Molecular and Mechanistic Properties of the Membrane-Bound Mitochondrial Monoamine Oxidases

Abstract

The last decade has brought major advances in our knowledge of the structures and mechanisms of MAO A and MAO B, which are pharmacological targets for specific inhibitors. In both enzymes, crystallographic and biochemical data show their respective C-terminal transmembrane helices anchor the enzymes to the outer mitochondrial membrane. Pulsed EPR data show both enzymes are dimeric in their membrane-bound forms with agreement between distances measured in their crystalline forms. Distances measure between active-site directed spin labels in membrane preparations show excellent agreement with those estimated from crystallographic data. Our knowledge of requirements for development of specific reversible MAO B inhibitors is in a fairly mature status. Less is known regarding the structural requirements for highly specific reversible MAO A inhibitors. In spite of their 70% sequence identity and similarities of Cα-folds, the two enzymes exhibit significant functional and structural differences that can be exploited in the ultimate goal of the development of highly specific inhibitors. This review summarizes the current structural and mechanistic information available that can be utilized in the development of future highly specific neuroprotectants and cardioprotectants.

Molecular aspects of monoamine oxidase B

“…for formation of the transition state of 16.1 kcal mol -1 (Repic et al, 2014) in excellent agreement with the experimental value of 16.5 kcal mol -1 (Edmondson et al, 2009).…”

“…4.1 MAO B protein: structure, active site and I 2 site MAO B forms a homo-dimer in which each subunit (59000 daltons) contains one covalently-bound FAD linked to cysteine 397 (Edmondson et al, 2009). Each monomer (Fig.…”

“…2) has one helix buried in the mitochondrial outer membrane and further surface area thought to associate with the membrane. In the membrane-bound dimer, the distance between the N5 atoms of the two FAD molecules, measured by pulsed dipolar ESR spectroscopy after irreversible modification of the FAD with a nitroxide spin-labeled irreversible inhibitor, was 4.4 nm (Upadhyay et al, 2008, Edmondson et al, 2009). …”

“…Based on the kinetic parameters reviewed in , Edmondson et al, 2009, Ramsay et al, 2011 common with many pharmacological studies, were performed in rats, where it was noted that the K M values for the amine substrates varied with the oxygen concentration (Fowler and Oreland, 1980). Successful cloning into Pichia pastoris (Newton-Vinson et al, 2000) enabled work on human MAO B.…”

“…The examples shown in Table 1 illustrate the main classes: the hydrazine, acetylenic (propargyl), and cyclopropyl compounds are activated by the enzyme itself. The reactive product forms a covalent bond with the enzyme, usually to the flavin cofactor (Mitchell et al, 2001, Edmondson et al, 2009, Bonivento et al, 2010. Activity in the cell is restored only by synthesis of new MAO B, a slow process with a half-life of 9 days in rat brain (Youdim and Tipton, 2002).…”