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How Monoamine Oxidase A Decomposes Serotonin: An EmpiricalValence Bond Simulation of the Reactive Step

Alja Prah†,‡,Miha Purg§,Jernej Stare†,Robert Vianello∥,Janez Mavri†,*
†Laboratoryfor Computational Biochemistry and Drug Design, National Institute of Chemistry, Ljubljana 1001, Slovenia
‡Facultyof Pharmacy, University of Ljubljana, Ljubljana 1001, Slovenia
§Departmentof Cell and Molecular Biology, Uppsala University, Uppsala SE-751 24, Sweden
∥Divisionof Organic Chemistry and Biochemistry, Rud̵erBošković Institute, Zagreb 10002, Croatia
*

Email:janez.mavri@ki.si.

Received 2020 Jul 16; Revised 2020 Aug 26; Issue date 2020 Sep 24.

Copyright © 2020 American Chemical Society

This is an open access article published under a Creative Commons Attribution (CC-BY)License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

PMCID: PMC7520887  PMID:32845149

Abstract

graphic file with name jp0c06502_0006.jpg

The enzyme-catalyzeddegradation of the biogenic amine serotoninis an essential regulatory mechanism of its level in the human organism.In particular, monoamine oxidase A (MAO A) is an important flavoenzymeinvolved in the metabolism of monoamine neurotransmitters. Despiteextensive research efforts, neither the catalytic nor the inhibitionmechanisms of MAO enzymes are currently fully understood. In thisarticle, we present the quantum mechanics/molecular mechanics simulationof the rate-limiting step for the serotonin decomposition, which consistsof hydride transfer from the serotonin methylene group to the N5 atomof the flavin moiety. Free-energy profiles of the reaction were computedby the empirical valence bond method. Apart from the enzymatic environment,the reference reaction in the gas phase was also simulated, facilitatingthe estimation of the catalytic effect of the enzyme. The calculatedbarrier for the enzyme-catalyzed reaction of 14.82 ± 0.81 kcalmol–1 is in good agreement with the experimentalvalue of 16.0 kcal mol–1, which provides strongevidence for the validity of the proposed hydride-transfer mechanism.Together with additional experimental and computational work, theresults presented herein contribute to a deeper understanding of thecatalytic mechanism of MAO A and flavoenzymes in general, and in thelong run, they should pave the way toward applications in neuropsychiatry.

1. Introduction

Serotonin or 5-hydroxytryptamineis an essential monoamine neurotransmitter.It is found in the gastrointestinal tract, platelets, and the centralnervous system (CNS). In the gastrointestinal tract, it is involvedin the regulation of intestinal movements, while its important rolein platelets is to act as a vasoconstrictor and help regulate hemostasisand blood clotting. In both cases, it is released from enterochromaffincells.1 Only 10% of serotonin is locatedin the CNS, where it has several functions that are only partiallyunderstood. It is involved in the regulation of mood, sleep, appetite,and cognition.2 A depletion of serotoninin the CNS is responsible for disorders such as obsessive–compulsivedisorders, depression, and anxiety,3 whileits role in mediating inflammation and immunity responses4 as well as its relevance for cardiac physiologyand pathology has also been proposed.5 Increasingserotonin levels is an important strategy in the pharmacological treatmentof depression, and typically, the levels are increased by inhibitingthe serotonin transporter or by inhibiting monoamine oxidase A (MAOA), an enzyme that breaks down serotonin.6 MAOs are flavoenzymes that catalyze the oxidative deamination ofbiogenic amines, producing aldehyde and hydrogen peroxide. Both productsare responsible for both the formation of amyloid plaques and thedegradation of neuron membranes, accompanied by massive inflammation,which manifests clinically as neurodegeneration, of which Alzheimer’sand Parkinson’s disease are the most common examples.7 As such, besides increasing monoamine levels,the inhibition of MAOs also has the potential to have a neuroprotectiveeffect.

