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

We investigated various aspects of the metabolism of monoamines and catalytic effects of monoamine oxidase enzymes, by using the empirical valence bond methodology in the first place

Domen Pregeljc; Urška Jug; Janez Mavri; Jernej Stare


Scholarcy highlights

  • monoamine oxidase enzymes enzymes exist in two forms, A and B, which share about 70% of the sequence identity, but differ in substrate specificity. both MAO A and MAO B share a wide array of common substrates
  • It has been accepted that the catalytic step of amine oxidation includes the cleavage of a C–H bond at the methylene group vicinal to the amino group, i.e., the a-C–H bond, accompanied by the hydrogen transfer to the flavin adenine dinucleotide prosthetic group covalently bound to the cysteine residue
  • The issues addressed in our studies include a comparison of preorganized electrostatics between MAO A and B,26 pKa calculations of selected residues near the active site, selectivity between MAO A and B for the decomposition of adrenaline, H/D kinetic isotope effects associated with nuclear quantum effects and various simulations of point mutation effects
  • The most illustrative output of the present simulations is the increase in the free energy barrier for the rate limiting step of PEA oxidation for MAO B by 1.06 kcal molÀ1 on the Y326I point mutation
  • We have elucidated the effect of Y326I point mutation in MAO B on the rate of decomposition of PEA, an endogenous amphetamine, by using multiscale empirical valence bond simulations
  • A slightly larger amount of water molecules is present near the reacting moiety in the mutant, which shields the catalytic effect of the enzyme
  • Another possible explanation is that the point mutation effect is due to entropic effects or to several small contributions not detectable by simulations

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