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Studies of antiparkinsonian and antidepressant drugs

Simulation of neurotransmitter metabolism by monoamine oxidase - an enzyme involved in patophysiology of Parkinsons and depression

Monoamine oxidases (MAO) A and B are flavoenzymes involved in the metabolism of biogenic amines that include the monoamine neurotransmitters dopamine, sero- tonin and some histamine metabolites. MAOs regulate the concentrations of neuro- transmitters in the central and peripheral nervous systems, having a major impact on cardiac output, blood pressure, sleep, mood, cognition, and movement. The two iso- forms, MAO A and MAO B, differ in tissue distribution, substrate selectivity and inhibitor susceptibility. Inhibitors that act mainly on MAO A are used in the treat- ment of depression due to their ability to raise serotonin concentrations, while inhibi- tors of MAO B decrease dopamine degradation and improve motor control in pa- tients with Parkinson disease. Inhibition of MAOs may also have a significant neuro- protective effect, since the products of its catalytic reaction are hydrogen peroxide, aldehydes, and ammonia, which contribute to oxidative stress in the cell. 

Figure 1: The catalytic cycle of monoamine oxidases is divided into the reductive half-reaction, in which the substrate is metabolized, and oxidative half-reaction, 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.

We study the rate-limiting step of the monoamine oxidase enzymatic reaction. Detailed mechanistic insight in the catalytic reaction can provide new ideas on which to base the development of novel and improved antiparkinsonian and antidepressant drugs.

Studies of the monoamine oxidase enzymatic reaction

By using quantum methods based on the cluster model approach we studied the reaction between dopamine and flavin. We calculated the free energy barriers for the polar nucleophillic mechanism, radical mechanism and hydride mechanism and arrived to the conclusion, that the hydride mechanism is by far the most energetically feasible. In conjunction with our findings we also proposed a new two-step hydride transfer mechanism.

By using the empirical valence bond method we study the reaction between monoamine neurotransmitters and monoamine oxidase. Our findigs have shown that the enyzme is specifically tuned to catalzye the hydride transfer step, oxidizing the amine to the corresponding imine. We also calculated that the enzyme enhances the reaction rate by nine orders of magnitude, compared to aqueous solution.

Selected publications

1. Borštnar Rok, Repič Matej, Kamerlin Shina Caroline Lynn, Vianello Robert, Mavri Janez, Computational study of the pK[sub]a values of potential catalytic residues in the active site of monoamine oxidase B, Journal of chemical theory and computation, 2012, vol. 8, iss. 10, str. 3864-3870.

2. Vianello Robert, Repič Matej, Mavri Janez, How are biogenic amines metabolized by monoamine oxidases?, European journal of organic chemistry, 2012, vol. 2012, iss. 36, str. 7057-7065.

3. Repič Matej, Purg Miha, Vianello Robert, Mavri Janez, Examining electrostatic preorganization in monoamine oxidases A and B by structural comparison and pK [sub] a calculations,  The journal of physical chemistry. B, Condensed matter, materials, surfaces, interfaces & biophysical, 2014, vol. 118, iss. 16, str. 4326-4332.

4. Poberžnik Matic, Purg Miha, Repič Matej, Mavri Janez, Vianello Robert. Empirical valence bond simulations of the hydride-transfer step in the monoamine oxidase A catalyzed metabolism of noradrenalineThe journal of physical chemistry. B, Condensed matter, materials, surfaces, interfaces & biophysical, 2016, vol. 120, iss. 44, str. 11419-11427.

5. Pregeljc, Domen, Jug, Urška, Mavri, Janez, Stare, Jernej. Why does the Y326I mutant of monoamine oxidase B decompose an endogenous amphetamine at a slower rate than the wild type enzyme? Reaction step elucidated by multiscale molecular simulations. PCCP. Physical chemistry chemical physics : a journal of European chemical societies, 2018, vol. 20, iss. 6, str. 4181-4188.

6. Mavri Janez, Matute Ricardo A, Chu Zhen T, Vianello Robert. Path integral simulation of the H/D kinetic isotope effect in monoamine oxidase B catalyzed decomposition of dopamineThe journal of physical chemistry. B, Condensed matter, materials, surfaces, interfaces & biophysical2016, vol. 120, iss. 14, str. 3488-3492.

7. Prah Alja, Ogrin Peter, Mavri Janez, Stare Jernej. Nuclear quantum effects in enzymatic reactions: simulation of the kinetic isotope effect of phenylethylamine oxidation catalyzed by monoamine oxidase APhys Chem Chem Phys2020, vol 13, str. 6838-6847.

Studies of monoamine oxidase (MAO) inhibition

The mode of MAO inhibition by acetylenic inhibitors is show in the figure as it was determined by our calculations. 

Selected publications

1. Borštnar Rok, Repič Matej, Kržan Mojca, Mavri Janez, Vianello Robert, Irreversible inhibition of monoamine oxidase B by the antiparkinsonian medicines rasagiline and selegiline : a computational studyEuropean journal of organic chemistry, 2011, vol. 2011, issue 32, str. 6419-6433.

2. Pavlin Matic, Mavri Janez, Repič Matej, Vianello Robert, Quantum-chemical approach to determining the high potency of clorgyline as an irreversible acetylenic monoamine oxidase inhibitor, 15th Amine Oxidase Conference : Re-Examining Amines : [16 to 18 July 2012, Toulouse, France], 2013, vol. 120, iss. 6, str. 875-882.

3. Tandarič, Tana, Prah, Alja, Stare, Jernej, Mavri, Janez, Vianello, Robert. Hydride abstraction as the rate-limiting step of the irreversible inhibition of monoamine oxidase B by rasagiline and selegiline : a computational empirical valence bond studyInternational journal of molecular sciences. 2020, vol. 21, str. 6151-1-6151-13.

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