Kynurenine Aminotransferase Isozyme Inhibitors: A Review.
Kynurenine aminotransferase isozymes (KATs 1-4) are members of the pyridoxal-5'-phosphate (PLP)-dependent enzyme family, which catalyse the permanent conversion of l-kynurenine (l-KYN) to kynurenic acid (KYNA), a known neuroactive agent. As KATs are found in the mammalian brain and have key roles in the kynurenine pathway, involved in different categories of central nervous system (CNS) diseases, the KATs are prominent targets in the quest to treat neurodegenerative and cognitive impairment disorders. Recent studies suggest that inhibiting these enzymes would produce effects beneficial to patients with these conditions, as abnormally high levels of KYNA are observed. KAT-1 and KAT-3 share the highest sequence similarity of the isozymes in this family, and their active site pockets are also similar. Importantly, KAT-2 has the major role of kynurenic acid production (70%) in the human brain, and it is considered therefore that suitable inhibition of this isozyme would be most effective in managing major aspects of CNS diseases. Human KAT-2 inhibitors have been developed, but the most potent of them, chosen for further investigations, did not proceed in clinical studies due to the cross toxicity caused by their irreversible interaction with PLP, the required cofactor of the KAT isozymes, and any other PLP-dependent enzymes. As a consequence of the possibility of extensive undesirable adverse effects, it is also important to pursue KAT inhibitors that reversibly inhibit KATs and to include a strategy that seeks compounds likely to achieve substantial interaction with regions of the active site other than the PLP. The main purpose of this treatise is to review the recent developments with the inhibitors of KAT isozymes. This treatise also includes analyses of their crystallographic structures in complex with this enzyme family, which provides further insight for researchers in this and related studies.
Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. anem7250@uni.sydney.edu.au.
Alireza
A
Nematollahi
Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. gsun2866@uni.sydney.edu.au.
Guanchen
G
Sun
Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. gjay8197@uni.sydney.edu.au.
Gayan S
GS
Jayawickrama
Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. bret.church@sydney.edu.au.
W Bret
WB
Church
D000818:Animals; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D004791:Enzyme Inhibitors; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase
KYNA; cognitive disorders; kynurenine aminotransferase; pyridoxal 5′-phosphate; schizophrenia