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Abstract Results 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 O2and 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 pKaof 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.
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This content will become publicly available on January 1, 2026
Evaluating potential impact of monoamine oxidase A missense L32S on the function of the enzyme monoamine oxidase A using in silico prediction tools and molecular modeling
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 6-7% of people worldwide (Wilcutt, 2012). MAOA is a gene that encodes monoamine oxidase A, an enzyme responsible for the regulation and metabolism of monoamines thought to be associated with ADHD. This study investigates a leucine to serine swap at amino acid position 32 in FAD-binding domain of the enzyme monoamine oxidase A. Results from in silico prediction tools and molecular dynamics modeling provide evidence to support pathogenicity of the L32S missense variant of monoamine oxidase A.
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- Award ID(s):
- 2120918
- PAR ID:
- 10614663
- Publisher / Repository:
- microPublication Biology
- Date Published:
- Journal Name:
- microPublication Biology
- Volume:
- 2025
- ISSN:
- 2578-9430
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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