Inactivation of monoamine oxidase B by benzyl 1-(aminomethyl)cyclopropane-1-carboxylate

Richard B Silverman*, Xingliang Lu, Geri D. Blomquist, Charles Z. Ding, Shengtian Yang

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Monoamine oxidase (MAO) is a flavoenzyme that catalyzes the oxidation of various biogenic and xenobiotic amines. Benzyl 1-(aminomethyl)cyclopropane-1-carboxylate (1) was designed as a diactivated cyclopropane mechanism-based inactivator of MAO (Silverman, R.B.; Ding, C.Z.; Borrillo, J.L.; Chang, J.T. J. Am. Chem. Sec. 1993, 115, 2982). [1,1-2H2]-1 exhibits a deuterium isotope effect of 4.5 on inactivation, but in D2O the isotope effect is only 2.3. [1-3H]-1 and [1-14C]-1 were synthesized; upon inactivation of MAO, 1.1 and 2.0 equiv of radioactivity, respectively, are incorporated into the enzyme. Tritium, as 3H2O, is released during inactivation with [1-3H]-1. The flavin absorption spectrum changes from that of oxidized to that of reduced flavin after inactivation; denaturation of the inactivated enzyme shows a reduced flavin spectrum, suggesting the formation of a modified flavin. Tryptic digestion of the enzyme labeled with [1-3H]-1 or [1-14C]-1, followed by HPLC analysis, monitoring at 450 nm (flavin), shows that the radioactivity comigrates with the 450 nm absorptions. The metabolites that are generated during in activation are benzyl 1-formylcyclopropane-1-carboxylate, benzyl alcohol, and 1-formylcyclopropane-1-carboxylic acid; no ring-cleaved products were detected. The partition ratio, as determined from the ratio of nonamines to enzyme, is 110. These results are rationalized in terms of a single-electron transfer mechanism leading to the imine of benzyl 1-formylcyclopropane-1-carboxylate, which alkylates the flavin coenzyme.

Original languageEnglish (US)
Pages (from-to)297-304
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume5
Issue number2
DOIs
StatePublished - Feb 1 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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