title: Molecular Insights into Human Monoamine Oxidase B Inhibition by the Glitazone Anti-Diabetes Drugs.
abstract: The widely employed anti-diabetic drug pioglitazone (Actos) is shown to be a specific and reversible inhibitor of human monoamine oxidase B (MAO B). The crystal structure of the enzyme-inhibitor complex shows the R-enantiomer is bound with the thiazolidinedione ring near the flavin. The molecule occupies both substrate and entrance cavities of the active site establishing non-covalent interactions with the surrounding amino acids. These binding properties differentiate pioglitazone from the clinically used MAO inhibitors, which act through covalent inhibition mechanisms and do not exhibit a high degree of MAO A versus B selectivity. Rosiglitazone (Avandia) and troglitazone, other members of the glitazone class, are less selective in that they are weaker inhibitors of both MAO A and MAO B These results suggest that pioglitazone may have utility as a "re-purposed" neuro-protectant drug in retarding the progression of disease in Parkinson's patients. They also provide new insights for the development of reversible isoenzyme-specific MAO inhibitors.
authors.affiliation: Department of Genetics and Microbiology, University of Pavia, 27100 Pavia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Binda
authors.forename: Milagros
authors.initials: M
authors.lastname: Aldeco
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Marcello
authors.initials: M
authors.lastname: Tortorici
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.forename: Dale E
authors.initials: DE
authors.lastname: Edmondson