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Conformational changes in monoamine oxidase A in response to ligand binding or reduction

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Author(s)

RMG Hynson, SM Kelly, NC Price, Rona Ruth Ramsay

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Abstract

The structure of monoamine oxidase B [Nat. Struct. Biol. 9 (2002) 22] revealed three aromatic amino acid residues within contact distance of the flavin cofactor and a large number of aromatic residues in the substrate binding site. Circular dichroism (CD) spectroscopy can detect alterations in the environment of aromatic residues as a result of ligand binding or redox changes. CD spectra of MAO A indicate that a small inhibitor such D-amphetamine perturbs the aromatic residues very little, but binding of the larger pirlindole (2,3,3a,4,5,6-hexahydro-8-methyl- 1H-pyrazino[3,2, 1-j,k] carbazole hydrochloride) causes spectral changes consistent with the alteration of the environment of tyrosine and tryptophan residues in particular. Reduction of the flavin cofactor induces large enhancement of the CD signals in the aromatic region (260-310 nm). When covalent modification of the flavin by clorgyline accompanies reduction, the perturbation is even greater. In contrast to the static picture offered by crystallography, this study reveals changes in the aromatic cage on ligand binding and suggests that reduction of the cofactor substantially alters the environment of aromatic residues presumably near the flavin. In addition, the covalently modified reduced MAO A shows significant differences from the substrate-reduced enzyme. (C) 2004 Elsevier B.V. All rights reserved.

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Details

Original languageEnglish
Pages (from-to)60-66
Number of pages7
JournalBiochimica et Biophysica Acta - General Subjects
Volume1672
Issue number1
DOIs
Publication statusPublished - 7 Apr 2004

    Research areas

  • circular dichroism, aromatic amino acid, difference spectra, flavin reduction, covalent modification, monoamine oxidase A, KINETIC MECHANISM, REDOX PROPERTIES, INHIBITORS

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