Premium
Interactions of imidazoline ligands with the active site of purified monoamine oxidase A
Author(s) -
Jones Tadeusz Z. E.,
Giurato Laura,
Guccione Salvatore,
Ramsay Rona R.
Publication year - 2007
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2007.05704.x
Subject(s) - agmatine , imidazoline receptor , monoamine oxidase , chemistry , monoamine oxidase b , monoamine neurotransmitter , stereochemistry , binding site , guanabenz , active site , biochemistry , enzyme , biology , pharmacology , receptor , putrescine , serotonin , agonist
The two forms of monoamine oxidase, monoamine oxidase A and monoamine oxidase B, have been associated with imidazoline‐binding sites (type 2). Imidazoline ligands saturate the imidazoline‐binding sites at nanomolar concentrations, but inhibit monoamine oxidase activity only at micromolar concentrations, suggesting two different binding sites [Ozaita A, Olmos G, Boronat MA, Lizcano JM, Unzeta M & García‐Sevilla JA (1997) Br J Pharmacol 121, 901–912]. When purified human monoamine oxidase A was used to examine the interaction with the active site, inhibition by guanabenz, 2‐(2‐benzofuranyl)‐2‐imidazoline and idazoxan was competitive with kynuramine as substrate, giving K i values of 3 µ m , 26 µ m and 125 µ m , respectively. Titration of monoamine oxidase A with imidazoline ligands induced spectral changes that were used to measure the binding affinities for guanabenz (19.3 ± 3.9 µ m ) and 2‐(2‐benzofuranyl)‐2‐imidazoline (49 ± 8 µ m ). Only one type of binding site was detected. Agmatine, a putative endogenous ligand for some imidazoline sites, reduced monoamine oxidase A under anaerobic conditions, indicating that it binds close to the flavin in the active site. Flexible docking studies revealed multiple orientations within the large active site, including orientations close to the flavin that would allow oxidation of agmatine.