Why Does Monoamine Oxidase (MAO) Catalyze the Oxidation of Some Tetrahydropyridines?

Author:

Price Nathan J.1,Nakamura Akiko2,Castagnoli Neal1,Tanko James M.1ORCID

Affiliation:

1. Department of Chemistry Virginia Tech Blacksburg VA 24061 USA

2. Department of Chemistry Colorado State University Fort Collins CO 80523 USA

Abstract

AbstractResults pertaining to the mechanism of the oxidation of the tertiary amine 1‐methyl‐4‐(1‐methyl‐1‐H‐pyrrol‐2‐yl)‐1,2,3,6‐tetrahydropyridine (MMTP, a close analog of the Parkinsonism inducing compound MPTP) by 3‐methyllumiflavin (3MLF), a chemical model for the FAD cofactor of monoamine oxidase, are reported. MMTP and related compounds are among the few tertiary amines that are monoamine oxidase B (MAO−B) substrates. The MMTP/3MLF reaction is catalytic in the presence of O2 and the results under anaerobic conditions strongly suggest the involvement of radical intermediates, consistent with a single electron transfer mechanism. These observations support a new hypothesis to explain the MAO‐catalyzed oxidations of amines. In general, electron transfer is thermodynamically unfavorable, and as a result, most 1° and 2° amines react via one of the currently accepted polar pathways. Steric constraints prevent 3° amines from reacting via a polar pathway. Those select 3° amines that are MAO substrates possess certain structural features (e. g., a C−H bond that is α‐ both to nitrogen and a C=C) that dramatically lower the pKa of the corresponding radical cation. Consequently, the thermodynamically unfavorable electron transfer equilibrium is driven towards products by an extremely favorable deprotonation step in the context of Le Chatelier's principle.

Funder

National Science Foundation

Publisher

Wiley

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