# A Biomimetic Study of the Behavior of N‑Cyclopropyl-Based Single Electron Transfer Probes in the Context of Monoamine Oxidase-Catalyzed Oxidations

## TL;DR

This study explores how N-cyclopropyl compounds behave during oxidation reactions, shedding light on their role in enzyme inactivation.

## Contribution

The paper presents new biomimetic experiments and calculations on N-cyclopropyl derivatives in monoamine oxidase-catalyzed reactions.

## Key findings

- The ring-opening process of N-cyclopropyl compounds is reversible, contrary to previous assumptions.
- Radical coupling or reaction with oxygen may disrupt the enzyme's active site.
- Hydrolysis of an intermediate produces aldehydes, potentially contributing to enzyme inactivation.

## Abstract

Monoamine oxidase-A and -B are important flavoenzymes
involved
in the oxidative metabolism of various biogenic amines. Mechanisms
including polar/nucleophilic, hydride transfer, and single electron
transfer (SET) have been proposed for the initial steps of the catalytic
mechanism. The most compelling evidence for the latter comes from
the observed inhibitory behavior of N-cyclopropyl
compounds. Enzyme inactivation presumably occurs when the primary
radical portion of the distonic radical cation, resulting from cyclopropyl
ring opening, couples to the enzyme. Previously, we hypothesized that
the unique substrate behavior of 1,4-disubstituted-1,2,3,6-tetrahydropyridinyl
systems was attributable to certain structural features which activate
the SET pathway. In the present work, the oxidation of several N-cyclopropyl derivatives of MPTP in a biomimetic system
(3MLF/hν) is reported. Calculations suggest
that the barrier to ring opening may not be as low as assumed, and
experiments show the process is reversible. The results also suggest
that the ring-opened (distonic) radical cation may disrupt the active
site through radical coupling, hydrogen atom abstraction, or through
reaction with O2 that can lead to reactive oxygen species.
Hydrolysis of an intermediate iminium moiety leads to the production
of low molecular weight aldehydes, which may also provide a pathway
for enzyme inactivation.