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Empirical Valence Bond Simulations of the Hydride-Transfer Step in the Monoamine Oxidase A Catalyzed Metabolism of Noradrenaline
Jozef Stefan Inst, Dept Phys & Organ Chem, Jamova Cesta 39, SI-1000 Ljubljana, Slovenia..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
Natl Inst Chem, Lab Biocomp & Bioinformat, Hajdrihova Ulica 19, SI-1000 Ljubljana, Slovenia..
Natl Inst Chem, Lab Biocomp & Bioinformat, Hajdrihova Ulica 19, SI-1000 Ljubljana, Slovenia..
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2016 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, no 44, 11419-11427 p.Article in journal (Refereed) Published
Abstract [en]

Monoamine oxidases (MAOs) A and B are flavoenzymes responsible for the metabolism of biogenic amines, such as dopamine, serotonin, and noradrenaline (NA), which is why they have been extensively implicated in the etiology and course of various neurodegenerative disorders and, accordingly, used as primary pharmacological targets to treat these debilitating cognitive diseases. The precise chemical mechanism through which MAOs regulate the amine Concentration, which is vital for the development of novel inhibitors, is still not unambiguously determined in the literature. In this work, we present atomistic empirical valence bond simulations of the rate-limiting step of the MAO-A-catalyzed NA (norepinephrine) degradation, involving hydride transfer from the substrate alpha-methylene group to the flavin moiety of the flavin adenine dinucleotide prosthetic group, employing the full dimensionality and thermal fluctuations of the hydrated enzyme, with extensive configurational sampling. We show that MAO-A lowers the free energy of activation by 14.3 kcal mol(-1) relative to that of the same reaction in aqueous solution, whereas the calculated activation free energy of Delta G(double dagger) = 20.3 +/- 1.6 kcal mori is found to be in reasonable agreement with the correlated experimental value of 16.5 kcal mol(-1). The results presented here strongly support the fact that both MAO-A and MAO-B isoforms function by the same hydride-transfer mechanism. We also considered a few point mutations of the "aromatic cage" tyrosine residue (Tyr444Phe, Tyr444Leu, Tyr444Trp, Tyr444His, and Tyr444Glu), and the calculated changes in the reaction barriers are in agreement with the experimental values, thus providing further support to the proposed mechanism.

Place, publisher, year, edition, pages
2016. Vol. 120, no 44, 11419-11427 p.
National Category
Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-310752DOI: 10.1021/acs.jpcb.6b09011ISI: 000387738300009OAI: oai:DiVA.org:uu-310752DiVA: diva2:1058042
Funder
EU, European Research Council, PCIG12-GA-2012-334493
Available from: 2016-12-20 Created: 2016-12-19 Last updated: 2016-12-20Bibliographically approved

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