title: Crystal structure-based selective targeting of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II for cognitive enhancement.
abstract: Fluctuations in the brain levels of the neuromodulator kynurenic acid may control cognitive processes and play a causative role in several catastrophic brain diseases. Elimination of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II reduces cerebral kynurenic acid synthesis and has procognitive effects. The present description of the crystal structure of human kynurenine aminotransferase II in complex with its potent and specific primary amine-bearing fluoroquinolone inhibitor (S)-(-)-9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid (BFF-122) should facilitate the structure-based development of cognition-enhancing drugs. From a medicinal chemistry perspective our results demonstrate that the issue of inhibitor specificity for highly conserved PLP-dependent enzymes could be successfully addressed.
authors.affiliation: University of Piemonte Orientale Amedeo Avogadro, Novara, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Rossi
authors.forename: Casazza
authors.initials: C
authors.lastname: Valentina
authors.forename: Silvia
authors.initials: S
authors.lastname: Garavaglia
authors.forename: Korrapati V
authors.initials: KV
authors.lastname: Sathyasaikumar
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Kojima
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okuwaki
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Ono
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kajii
authors.forename: Menico
authors.initials: M
authors.lastname: Rizzi
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D018360:Crystallography, X-Ray; D024841:Fluoroquinolones / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D018697:Nootropic Agents / Q000737:chemistry* / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D011732:Pyridoxal Phosphate / Q000502:physiology*; D013237:Stereoisomerism; D000637:Transaminases / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: C551951:9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid; D024841:Fluoroquinolones; D018697:Nootropic Agents; D010879:Piperazines; D011732:Pyridoxal Phosphate; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase