Characterization of the Covalently Bound Anionic Flavin Radical in Monoamine Oxidase A by Electron Paramagnetic Resonance
Open Access
- 29 November 2007
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 129 (51), 16091-16097
- https://doi.org/10.1021/ja076090q
Abstract
It was recently suggested that partially reduced monoamine oxidase (MAO) A contains an equilibrium mixture of an anionic flavin radical and a tyrosyl radical (Rigby, S. E.; et al. J. Biol. Chem.2005, 280, 4627−4632). These observations formed the basis for a revised radical mechanism for MAO. In contrast, an earlier study of MAO B only found evidence for an anionic flavin radical (DeRose, V. J.; et al. Biochemistry1996, 35, 11085−11091). To resolve the discrepancy, we have performed continuous-wave electron paramagnetic resonance at 94 GHz (W-band) on the radical form of MAO A. A comparison with d-amino acid oxidase (DAAO) demonstrates that both enzymes only contain anionic flavin radicals. Pulsed electron−nuclear double resonance spectra of the two enzymes recorded at 9 GHz (X-band) reveal distinct hyperfine coupling patterns for the two flavins. Density functional theory calculations show that these differences can be understood in terms of the difference at C8α of the isoalloxazine ring. DAAO contains a noncovalently bound flavin whereas MAO A contains a flavin covalently bound to a cysteinyl residue at C8α. The similar electronic structures and hydrophobic environments of MAO and DAAO, and the similar structural motifs of their substrates suggest that a direct hydride transfer catalytic mechanism established for DAAO (Umhau, S.; et al. Proc. Natl. Acad. Sci. U.S.A.2000, 97, 12463−12468) should be considered for MAO.This publication has 45 references indexed in Scilit:
- The therapeutic potential of monoamine oxidase inhibitorsNature Reviews Neuroscience, 2006
- Chemical aspects of amine oxidation by flavoprotein enzymesNatural Product Reports, 2004
- Structure and Mechanism of Monoamine OxidaseCurrent Medicinal Chemistry, 2004
- The Chemical and Biological Versatility of RiboflavinBiochemical Society Transactions, 2000
- Flavoenzymes: diverse catalysts with recurrent featuresTrends in Biochemical Sciences, 2000
- Observation of a Flavin Semiquinone in the Resting State of Monoamine Oxidase B by Electron Paramagnetic Resonance and Electron Nuclear Double Resonance Spectroscopy,Biochemistry, 1996
- Radical Ideas about Monoamine OxidaseAccounts of Chemical Research, 1995
- Structure-Activity Relationships in the Oxidation of Benzylamine Analogs by Bovine Liver Mitochondrial Monoamine Oxidase BBiochemistry, 1994
- Catalytically active monoamine oxidase type A from human liver expressed in Saccharomyces cerevisiae contains covalent FADBiochemical and Biophysical Research Communications, 1990
- The Covalently‐Bound Flavin of Hepatic Monoamine OxidaseJBIC Journal of Biological Inorganic Chemistry, 1971