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01 September 2005

Alteration in spectral properties on ligand binding reveals flexibility inmonoamine oxidase.

Rona R Ramsay, Tadeusz Z.E. Jones, Robert M.G. Hynson

Med Sci Monit 2005; 11(9): SR15-20 :: ID: 428462

Abstract

Crystal structures have opened the door to understanding the mechanismand ligand specificities of MAO A and MAO B. We review here functional properties that suggest a flexibilityin MAO that is likely to influence catalysis under different cellular conditions. The flexibility indicatedby altered oxidation kinetics and a changed redox potential in the presence of a substrate was confirmedby circular dichroism spectroscopy. Circular dichroism also demonstrated alterations in the conformationof aromatic residues during reduction of MAO A and after covalent modification of the flavin. Visiblespectra provide a convenient way to monitor ligand binding in the active site. Different groups nearthe flavin give different spectral changes. During reduction of MAO A, a distinct 412 nm peak appearsafter partial reduction. Recent work suggests that this may be a tyrosyl radical in equilibrium withthe semiquinone of the flavin. Substrates prevent the appearance of the 412 nm peak but many inhibitorsenhance it by preventing further reduction. We propose that steric effects in the active site could bethe mechanism of this difference. Flexibility is also important for the transmission of the effects ofmodifying the surface thiols to the active site. Modification of multiple thiols results in inactivationbut mutation of a single thiol, cysteine 374 in MAO A to alanine, decreased the catalytic potency (kcat/Km)by 30%. Thus, surface modification of MAO (for example, by oxidative stress) could reduce its activity.

Keywords: Cysteine - chemistry, Catalytic Domain, Allosteric Regulation, Kinetics, Ligands, Models, Molecular, Monoamine Oxidase - metabolism, Monoamine Oxidase Inhibitors - pharmacology, Oxidation-Reduction, Protein Conformation

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750