A comparative computational investigation on the proton and hydride transfer mechanisms of monoamine oxidase using model molecules

Atalay, Vildan Enisoğlu; Erdem, Safiye Sağ

doi:10.1016/j.compbiolchem.2013.08.007

Cited by 40 publications

(30 citation statements)

References 44 publications

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“…Akyüz and Erdem later utilized the ONIOM QM/MM approach to assess the energetics of hydride transfer and also reached the conclusion that hydride transfer is the most likely mechanism . Following their previous study, Atalay and Erdem performed a comparative computational study on a series of model systems and again demonstrated the prevailing feasibility of the hydride transfer reaction over the proton transfer reaction, in agreement with our results . Recently, Abad et al .…”

Section: Introductionsupporting

confidence: 86%

“…The availability of high‐resolution crystal structures for MAO A and MAO B has opened the possibility to study the catalytic mechanism by computational approaches . In recent years, there have been several computational studies showing the prevailing energetic feasibility of the hydride transfer mechanism . Our group performed the first quantum mechanical study that convincingly demonstrated the feasibility of hydride transfer mechanism and showed that, because of the strong electron donating ability of the vicinal amino group, the atomic charge on the α‐carbon atom of the substrate remains negative upon the hydride anion abstraction, which explains why in some instances the reaction could be facilitated even by the electron withdrawing substituents, in line with experimental findings .…”

Section: Introductionmentioning

confidence: 99%

“…18 In recent years, there have been several computational studies showing the prevailing energetic feasibility of the hydride transfer mechanism. 26,34,35 Our group performed the first quantum mechanical study that The catalytic cycle of monoamine oxidases is divided into the reductive half-reaction, in which the substrate is metabolized, and oxidative halfreaction, in which the enzyme is regenerated by molecular oxygen. The grey area represents the enzyme interior while the red dot represents the rate-limiting step of the reductive half-reaction.…”

Section: Introductionmentioning

confidence: 99%

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Empirical valence bond simulations of the hydride transfer step in the monoamine oxidase B catalyzed metabolism of dopamine

et al. 2014

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Monoamine oxidases (MAOs) A and B are flavoenzymes responsible for the metabolism of biogenic amines such as dopamine, serotonin and noradrenaline. In this work, we present a comprehensive study of the rate-limiting step of dopamine degradation by MAO B, which consists in the hydride transfer from the methylene group of the substrate to the flavin moiety of the FAD prosthetic group. This article builds on our previous quantum chemical study of the same reaction using a cluster model (Vianello et al., Eur J Org Chem 2012; 7057), but now considering the full dimensionality of the hydrated enzyme with extensive configurational sampling. We show that MAO B is specifically tuned to catalyze the hydride transfer step from the substrate to the flavin moiety of the FAD prosthetic group and that it lowers the activation barrier by 12.3 kcal mol⁻¹ compared to the same reaction in aqueous solution, a rate enhancement of more than nine orders of magnitude. Taking into account the deprotonation of the substrate prior to the hydride transfer reaction, the activation barrier in the enzyme is calculated to be 16.1 kcal mol⁻¹, in excellent agreement with the experimental value of 16.5 kcal mol⁻¹. Additionally, we demonstrate that the protonation state of the active site residue Lys296 does not have an influence on the hydride transfer reaction.

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Section: Introductionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Empirical valence bond simulations of the hydride transfer step in the monoamine oxidase B catalyzed metabolism of dopamine

et al. 2014

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“…The overall reaction has been proposed to be concerted, with nonsynchronous electron transfer and deprotonation, which involved a singlet biradical transition state. Yet, other new computational studies and in vitro experiments supported the proposed hydride transfer mechanism.…”

Section: Mao: a Principal Metabolizing Enzymementioning

confidence: 85%

“…Amr et al 199 synthesized a series of chiral linear and macrocyclic pyridines (126)(127)(128)(129)(130)(131)(132)(133) and screened them for MAO-B inhibition activity using rat brain synaptosome ( Figure 55). All the compounds showed potent inhibitory activity against MAO-B and were found to be more potent than selegiline.…”

Section: Linear and Macrocyclic Carboxamide Derivativesmentioning

confidence: 99%

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

Tripathi

Ayyannan

2019

Medicinal Research Reviews

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Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

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EVBSimulations of the Catalytic Activity of Monoamine Oxidases: From Chemical Physics to Neurodegeneration

Vianello

Mavri

2017

Theory and Applications of the Empirical Valence Bond Approach

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A comparative computational investigation on the proton and hydride transfer mechanisms of monoamine oxidase using model molecules

Cited by 40 publications

References 44 publications

Empirical valence bond simulations of the hydride transfer step in the monoamine oxidase B catalyzed metabolism of dopamine

Empirical valence bond simulations of the hydride transfer step in the monoamine oxidase B catalyzed metabolism of dopamine

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

EVBSimulations of the Catalytic Activity of Monoamine Oxidases: From Chemical Physics to Neurodegeneration

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