152 electrons) exceeds our available resources by quite a large margin.…”

“…The choice of DFT for the present study derives from the fact that DFT has been massively and successfully used in the modeling of a wide variety of related chemical reactions, including those in biomolecular systems and also involving flavin structure and chemistry . In addition, our experience with DFT modeling of (enzymatic) reactions involving flavin is exclusively positive. ,, We are aware that the present investigations of higher spin states should be taken with caution, but at the same time, we stress that full engagement of superior post-Hartree–Fock electronic structure techniques to the presently studied system (35 atoms and 152 electrons) exceeds our available resources by quite a large margin.…”

Rumors of Psychedelics, Psychotropics and Related Derivatives in Vachellia and Senegalia in Contrast with Verified Records in Australian Acacia

“…The histamines are normally metabolized by MAO-B [ 78 ], but amide derivatives are unlikely to follow this pathway. Only two histamines ( N -(2-imidazol-4-yl-ethyl)- E -cinnamamide and N -(2-imidazol-4-yl-ethyl)-deca- E -2, Z -4-dienamide) ( Figure 5 ) have been identified in one species of Acacia , namely A. longifolia ( Table 1 ).…”

Brunner syndrome caused by point mutation explained by multiscale simulation of enzyme reaction

“…2) [11][12][13][14][15] , allowing for the construction of computational models that include not only a detailed description of the reacting moiety, but also the entire enzymatic environment that enhances reaction kinetics predominantly via electrostatics. Using the established Empirical Valence Bond (EVB) protocol, we were able to reproduce the catalytic performance of MAO enzymes at a quantitative level, specifically focusing on point mutation effects [16][17][18] , as well as substrate selectivity [19][20][21] . In addition, we devised our own multiscale model (see below) to demonstrate the critical role of electrostatics in the catalytic function of MAO-A 22 , and further expanded that model to elucidate the very subtle performance differences between the MAO-A and MAO-B isoenzymes 23 .…”