Reversible inhibition and mechanism-based irreversible inactivation of monoamine oxidases by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) |
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Authors: | T P Singer J I Salach D Crabtree |
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Institution: | 2. Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA;4. Molecular Biology Division, Veterans Administration Medical Center, San Francisco, California 94121, USA |
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Abstract: | It has been suggested (Chiba et al., Biochem. Biophys. Res. Communs. (1984) 120, 574) that the neurotoxic effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which causes Parkinsonian symptoms in humans and other primates, are due to compounds resulting from the oxidation of MPTP by monoamine oxidase B in the brain. We reported recently that both monoamine oxidase A and B oxidize MPTP to MPDP+, the 2,3-dihydropyridinium form and that the reaction is accompanied by time-dependent, irreversible inactivation of the enzymes. Of the two forms of monoamine oxidase, the B enzyme oxidizes MPTP more rapidly and is also more sensitive to inactivation. We now wish to report that MPTP, as well as its oxidation products, MPDP+ and MPP+, the 4-phenylpyridinium form, are also potent reversible, competitive inhibitors of both monoamine oxidase A and B, particularly the former, and that the order of inhibition for the A enzyme is MPDP+ greater than MPP+ greater than MPTP, while for the B enzyme MPTP greater than MPDP+ greater than MPP+. We further report on the spectral changes and isotope incorporation accompanying the irreversible inactivation. |
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