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Neurology supplements are not peer-reviewed. Information contained in Neurology supplements represent the opinions of the authors and are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology.

Structure of the human mitochondrial monoamine oxidase B

New chemical implications for neuroprotectant drug design

From the Departments of Biochemistry and Chemistry, Emory University, Atlanta, Georgia (F.H., M.L., D.E.E.), Department of Genetics and Microbiology, University of Pavia, Italy (C.B., A.M.), and Department of Chemistry, Virginia Tech, Blacksburg, Virginia (N.C.).

Address correspondence and reprint requests to Dr. Andrea Mattevi, Department of Genetics and Microbiology, University of Pavia, via Abbiategrasso 207, Pavia, 27100 Italy; e-mail: mattevi{at}ipvgen.unipv.it

Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound flavoenzyme that is a well-known target for antidepressant and neuroprotective drugs. The 3Å resolution structure of recombinant human MAO-B originally determined was of the enzyme complexed with pargyline, an irreversible inhibitor covalently bound to the N5 atom of the flavin coenzyme. The crystal structure shows that the enzyme is dimeric. Each monomer binds to the membrane via a C-terminal transmembrane helix and by apolar loops located at various positions in the sequence. Substrate binding to the enzyme involves negotiating a loop covering a 290ų entrance apolar cavity before reaching an apolar 420ų substrate cavity where the flavin coenzyme is located. The 1.7Å isatin–MAO-B structure allowed a detailed examination of the enzyme’s active site. A novel specific reversible MAO-B inhibitor, which is found as a contaminant in polystyrene plastics (1,4-diphenyl-2-butene), binds in both the entrance and the substrate cavity. Analogous MAO-B-specific inhibitors that bind in a manner traversing both cavities include trans-trans farnesol and chlorostyrylcaffeine. The rotation of the Ile199 side chain to an "open" conformation plays an essential role in this specificity. These results form a molecular basis for the design of new human MAO-B-specific reversible inhibitors.

This work was supported by grants from the National Institute of General Medical Sciences (GM-29433) and the MIUR (FIRB and COFIN04). C.B. received support from Collegio Ghislieri, Pavia.

Publication of this supplement was supported by a grant from Newron Pharmaceuticals.

Disclosure: A.M. has received grant support from the sponsor during his career. C.B., F.H., M.L., N.C., and D.E.E. have not reported conflicts with the sponsor.

Neurology supplements are not peer-reviewed. Information contained in Neurology supplements represents the opinions of the authors and is not endorsed by nor does it reflect the views of the American Academy of Neurology, Editorial Board, Editor-in-Chief, or Associate Editors of Neurology.