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Originally published In Press as doi:10.1074/jbc.M006972200 on December 29, 2000

J. Biol. Chem., Vol. 276, Issue 13, 9877-9882, March 30, 2001
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Substrate and Inhibitor Specificities for Human Monoamine Oxidase A and B Are Influenced by a Single Amino Acid*

Rani Maurice GehaDagger , Igor RebrinDagger , Kevin ChenDagger , and Jean Chen ShihDagger §

From the Dagger  Department of Molecular Pharmacology and Toxicology, School of Pharmacy and the § Department of Cell and Neurobiology, School of Medicine, University of Southern California, Los Angeles, California 90089

Monoamine oxidase (MAO) is responsible for the oxidation of biogenic and dietary amines. It exists as two isoforms, A and B, which have a 70% amino acid identity and different substrate and inhibitor specificities. This study reports the identification of residues responsible for conferring this specificity in human MAO A and B. Using site-directed mutagenesis we reciprocally interchanged three pairs of corresponding nonconserved amino acids within the central portion of human MAO. Mutant MAO A-I335Y became like MAO B, which exhibits a higher preference for beta -phenylethylamine than for the MAO A preferred substrate serotonin (5-hydroxytryptamine), and became more sensitive to deprenyl (MAO B-specific inhibitor) than to clorgyline (MAO A-specific inhibitor). The reciprocal mutant MAO B-Y326I exhibited an increased preference for 5-hydroxytryptamine, a decreased preference for beta -phenylethylamine, and, similar to MAO A, was more sensitive to clorgyline than to deprenyl. These mutants also showed a distinct shift in sensitivity for the MAO A- and B-selective inhibitors Ro 41-1049 and Ro 16-6491. Mutant pair MAO A-T245I and MAO B-I236T and mutant pair MAO A-D328G and MAO B-G319D reduced catalytic activity but did not alter specificity. Our results indicate that Ile-335 in MAO A and Tyr-326 in MAO B play a critical role in determining substrate and inhibitor specificities in human MAO A and B.

* This work was supported by National Institute of Mental Health Grants R01 MH37020, R37 MH39085 (MERIT Award), and Research Scientist Award K05 MH00796 and by the Welin Professorship.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 1985 Zonal Ave., Los Angeles, CA 90089. Tel.: 323-442-1441; Fax: 323-442-3229; E-mail: jcshih@hsc.usc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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