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What a difference a methyl group makes - the selectivity of monoamine oxidase B towards histamine and N-methylhistamine

Maršavelski, Aleksandra; Vianello, Robert (2017) What a difference a methyl group makes - the selectivity of monoamine oxidase B towards histamine and N-methylhistamine. Chemistry - A European Journal, 23 (12). pp. 2915-2925. ISSN 0947-6539

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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, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Despite this functional importance, the contributions affecting MAO selectivity are poorly understood. Here we used a combination of MD simulations, MM–PBSA binding free energy evaluations, and 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 centre. We show 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 ΔΔG‡ EXP = 1.4 kcal mol–1, together with a more favourable 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.

Item Type: Article
Additional Information: A.M. wishes to thank the Croatian Science Foundation for a doctoral stipend through the Career Development Project for Young Researchers (contract number I-3376-2014). R.V. gratefully acknowledges the European Commission for an individual FP7 Marie Curie Career Integration Grant (contract number PCIG12-GA-2012-334493). We would like to thank the Zagreb University Computing Centre (SRCE) for granting computational resources on the ISABELLA cluster and the CRO-NGI infrastructure.
Uncontrolled Keywords: MAO B; MM-PBSA; MD; QM; histamine; N-methylhistamine
Divisions: Division of Organic Chemistry and Biochemistry
Project titleProject leaderProject codeProject type
Computational Studies of the Biogenic Amines of the Brain for Targeting Neurological Diseases-COMPBANDRobert Vianello334493EK
Depositing User: Robert Vianello
Date Deposited: 20 Nov 2018 10:29
DOI: 10.1002/chem.201605430

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