Alteration in spectral properties on ligand binding reveals flexibility
in monoamine oxidase.
Med Sci Monit, (September 2005)Abstract
Crystal structures have opened the door to understanding the mechanism
and ligand specificities of MAO A and MAO B. We review here functional
properties that suggest a flexibility in MAO that is likely to influence
catalysis under different cellular conditions. The flexibility indicated
by altered oxidation kinetics and a changed redox potential in the
presence of a substrate was confirmed by circular dichroism spectroscopy.
Circular dichroism also demonstrated alterations in the conformation
of aromatic residues during reduction of MAO A and after covalent
modification of the flavin. Visible spectra provide a convenient
way to monitor ligand binding in the active site. Different groups
near the flavin give different spectral changes. During reduction
of MAO A, a distinct 412 nm peak appears after partial reduction.
Recent work suggests that this may be a tyrosyl radical in equilibrium
with the semiquinone of the flavin. Substrates prevent the appearance
of the 412 nm peak but many inhibitors enhance it by preventing
further reduction. We propose that steric effects in the active
site could be the mechanism of this difference. Flexibility is also
important for the transmission of the effects of modifying the surface
thiols to the active site. Modification of multiple thiols results
in inactivation but 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.