Cited by 85Metal-Catalyzed Oxygenation MechanismsEnzyme Structure and FunctionEnzyme function and inhibition

Structural and Mechanistic Studies of Arylalkylhydrazine Inhibition of Human Monoamine Oxidases A and B

Binda, Claudia, Wang, Jin, Li, Min, Hubalek, Frantisek, Mattevi, Andrea, Edmondson, Dale E.·2008·Biochemistry

Abstract

The structure and mechanism of human monoamine oxidase B (MAO B) inhibition by hydrazines are investigated and compared with data on human monoamine oxidase A (MAO A). The inhibition properties of phenylethylhydrazine, benzylhydrazine, and phenylhydrazine are compared for both enzymes. Benzylhydrazine is bound more tightly to MAO B than to MAO A, and phenylhydrazine is bound weakly by either enzyme. Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine. Mass spectral analysis of either inhibited enzyme shows the major product is a single covalent addition of the hydrazine arylalkyl group, although lower levels of dialkylated species are detected. Absorption and mass spectral data of the inhibited enzymes show that the FAD is the major site of alkylation. The three-dimensional (2.3 A) structures of phenylethylhydrazine- and benzylhydrazine-inhibited MAO B show that alkylation occurs at the N(5) position on the re face of the covalent flavin with loss of the hydrazyl nitrogens. A mechanistic scheme is proposed to account for these data, which involves enzyme-catalyzed conversion of the hydrazine to the diazene. From literature data on the reactivities of diazenes, O2 then reacts with the bound diazene to form an alkyl radical, N2 and superoxide anion. The bound arylalkyl radical reacts with the N(5) of the flavin, while the dissociated diazene reacts nonspecifically with the enzyme through arylalkylradicals.

Integrity signals

Registry

Crossref · 10.1021/bi8002814

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several hydrazine-containing compounds act as mechanism-based inhibitors of MAO A and B, with MAO activation enabling alkylation of a flavin cofactor and enzyme inhibition.

    “Several hydrazine-containing compounds act as mechanism-based inhibitors of monoamine oxidase (MAO) A and B, whereby activation by MAO enables alkylation of a flavin cofactor, inhibiting the enzyme196.”

    From Advances in covalent drug discovery (2022) · cites this paper as [196]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Binda, C., Wang, J., Li, M., Hubalek, F., Mattevi, A., & Edmondson, D. E.
Affiliations
  • Emory University (US)
  • Department of Genetics and Microbiology, University of Pavia, via Ferrata 1, Pavia 27100, Italy, and Departments of Biochemistry and Chemistry, Emory University, Atlanta, Georgia 30322
Corresponding author
Edmondson, Dale E.
Venue
Biochemistry
Published
2008-04-22
Volume
47
Issue
20
Pages
5616-5625
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
OpenAlex
W2122450959
Cited by
75
References
46
Citations by year
2026: 3 · 2025: 3 · 2024: 5 · 2023: 1 · 2022: 6 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 8 · 2017: 3 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 4 · 2012: 6
FWCI
3.84
Type
journal article
Language
en
Open access
closed
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1s10rr012878-01, 1s10rr013948-01, 1s10rr002878-01)
  • National Institute of General Medical Sciences (GM29433, R01GM029433)
  • National Center for Research Resources (RR 02878, RR13948, RR 12878)
Topics
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Keywords
monoamine oxidase B, monoamine oxidase A, benzylhydrazine, phenylhydrazine, covalent enzyme inhibition, diazene, oxygen consumption, superoxide, enzyme-inhibitor complex structure, inhibition mechanism
MeSH terms
Binding Sites, Enzyme Activation, Humans, Hydrazines, Models, Molecular, Monoamine Oxidase, Monoamine Oxidase Inhibitors, Oxygen, Protein Binding, Spectrophotometry, Molecular Structure, Crystallography, X-Ray, Spectrometry, Mass, Electrospray Ionization

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review