1985
DOI: 10.1021/bi00344a035
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Revised mechanism for inactivation of mitochondrial monoamine oxidase by N-cyclopropylbenzylamine

Abstract: A mechanism previously proposed for inactivation of monoamine oxidase (MAO) by N-cyclopropylbenzylamine (N-CBA) [Silverman, R. B., & Hoffman, S. J. (1980) J. Am. Chem. Soc. 102, 884-886] is revised. Inactivation of MAO by N-[1-3H]CBA results in incorporation of about 3 equiv of tritium into the enzyme and release of [3H]acrolein. Treatment of inactivated enzyme with benzylamine, a reactivator for N-CBA-inactivated MAO, releases only 1 equiv of tritium as [3H]acrolein concomitant with reactivation of the enzyme… Show more

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Cited by 32 publications
(19 citation statements)
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“…The presence of a cyclopropylamine moiety within a potential drug candidate should be viewed with some caution since this group is a well-known mechanism-based inactivator of cytochrome P450 [124,125]. Cyclopropylamines have also been implicated in the suicide inactivation of other human enzymes, such as the inactivation of MAO by tranylcypromine [126] and benzylcyclopropylamine [127], and alcohol dehydrogenase (ADH) by the mushroom toxin coprine [128].…”
Section: Occurrence and Frequencymentioning
confidence: 99%
See 1 more Smart Citation
“…The presence of a cyclopropylamine moiety within a potential drug candidate should be viewed with some caution since this group is a well-known mechanism-based inactivator of cytochrome P450 [124,125]. Cyclopropylamines have also been implicated in the suicide inactivation of other human enzymes, such as the inactivation of MAO by tranylcypromine [126] and benzylcyclopropylamine [127], and alcohol dehydrogenase (ADH) by the mushroom toxin coprine [128].…”
Section: Occurrence and Frequencymentioning
confidence: 99%
“…For enzymes which are unequivocally known to oxidize amines by a single electron transfer (SET) mechanism and be irreversibly inhibited by cyclopropylamines, such as MAO-B, a cyclopropyl ring fragmented distonic cation radical intermediate 100 or resulting α, β-unsaturatedcarbonyl metabolite 101 are the reactive enzyme modifying species [126,127]. However, in the case of cytochrome P450, for which the mechanism of cyclopropylamine oxidation has no definitive consensus, the suicide intermediate may be generated either by SET or by direct hydroxylation (HAT) at the α-carbon of the cyclopropyl group.…”
Section: Mechanismmentioning
confidence: 99%
“…Cyclopropylamines have also been implicated in the irreversible inactivation of other drug metabolizing enzymes, as exemplified by the inactivation of monoamine oxidase (MAO) by the anti-depressant tranylcypromine [145,146], and alcohol dehydrogenase by the mushroom toxin coprine [147]. (21)) is thought to involve SET oxidation on the amine nitrogen to the cation radical intermediate, followed by spontaneous cyclopropane ring opening to a ring fragmented distonic cation radical intermediate or an , -unsaturatedcarbonyl metabolite, which then covalently bind to the enzyme [148][149][150]. (19).…”
Section: Cyclopropylaminesmentioning
confidence: 99%
“…One mechanism proposed to account for this 2‐electron α‐carbon oxidation proceeds via an initial single electron transfer (SET) step to form the corresponding aminyl radical cation 1 •+ . Ring α‐carbon deprotonation of 1 •+ yields the neutral radical 2 • that undergoes further oxidation to the 2,3‐dihydropyridinium product 3H + 5, 6. An alternative proposal assumes an initial hydrogen atom transfer (HAT) step to yield 2 • directly 7–9.…”
Section: Introductionmentioning
confidence: 99%