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The major structural difference between human monoamine oxidases A (MAO A) and B (MAO B) is that MAO A has a monopartite substrate cavity of 550 A ˚ 3 volume and MAO B contains a dipartite cavity struc-ture with volumes of 290 A ˚ 3 (entrance cavity) and 400 A ˚ 3 (substrate cavity). | IFEBS Journal The gating residues Ile199 and Tyr326 in human monoamine oxidase B function in substrate and inhibitor recognition Erika M. Milczek1 z Claudia Binda2 Stefano Rovida2 Andrea Mattevi2 and Dale E. Edmondson1 1 Departments of Chemistry and Biochemistry Emory University Atlanta Georgia USA 2 Department of Genetics and Microbiology University of Pavia Italy Keywords dipartite to monopartite cavity conversion inhibitor specificity monoamine oxidase B mutations of gating residues structure of methylene blue complex Correspondence D. E. Edmondson Department of Biochemistry Emory University 1510 Clifton Road Atlanta GA 30322 USA Fax 1 404 727 2738 Tel 1 404 727 5972 E-mail deedmon@emory.edu Present address Department of Chemistry Princeton University Princeton NJ 08544 USA. Received 23 August 2011 revised 29 September 2011 accepted 30 September 2011 doi 10.1111 j.1742-4658.2011.08386.x The major structural difference between human monoamine oxidases A MAO A and B MAO B is that MAO A has a monopartite substrate cavity of 550 A3 volume and MAO B contains a dipartite cavity structure with volumes of 290 A3 entrance cavity and 400 A3 substrate cavity . Ile199 and Tyr326 side chains separate these two cavities in MAO B. To probe the function of these gating residues Ile199Ala and Ile199Ala-Tyr326Ala mutant forms of MAO B were investigated. Structural data on the Ile199Ala MAO B mutant show no alterations in active site geometries compared with wild-type enzyme while the Ile199Ala-Tyr326Ala MAO B mutant exhibits alterations in residues 100-103 which are part of the loop gating the entrance to the active site. Both mutant enzymes exhibit catalytic properties with increased amine KM but unaltered kcat values. The altered Km values on mutation are attributed to the influence of the cavity structure in the binding and subsequent deprotonation of the amine substrate. Both mutant enzymes exhibit weaker binding affinities relative to wild-type enzyme for small reversible .
