Journal
JOURNAL OF NEURAL TRANSMISSION
Volume 118, Issue 7, Pages 1003-1019Publisher
SPRINGER WIEN
DOI: 10.1007/s00702-011-0657-y
Keywords
Monoamine oxidase; Steady-state kinetics; Equations; Inhibition; GraphPad Prism
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Funding
- Canadian Institutes of Health Research [MOP 77529]
- Canada Foundation for Innovation [CFILOFS123945]
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The search for new monoamine oxidase inhibitors aims to identify potential lead compounds that are more potent and selective than current drugs for use in treating a variety of neuropsychiatric and neurodegenerative conditions. An integral part of this process is a kinetic examination of monoamine oxidases in the presence of the inhibitor, to determine potency and selectivity and to obtain information on mechanism. To date, kinetic data obtained with a probe substrate have been analysed by fitting to the Michaelis-Menten equation which describes a unireactant process in which velocity is related to substrate concentration in a rectangular hyperbolic manner. In this study, we present evidence that monoamine oxidase activity is often not adequately described by this approach. We outline a novel equation strategy that takes account of substrate and inhibitor binding to oxidised and reduced enzyme forms, and quantifies differences between substrates and inhibitors in this regard. When combined with plate reader-based experimental techniques that allow large numbers of substrate and inhibitor concentrations to be used, and the global nonlinear regression facilities of GraphPad Prism software, this straightforward approach allows more appropriate analyses of monoamine oxidase by non-experts than has previously been possible.
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