Despite extensive research efforts in the field of MAOs,the exactcatalytic steps are still difficult to determine. MAOs convert aminesinto the corresponding imines by transferring two electrons and twoprotons from the substrate to the enzyme flavin adenine dinucleotide(FAD) cofactor, which converts the latter into its reduced FADH2 form. Although this fact is widely accepted, the rate-limitingstep of the mechanistic pathway is still under debate. Several computationalstudies addressed this issue.8−12 We have shown in a previous study that the transfer of a hydrideanion in the initial step has a much lower free activation energythan alternative mechanistic proposals.13 Until recently, all mechanistic proposals shared the common assumptionthat MAO A and MAO B operate by the same mechanism. However, Orruet al.14 came up with an interesting proposalthat MAO A works via a polar nucleophilic mechanism involving protontransfer in the rate-limiting step, while MAO B works via a hydridemechanism. Kästner and co-workers conducted a quantum mechanics/molecularmechanics (QM/MM) study of the MAO B-catalyzed decomposition of benzylamineand proposed that the transfer of two electrons and a proton in therate-limiting step is concerted yet asynchronous, which is in accordancewith the polar nucleophilic mechanism,15 although they could not provide the evidence for the initial substrate–flavincomplex originally postulated to facilitate the aforementioned protontransfer.16 One is tempted to concludethat the absence of the complex formation in Kästner’sstudy indirectly supports the hydride-transfer mechanism we proposed.13 Akyüz and Erdem utilized QM/MM calculationsat the ONIOM level, taking into account the full dimensionality ofthe enzyme, and confirmed the hydride mechanism for both MAOs butproposed what they called a “slightly different hydride-transfermechanism” among the isoforms.17 Soon after, the same group conducted a computational study on amodel system to convincingly demonstrate the predominant feasibilityof hydride-transfer versus proton-transfer reaction,18 followed by the MAO B-catalyzed serotonin decompositionat the ONIOM M06-2X/6-31+G(d,p):PM6 level, confirming that the rate-determiningstep is a hybrid of hydride and proton transfer where the hydridetransfer dominates over the proton transfer.19 The mechanism of the rate-limiting step of the MAO A-catalyzed serotonindecomposition, involving hydride transfer proposed by us, is showninFigure1.

Figure 1.

Figure 1

Mechanism ofthe rate-limiting step of MAO A-catalyzed serotonindecomposition, involving hydride transfer from the serotonin methylenegroup to the N5 atom of the FAD cofactor. Please note that the intermediateformally consists of two ionic species and the reaction in this respectis strongly dependent on the polar environment. It is worth to emphasizethat in the following reactions, which do not represent the rate-limitingsteps, the formed imine is deprotonated by FADH– and hydrolyzed, while the reduced flavin is reoxidized back to FAD.

Enzyme catalysis is the speed up of the enzymaticreaction comparedto the corresponding reaction in aqueous solution.20 Warshel and co-workers clearly showed that the majorityof the catalytic power of enzymes originates from the electrostaticpreorganization of the active site.21,22 Recently,our group demonstrated the significant role of electrostatics in thecatalytic function of the MAO A enzyme.23 Therefore, because of the long-range nature of the electrostaticinteractions, it is essential to include a large part of the enzymein the modeling of an enzymatic reaction, correctly assign the protonationstates of the ionizable residues, and obtain the converged free activationenergy through intensive thermal averaging. To evaluate the catalyticeffect of the enzymatic environment, it is also essential to considerthe reference reaction. From a practical point of view, a hierarchicaltreatment of the reactive system at the QM/MM level should be used,and computationally inexpensive quantum chemistry should allow forconverged free-energy calculations. The Empirical Valence Bond (EVB)approach developed by Warshel is the method of choice for computationalenzymology because it is computationally inexpensive and elegantlyincorporates the parameters for the reference reaction.

In thisarticle, we calculated the activation free energy for theserotonin decomposition by MAO A. The calculations were performedusing the multiscale QM/MM approach, where the quantum subsystem wasdescribed by the EVB methodology in conjunction with an all-atom classicalrepresentation of the hydrated enzyme. In order to properly calibratethe EVB treatment, the thermodynamic and kinetic parameters of thereference reaction (in the aqueous solution or in the gas phase) needto be evaluated. For the amine oxidation reaction studied herein,experimental assessment of these parameters is not practical becausein the solution, the reaction proceeds at vanishingly slow rates.Therefore, the parameters of the reference reaction were obtainedby quantum calculations, which is standard practice. Presently, wecomputed the reaction energy and barrier at the M06-2X/6-31+G(d,p)level of theory in line with our previous reports.24−27

