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Crystal structures of human 3-hydroxyanthranilate 3,4-dioxygenase with native and non-native metal bound in the active site

Published

Author(s)

John L. Molloy, Swarna Lakshmi, Tin L. Wong, Heather Neu, Sarah Michel, Eric A. Toth

Abstract

3-hydroxyanthranilate 3,4-dioxygenase (3HAO) is an enzyme in the microglial branch of the kynurenine pathway of tryptophan degradation. 3HAO is a non-heme iron-containing, ring-cleaving extradiol dioxygenase that catalyzes addition of both atoms of O2 to the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3-HANA) to form quinolinic acid (QUIN). QUIN is a highly potent excitotoxin that has been implicated in a number of neurodegenerative conditions, making 3HAO a target for pharmacologic downregulation. Here we present the first crystal structure of human 3HAO with the native iron bound in its active site and an additional structure with zinc (a known inhibitor of human 3HAO) bound in the active site. We examine the metal binding environment both structurally and via inductively coupled plasma mass spectrometry (ICP-MS), X-ray fluorescence spectroscopy (XRF), and electron paramagnetic resonance spectroscopy (EPR). Our studies also identified Met35 as the source of potential new interactions with substrates and inhibitors, which may prove useful in future therapeutic efforts.
Citation
ACTA Crystallographica Section D-Biological Crystallography
Volume
73

Citation

Molloy, J. , Lakshmi, S. , Wong, T. , Neu, H. , Michel, S. and Toth, E. (2017), Crystal structures of human 3-hydroxyanthranilate 3,4-dioxygenase with native and non-native metal bound in the active site, ACTA Crystallographica Section D-Biological Crystallography, [online], https://doi.org/10.1107/S2059798317002029 (Accessed June 22, 2024)

Issues

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Created April 1, 2017, Updated November 10, 2018