3UE8

Kynurenine Aminotransferase II Inhibitors

3UE8 の概要

• エントリーDOI: 10.2210/pdb3ue8/pdb
• 分子名称: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial, (5-hydroxy-4-{[(1-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)amino]methyl}-6-methylpyridin-3-yl)methyl dihydrogen phosphate, CHLORIDE ION (3 entities in total)
• 機能のキーワード: kat ii, kynurenine aminotransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion : Q8N5Z0
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99050.14

構造登録者

Dounay, A.B.,Anderson, M.,Bechle, B.M.,Campbell, B.M.,Claffey, M.M.,Evdokimov, A.,Edelweiss, E.,Fonseca, K.R.,Gan, X.,Ghosh, S.,Hayward, M.M.,Horner, W.,Kim, J.Y.,McAllister, L.A.,Pandit, J.,Paradis, V.,Parikh, V.D.,Reese, M.R.,Rong, S.B.,Salafia, M.A.,Schuyten, K.,Strick, C.A.,Tuttle, J.B.,Valentine, J.,Wang, H.,Zawadzke, L.E.,Verhoest, P.R. (登録日: 2011-10-28, 公開日: 2012-02-01, 最終更新日: 2024-02-28)

主引用文献

Dounay, A.B.,Anderson, M.,Bechle, B.M.,Campbell, B.M.,Claffey, M.M.,Evdokimov, A.,Evrard, E.,Fonseca, K.R.,Gan, X.,Ghosh, S.,Hayward, M.M.,Horner, W.,Kim, J.Y.,McAllister, L.A.,Pandit, J.,Paradis, V.,Parikh, V.D.,Reese, M.R.,Rong, S.,Salafia, M.A.,Schuyten, K.,Strick, C.A.,Tuttle, J.B.,Valentine, J.,Wang, H.,Zawadzke, L.E.,Verhoest, P.R.
Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.
ACS Med Chem Lett, 3:187-192, 2012

PubMed Abstract: Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

PubMed: 24900455
DOI: 10.1021/ml200204m

実験手法

X-RAY DIFFRACTION (3.22 Å)