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J. Biol. Chem., Vol. 280, Issue 16, 15761-15766, April 22, 2005

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Demonstration of Isoleucine 199 as a Structural Determinant for the Selective Inhibition of Human Monoamine Oxidase B by Specific Reversible Inhibitors^*

Frantisek Hubálek, Claudia Binda¶, Ashraf Khalil||, Min Li, Andrea Mattevi¶, Neal Castagnoli||, and Dale E. Edmondson**

From the Departments of Biochemistry and Chemistry, Emory University, Atlanta, Georgia 30322, the ^¶Department of Genetics and Microbiology, University of Pavia, via Abbiategrasso 207, Pavia, 27100 Italy, and the ^||Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061

Several reversible inhibitors selective for human monoamine oxidase B (MAO B) that do not inhibit MAO A have been described in the literature. The following compounds: 8-(3-chlorostyryl)caffeine, 1,4-diphenyl-2-butene, and trans,trans-farnesol are shown to inhibit competitively human, horse, rat, and mouse MAO B with K_i values in the low micromolar range but are without effect on either bovine or sheep MAO B or human MAO A. In contrast, the reversible competitive inhibitor isatin binds to all known MAO B and MAO A with similar affinities. Sequence alignments and the crystal structures of human MAO B in complex with 1,4-diphenyl-2-butene or with trans,trans-farnesol provide molecular insights into these specificities. These inhibitors span the substrate and entrance cavities with the side chain of Ile-199 rotated out of its normal conformation suggesting that Ile-199 is gating the substrate cavity. Ile-199 is conserved in all known MAO B sequences except bovine MAO B, which has Phe in this position (the sequence of sheep MAO B is unknown). Phe is conserved in the analogous position in MAO A sequences. The human MAO B I199F mutant protein of MAO B binds to isatin (K_i = 3 µM) but not to the three inhibitors listed above. The crystal structure of this mutant demonstrates that the side chain of Phe-199 interferes with the binding of those compounds. This suggests that the Ile-199 "gate" is a determinant for the specificity of these MAO B inhibitors and provides a molecular basis for the development of MAO B-specific reversible inhibitors without interference with MAO A function in neurotransmitter metabolism.

Received for publication, January 26, 2005 , and in revised form, February 9, 2005.

^* This work was supported by Grant GM-29433 from NIGMS, National Institutes of Health, by Ministry of Science and Education (Italy) Grants FIRB and COFIN04, and by Fondazione MINTAS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2BK3, 2BK4, and 2BK5) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Present address: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark.

^** To whom correspondence should be addressed: Dept. of Biochemistry, Emory University, 1510 Clifton Rd., Rollins Research Bldg., Atlanta, GA 30322. Tel.: 404-727-5972; Fax: 404-727-2738; E-mail: deedmon{at}emory.edu.

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