2. Materialsand Methods

2.1. Gas-Phase Calculations

At the initialstage, the reference reaction in the gas phase was characterized bydensity functional theory calculations employing the M06-2X functional(developed by Zhao and Truhlar) that proved to be accurate for thecalculation of the barriers of organic reactions.28 In conjunction with the M06-2X functional, the 6-31+G(d,p)basis set was used for geometry optimization of the reacting moietyin the state of reactants, in the transition state, and in the stateof products. Because in the gas phase, the FADH– anion and the serotonin cation form an adduct immediately upon thehydride transfer, we approximated the products by selecting a structureof the FADH– group that matches the geometry ofthe gas-phase-optimized isolated FADH–. This approachwas applied and rationalized in our previous work.24,27 All quantum computations were carried out by theGaussian16 software package.29 The gas-phase modelconsisted of a serotonin molecule accompanied by lumiflavin, the latterrepresenting the FAD prosthetic group located in the active site ofMAO A. Vibrational analysis of the optimized species resulted in allreal harmonic frequency values for reactants and products and oneimaginary frequency value for the transition state (νimag = 1240i cm–1). Visualizationof the corresponding eigenvector revealed that the imaginary modemainly corresponds to the reactive C–H stretching motion. Usingthe energies of the optimized species corrected for the vibrationalzero-point energy, the reaction energy and barrier were computed andsubsequently used in the calibration of the EVB protocol (see below),which is standard practice.30 The calculatedgas-phase barrier was ΔGgas⧧ = 30.90 kcal mol–1, and the reaction energy ΔGgas = 22.93kcal mol–1.

2.2. FreeEnergy of Serotonin Deprotonation

Serotonin is a weak basewith an experimental pKa value of theamino group of 10.02 in aqueous solution,31 which indicates that the vast majority of serotoninis protonated at a physiological pH of 7.4, yet our mechanistic proposal(Figure1) requiresthe metabolizing amine to be unionized in order to undergo MAO degradation.Our previous research shows that protonated monoamines enter the reactionwith MAO enzymes extremely slowly, and therefore, the reaction channelwith protonated species does not contribute to the kinetics.13 In this respect, it is a good strategy to calculatethe free energy for serotonin deprotonation and add this value tothe reaction barrier calculated for neutral serotonin.24−27 In addition, based on our previous studies, we concluded that thepKa value of dopamine does not changeduring transfer from water to the MAO B active site.32 Because the MAO A and MAO B active sites are very similarin terms of structure and electric field,33 we can safely assume that the serotonin pKa value would also not change significantly during transferfrom water to the MAO A active site.

With this in mind, thefree energy for the deprotonation of a Brønsted acid with a particularpKa value to a bulk solution with a certainpH value is given as

2.2.1

wherekBT is 0.59 kcalmol–1 at room temperatureand the value of ln(10) is 2.303.

At a pKa value of 10.02 for serotoninand a physiological pH of 7.4, we obtain the free energy for serotonindeprotonation of 3.56 kcal mol–1. According to ourassumptions, this value is the same for the enzyme-catalyzed reactionas well as for the reaction in water, while it is zero for the gasphase.

2.3. EVB Calculations

A high-resolutioncrystal structure of MAO A was obtained from the Protein Data Bank(accession code 2Z5X). The protein chain and FAD cofactor were retained,while the inhibitor and water molecules were removed from the crystalstructure. The serotonin molecule was built and manually docked intothe active site by utilizing the UCSF Chimera program package.34 Special attention was paid to the protonationstates—the serotonin molecule was neutral and the protonationstates of the ionizable MAO A residues were selected based on theirpKa values,33 calculated with the help of the PROPKA server.35 The obtained protonation state of MAO A residues was thesame as that described in our previous studies.36

Simulation of the enzyme-catalyzed reaction was basedon the EVB description of the reactive subsystem consisting of lumiflavinand the neutral serotonin molecule embedded in the classically treatedsolvated enzyme. Two EVB states were used: the first correspondingto the reacting Michaelis complex and the second to the intermediatestate in which the hydride is already transferred to the N5 atom ofthe lumiflavin moiety. The atomic charges for both EVB states werecalculated by fitting to the electrostatic potential calculated atthe HF/6-31G(d) level of theory according to the RESP scheme. Theenzyme–substrate complex was solvated in a spherical cell witha radius of 30 Å, centered on the N5 atom of the flavin moiety,encompassing 1649 water molecules in total, all described with theOPLS-AA force field.37 The structure ofMAO A with the serotonin molecule in the active site is shown inFigure2.

Figure 2.

Figure 2

Structure of MAO A withserotonin in the active site. The flavinand serotonin moieties are represented using colored sticks, serotonincarbon atoms are depicted in green, and flavin carbon atoms are depictedin black.

