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Inactivation of mitochondrial monoamine oxidase B by methylthio-substituted benzylamines

Xingliang Lu1, María Rodríguez, Wenxin Gu

  • 1Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, and the Drug Discovery Program, Northwestern University, Evanston, IL 60208-3113, USA.

Bioorganic & Medicinal Chemistry
|September 18, 2003
PubMed

Insights

Certain benzylamine derivatives inactivate mitochondrial monoamine oxidase (MAO). Researchers propose two mechanisms, SNAr and dealkylation, supported by radiolabeling and chemical studies.

Area of Science:

  • Biochemistry
  • Enzymology
  • Pharmacology

Background:

  • Mitochondrial monoamine oxidase (MAO) is a key enzyme in neurotransmitter metabolism.
  • Understanding MAO inhibition is crucial for developing treatments for neurological disorders.

Purpose of the Study:

  • To investigate the inactivation mechanisms of mitochondrial monoamine oxidase (MAO) by specific benzylamine derivatives.
  • To elucidate the chemical pathways involved in MAO inhibition.

Main Methods:

  • Enzyme inactivation assays using o-mercaptobenzylamine, o- and p-methylthiobenzylamine.
  • Synthesis and use of radiolabeled analogues to quantify inactivator incorporation.
  • Electrophile scavenger and catalase treatments to probe reaction mechanisms.
  • Cysteine titration to assess enzyme structural changes.
  • Chemical model studies to support proposed mechanisms.

Main Results:

  • o-Mercaptobenzylamine, o-, and p-methylthiobenzylamine inactivated MAO, while hydroxybenzylamines did not.
  • Multiple equivalents of radiolabeled inactivators incorporated into the enzyme.
  • Inactivation involved flavin reduction, with reoxidation upon denaturation, suggesting non-flavin attachment.
  • Loss of four cysteine residues upon inactivation and denaturation.
  • Evidence supported both nucleophilic aromatic substitution (SNAr) and dealkylation mechanisms.

Conclusions:

  • Specific benzylamine derivatives effectively inactivate mitochondrial MAO through complex mechanisms.
  • Proposed mechanisms include SNAr and dealkylation, supported by extensive experimental evidence.
  • Findings contribute to understanding enzyme inhibition and designing novel MAO inhibitors.

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