Reaction profiling of the MAO-B catalyzed oxidative deamination of amines in Alzheimer's disease

Donna M. Gasparro, David R.P. Almeida, Luca F. Pisterzi, Jason R. Juhasz, Bela Viskolcz, Botond Penke, Imre G. Csizmadia

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Abstract

Monoamine oxidase type B (MAO-B) catalyzes the oxidative deamination of various endogenous and exogenous primary, secondary, and tertiary amines. During this reaction, reactive oxygen species (ROS) are produced which contribute to the oxidative stress in a biological system. Further, research has indicated that increased MAO-B levels and increased ROS production may lead to deposition of β-amyloid (Aβ) and act as contributing factors to the pathogenesis of Alzheimer's disease (AD). As such, irreversible MAO-B inhibitors like selegiline, which decrease the rate of MAO-B catalyzed oxidative deamination, and thus the production of ROS, may have therapeutic potential via neuroprotection. In the current study, molecular orbital calculations were performed using the complete basis set 4m (CBS-4m) theoretical framework employed within the GAUSSIAN 98 software to elucidate the full energetic and thermodynamic profile of the MAO-B catalyzed oxidative deamination reaction. Full geometry optimizations were performed on model compounds to reveal the energies (ΔE) and Gibbs Free Energies (ΔG) of the oxidative deamination reaction as a means to clarify the details of this paramount reaction and how it relates to AD and selegiline's therapeutic potential. Results reveal that the oxidative deamination reaction consists of three successive energy-consuming steps for all amines. Trends indicate that for all amines, as amine substitution increases: (1) energetic investments needed for steps 1 and 3 increase, (2) ΔEReaction and ΔGReaction values for the oxidative deamination reaction as a whole increase, (3) differences between ΔGReaction and ΔEReaction values increase, and (4) ΔG and ΔE values for step 2 of the reaction decrease. The second step of the MAO-B catalyzed reaction is the only step, where increased amine substitution correlates with decreased ΔE and ΔG values. Due to the fact that step two possesses the lowest investment of energy for tertiary and secondary amines but the highest investment of energy for primary amines, it can be postulated that MAO-B has preferred secondary and tertiary substrates. The fact that step 2 is the rate-limiting step relates to the notion that it modulates the potential to increase oxidative stress, and thus, must be tightly regulated to maintain oxidant and anti-oxidant homeostasis. Finally, in disease states such as AD, where increased MAO-B levels have been documented, it is possible that MAO-B mediated oxidative stress is a contributing factor to AD. Thus, MAO-B inhibition by drugs like selegiline will provide neuroprotective benefits and help to prevent AD pathogenesis.

Original languageEnglish
Pages (from-to)527-536
Number of pages10
JournalJournal of Molecular Structure: THEOCHEM
Volume666-667
DOIs
Publication statusPublished - Dec 29 2003

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Keywords

  • Alzheimer's disease
  • Complete basis set 4m
  • Monoamine oxidase
  • Monoamine oxidase type B
  • Oxidative deamination
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Condensed Matter Physics
  • Physical and Theoretical Chemistry

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