All simulations and free-energycalculations were performed withtheQ5(38) software package.The system was first equilibrated by slowly raising the temperaturefrom 1 to 300 K while at the same time increasing the time step forintegration from 0.1 to 1 fs and gradually releasing the applied positionalrestraints. The classical molecular dynamics (MD) trajectories forthe reaction step were obtained using a mapping potential21,39,40 of the type

2.3.2

where the force field of the reactants(ε1) was gradually transformed into the force fieldof the products(ε2) via the coupling parameter λ. We simulateda total of 10 replicas using 51 λ-frames, each 10 ps long, resultingin 5.1 ns of MD. The same protocol was employed in our previous work.26 The production runs were performed at a temperatureof 300 K, with a time step of 1 fs. A spherical cutoff of 10 Åwas used for protein–protein, protein–water, and water–waterinteractions, and the local reaction field was applied for long-rangeinteractions beyond 10 Å. All interactions between the EVB region(serotonin and FAD, truncated to the lumiflavin molecule LFN) andthe solvated protein were included. The structure of the MAO A activesite with the serotonin molecule (corresponding to the reactants,transition state, and products) is shown inFigure3, with a clear indication of the hydrideion being transferred from the methylene group on serotonin to theN5 atom of the FAD cofactor (Figure1).

Figure 3.

Figure 3

Reactant (left), transition-state (middle), and product(right)structures of the MAO A active site with the reacting serotonin molecule.The serotonin moiety is denoted by SRO and the flavin moiety by FAD.Serotonin carbon atoms are depicted in green, and flavin carbon atomsare depicted in black. Please note that in the transition state, thetransferring hydride ion is located about halfway between the reactivecarbon Cα atom of serotonin and the flavin N5 atom. The averageddistances between the reactive carbon Cα atom and the flavinN5 atom are 3.01, 2.67, and 3.21 Å for the reactants, transitionstate, and products, respectively.

The corresponding free-energy profiles were then computed fromthese simulations by using the well-established Free Energy Perturbation/UmbrellaSampling approach,21,39,40 as described in our previous work.36,41

In additionto the enzymatic environment, the same reaction wasalso simulated in the gas phase and in the aqueous solution. The free-energyprofile in the gas phase was fitted to the quantum chemically calculatedbarrier height of ΔGgas⧧ = 30.90 kcal mol–1 and the reaction energy of ΔGgas = 22.93 kcalmol–1. The mapping yielded calibrated EVB parameters,namely, the off-diagonal matrix elementHij of 44.28 kcal mol–1 and the gas-phase shift αof 103.94 kcal mol–1. By using identical valuesof the parametersHij and α, mappingwas performed for reactions in the enzyme and in water. Visualizationof the trajectories was performed with the VMD program.42

3. Results

The reactionprofiles for the reaction in the gas phase and inthe MAO A enzyme are shown inFigure4.

Figure 4.

Figure 4

Reaction profiles for the decomposition of neutral serotonin.Thegas-phase profiles are depicted in black, while the MAO A-catalyzedprofiles are in red. The reaction coordinate is defined as the energydifference between EVB states 2 and 1 and is commonly used in displayingEVB free-energy profiles.

The calculated barrier for the neutral serotonin decompositionof 11.26 ± 0.81 kcal mol–1 was subsequentlycorrected for the free-energy cost of serotonin deprotonation of 3.56kcal mol–1 at a pH value of 7.4, resulting in anoverall barrier of 14.82 ± 0.81 kcal mol–1,which is in very good agreement with the experimental value of 16.0kcal mol–1.43 The errorof the calculated activation energy was estimated as the standarddeviation for the barrier obtained from 10 replicas. The reactionfree energy for the enzyme-catalyzed reaction is exergonic at −8.46± 1.88 kcal mol–1. The experimental and calculatedkinetic parameters for the enzyme-catalyzed reaction are listed inTable1.

Table 1. Experimental and Calculated KineticParameters for the MAO A-Catalyzed Decomposition of Serotonina.

kexpcat (s–1)ΔGexp⧧ (kcal mol–1)ΔGcalc⧧ (kcal mol–1)
3.016.014.82 ± 0.81
a

Please note thatthe experimentalbarrier value ΔGexp⧧ was calculated from the experimentalrate constantkexp(43) by using theEyring–Polanyi equation.

In the aqueous environment, the corresponding reaction barrieris computed to be 18.53 ± 0.56 kcal mol–1,resulting in a barrier value of 22.09 ± 0.56 kcal mol–1, after applying the correction for the free energy of serotonindeprotonation (3.56 kcal mol–1). The reaction freeenergy for the reaction in water is −5.27 ± 0.38 kcalmol–1. Interestingly, this value is by 3.2 kcalmol–1 less exergonic than that for the MAO A activesite, suggesting that the charged intermediates, following the hydrideion transfer, are better stabilized within the enzyme than in theaqueous solution. Comparison of the activation free energies betweenthe aqueous and enzymatic environments reveals that MAO A lowers thebarrier by 7.27 kcal mol–1 relative to water. Byemploying the transition-state theory, the corresponding increasein the reaction rate constant can therefore be estimated to be about5 orders of magnitude at room temperature, implying that the reactionin the enzymatic environment proceeds much faster as compared to thereaction in the aqueous solution. In contrast to the aqueous and enzymaticenvironments, the same reaction in the gas phase is much less favorableboth kinetically and thermodynamically, the latter being even highlyendergonic at ΔGgasr = 22.93 kcal mol–1, as demonstrated by quantum calculations. With the present resultsat hand, it is interesting to observe that our earlier report forthe MAO B-catalyzed dopamine degradation24 showed that the catalytic effect of this enzyme is 12.3 kcal mol–1, which analogously corresponds to 9 orders of magnitudeincrease in the rate constant relative to the reference reaction inthe aqueous solution. This indicates a higher catalytic efficiencyof MAO B as compared to that of MAO A, likely hinting at its predominancein the CNS, where a fast and efficient regulation and clearance ofthe brain monoamines is of great importance.

