The active centers of monoamine oxidase types “A” and “B”: Binding with (14C)-clorgyline and (14C)-deprenyl
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- Youdim, M.B.H. J. Neural Transmission (1978) 43: 199. doi:10.1007/BF01246956
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The use of deprenyl, a monoamine oxidase (MAO) “type B” inhibitor, in potentiating the action of L-Dopa in the treatment of Parkinson's disease has attracted wide interest. Acetylenic amines as exemplified by pargyline, clorgyline, deprenyl and 3-dimethylamino-1-propylene have been called “suicide inhibitors” because an irreversible inhibition is produced by the action of the target enzyme on these compounds which act as substrates. MAO is a sulphydryl flavoprotein and nutritional iron is required for full enzyme activity. There is one mole of covalently bound flavin per mole enzyme. The isolated flavin is associated with the pentapeptide, Ser-Gly-Gly-Cys-Tyr. The mode of attachment is via the thio-ether of cysteine to the 8α-position of the flavin, this being the case for the liver as well as the brain enzyme. The evidence that this enzyme exists in different functional forms which can be selectively inhibited by acetylenic inactivators prompted the study of the binding of inhibitors to the enzyme. It has been established that (14C)-clorgyline, (14C)-deprenyl and (14C)-2-phenylethylhydrazine (phenelzine) bind irreversibly and stoichiometrically (mole/mole) to the enzyme at its active centre. Substrates protect from inhibition. Isolation of (14C)-inhibitor adducts from fully inhibitor inactivated enzyme preparations after proteolytic digestion with Pronase/trypsin have shown that more than 90% of (14C)-inhibitor bound to the enzyme is associated with the MAO flavinpeptide adduct. Chemical and physical properties of the enzymatically derived (14C)-acetylenic-flavin-peptide adducts compared to model compounds suggest that the inhibitor binds with the 5-position N of the flavin.