4GE4

Kynurenine Aminotransferase II Inhibitors

Summary for 4GE4

• Entry DOI: 10.2210/pdb4ge4/pdb
• Related: 3UE8 4GDY 4GE7 4GE9 4GEB
• Descriptor: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial, (5-hydroxy-4-{[(1-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)amino]methyl}-6-methylpyridin-3-yl)methyl dihydrogen phosphate (3 entities in total)
• Functional Keywords: aminotransferase, irreversible inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion (Potential): Q8N5Z0
• Total number of polymer chains: 2
• Total formula weight: 98774.83

Authors

Pandit, J. (deposition date: 2012-08-01, release date: 2012-11-07, Last modification date: 2023-09-13)

Primary citation

Tuttle, J.B.,Anderson, M.,Bechle, B.M.,Campbell, B.M.,Chang, C.,Dounay, A.B.,Evrard, E.,Fonseca, K.R.,Gan, X.,Ghosh, S.,Horner, W.,James, L.C.,Kim, J.Y.,McAllister, L.A.,Pandit, J.,Parikh, V.D.,Rago, B.J.,Salafia, M.A.,Strick, C.A.,Zawadzke, L.E.,Verhoest, P.R.
Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions.
ACS Med Chem Lett, 4:37-40, 2013

PubMed Abstract: A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure-activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact/K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.

PubMed: 24900560
DOI: 10.1021/ml300237v

Experimental method

X-RAY DIFFRACTION (2.41 Å)