4. Conclusions

In this article, we conducted a multiscale study of the catalyticstep of the serotonin decomposition catalyzed by MAO A by using thestate-of-the-art EVB treatment. By properly including a fully featuredenzymatic environment, well-converged free-energy profiles were obtained.The calculated free activation energy of 14.82 ± 0.81 kcal mol–1 reasonably reproduces the experimental free activationenergy of 16.0 kcal mol–1, which gives very strongevidence for the validity of Vianello’s hydride-transfer mechanism13 for the MAO A-catalyzed serotonin decompositionas well.

By comparing the activation free energy between theenzymatic andaqueous environments, the catalytic effect (barrier lowering) providedby MAO A is estimated to be 7.27 kcal mol–1, whichranks MAO A among the enzymes with mid-range proficiency. Accordingto Warshel, the catalytic effect of enzymes is mainly attributed topreorganized electrostatics,30 whereasother factors, including steric strain or dynamical effects, are lessrelevant. The assumed decisive role of electrostatics can also bedevised for the presently studied reaction, that is, the reactioninvolves the formation of two charged species as a result of the hydridetransfer from serotonin to lumiflavin—because of this, thereaction profiles are strongly dependent on the environment. The waterenvironment significantly reduces the gas-phase barrier and enablesthe reaction thermodynamically, while the preorganized enzyme electrostaticsprovides an additional (and for physiological purposes probably decisive)contribution to the barrier lowering.

The present study representsone of several attempts to elucidatethe catalytic effect of MAO enzymes. A number of open questions tobe addressed in future research remain, including consecutive stepsin the catalytic process, MAO A versus MAO B selectivity, and effectsof point mutations. Point mutations lead to altered enzyme activityby changing the electrostatic stabilization of the reactants and thetransition state, which results in a changed free activation energyand thus in a changed turnover rate. A particular challenge is theapplication of the MAO A function to genomic medicine. MAO A activitycan be modulated by the level of its expression and by altered activitiesof its mutants. The effects of point mutations can be studied experimentallyand theoretically (see ref (36)) and can be obtained relatively easily from the genomicinformation, whereas the level of MAO A expression is not easily linkedto the genomic information. High MAO A activity, along with highlyactive transporters for its reuptake (serotonin transporter—SERT),leads to decreased serotonin and noradrenalin levels, typically followedby pathologies such as depression, anxiety, and other mood disorders.44−46 Low MAO A activity leads to increased serotonin and noradrenalinelevels, which have pathological effects on brain plasticity in theprocess of prenatal neurogenesis. In psychiatry, the term “warriorgene” is established for the gene that encodes a less activeMAO A. The Brunner syndrome is a well-established pathology that canbe caused by the complete absence of MAO A, truncation of the enzyme,or point mutations, as shown in clinical studies and animal models.47−50 Summarizing this, it remains a major challenge for the future todevelop a macroscopic model that combines genomic information, experimentalkinetic data from MAOs, and experimental data on monoamine transporters(such as the serotonin or dopamine transporters) with molecular simulationdata to predict neuropsychiatric pathologies such as depression. Themethod of choice in this case is a description of the synapse usinga system of ordinary differential equations, as we did in our recentstudy concerning the effects of cocaine and amphetamines on dopamineautoxidation and therewith associated induction of Parkinsonism.51

Acknowledgments

We wouldlike to thank Dr. Matej Repič, KrkaLtd., Novo mesto, for many stimulating discussions.

Author Contributions

A.P. and M.P.contributed equally. The manuscript was written through contributionsof all authors. All authors have given approval to the final versionof the manuscript.

A.P., J.S., andJ.M. would like to thank the Slovenian Research Agency for financialsupport in the framework of the program group P1-0012. R.V. acknowledgesthe financial support from the Croatian Science Foundation.

The authors declare nocompeting financial interest.

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