Crystal structure and mechanistic analysis of a novel human kynurenine aminotransferase-2 reversible inhibitor

NS-1502 is a reversible inhibitor of human kynurenine aminotransferase-2 (hKAT-2), which is implicated in a number of central nervous system disorders. Although direct inhibition of KAT isozymes has been reported as an approach to manage neurodegenerative and cognitive impairments, the binding mechanism of the reversible inhibitors has not yet been established. To this end the crystal structure of hKAT-2 in complex with NS-1502 was determined at 1.81 A resolution. In addition, an examination of its reversibility using matrix assisted laser desorption ionization time-of-flight MS as a technique for comparing NS-1502 binding with a known potent irreversible KAT-2 inhibitor, PF-04859989, was conducted. Furthermore, the examination of the antagonist activity of NS-1502 towards the glycine site of N-methyl-d-aspartate receptors showed an IC50 of 7.61 μM, suggesting it can possess neuroprotective properties. The structure of hKAT-2 in complex with this reversible inhibitor defines the active site residues that play key roles in the binding interactions.