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

  • Silverman R
  • Lu X
  • Blomquist G
 et al. 
  • 3

    Readers

    Mendeley users who have this article in their library.
  • 11

    Citations

    Citations of this article.

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, as3H2O, 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.

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

  • Richard B. Silverman

  • Xingliang Lu

  • Geri D. Blomquist

  • Charles Z. Ding

  • Shengtian Yang

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free