Variations in activity and inhibition with pH: the protonated amine is the substrate for monoamine oxidase, but uncharged inhibitors bind better

Variations in activity and inhibition with pH: the protonated amine is the substrate for monoamine oxidase, but uncharged inhibitors bind better

It has been accepted that, as required mechanistically, the neutral form of the amine is the substrate for monoamine oxidase, despite the amine pK (a) of above 9.5. The pH dependence of the kinetic parameters for kynuramine oxidation by purified human MAO-A and for phenylethylamine oxidation by MAO-...

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Bibliographic Details
Published in:Journal of Neural Transmission Vol. 114; no. 6; pp. 707 - 712
Main Authors: Jones, T Z E, Balsa, D, Unzeta, M, Ramsay, R R
Format: Journal Article
Language:English
Published: Austria Springer Nature B.V 01-06-2007
Subjects:
Binding Sites - physiology
Biogenic Amines - chemistry
Biogenic Amines - metabolism
Enzyme Activation - physiology
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Flavins - chemistry
Granulocytes - enzymology
Humans
Hydrogen-Ion Concentration
Kynuramine - chemistry
Kynuramine - metabolism
Molecular Structure
Monoamine Oxidase - chemistry
Monoamine Oxidase - drug effects
Monoamine Oxidase - metabolism
Oxazolidinones - chemistry
Oxazolidinones - pharmacology
Phenethylamines - chemistry
Phenethylamines - metabolism
Protons
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Summary:It has been accepted that, as required mechanistically, the neutral form of the amine is the substrate for monoamine oxidase, despite the amine pK (a) of above 9.5. The pH dependence of the kinetic parameters for kynuramine oxidation by purified human MAO-A and for phenylethylamine oxidation by MAO-B in granulocytes at pH values from 5 to 10 was consistent with the protonated amine being used. Deprotonation of a group of pK (a) = 7.1 in MAO-B and pK (a) = 7.5 +/- 0.1 (n = 4) in MAO-A was important for efficient catalysis. The K(i) values for two oxazolidinone inhibitors of MAO-A gave opposite pH-dependence indicating that the uncharged form of each inhibitor bound better than the charged form. Decreased pH induced a blue shift in the spectral maximum of MAO-A indicative of a more hydrophobic environment around the flavin, and also influenced the redox properties of the flavin.
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ISSN:0300-9564
1435-1463
DOI:10.1007/s00702-007-0675-y