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MOLECULAR PHARMACOLOGY 52:549-553 (1997).

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Localization of the Imidazoline Binding Domain on Monoamine Oxidase B

Rita Raddatz, Angelo Parini, and Stephen M. Lanier

Department of Pharmacology, Medical University of South Carolina, Charleston, SC 29425 (R.R., S.M.L.) and Institut National de la Santé et de la Recherche Médicale U388 Pharmacologie Moleculaire et Physiopathologie Renale, Institut Louis Bugnard Toulouse, France (A.P.)

Monoamine oxidase B (MAO-B) was recently identified as a member of the family of imidazoline binding proteins. To localize the imidazoline binding domain on MAO-B, we labeled the domain with the imidazoline photoaffinity adduct [¹²⁵I]2-(3-azido-4-iodophenoxy)methylimidazoline in rat and human liver and visualized labeled peptides by autoradiography/sodium dodecyl sulfate-polyacrylamide gel electrophoresis after CNBr cleavage of the labeled protein. Based on species-specific fragmentation patterns and immunoprecipitation of labeled peptides, the imidazoline binding domain was localized to residues K149 to M222 of human MAO-B. The imidazoline binding domain is encompassed within a region that influences substrate processing but is distinct from primary sites of interaction for the enzyme inhibitors pargyline and lazabemide (Ro 19-6327). Radioligand binding assays and photoaffinity labeling also indicated that the various classes of compounds did not cross-compete at the different enzyme domains. Identification of an imidazoline binding domain on MAO-B provides a new opportunity for the potential pharmacological development of imidazoline/guanidinium compounds and also presents additional avenues for structure/function analysis of the monoamine oxidase enzymes.