Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2514–2519 | Cite as

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

Original Research
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Abstract

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 Å 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.

Keywords

Kynurenine aminotransferase-2 Enzyme structure Reversible inhibitor Glycine-site NMDA CNS diseases 

Notes

Acknowledgements

Authors acknowledge the University of Sydney Postgraduate Research Awards (AN) to conduct this study and Dr. Nick Proschogo, Mass Spectroscopy Facility, School of Chemistry, University of Sydney for advice and discussions. Also authors would like to acknowledge Dr. Alan Riboldi-Tunnicliffe at the Australian Synchrotron MX2 for assistance with collecting the crystallographic data. The authors also acknowledge the support received from the Bosch Institute’s Molecular Biology Facility, and the expert help of Facility staff, especially Dr. Donna L ai and Dr. Sheng Hua on using the Biacore T200 system.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Group in Biomolecular Structure and Informatics, Faculty of PharmacyUniversity of SydneyCamperdownAustralia
  2. 2.Faculty of PharmacyUniversity of SydneyCamperdownAustralia

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