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Crystal structures of human 3‐hydroxyanthranilate 3,4‐dioxygenase with native and non‐native metals bound in the active site
Author(s) -
Pidugu Lakshmi Swarna Mukhi,
Neu Heather,
Wong Tin Lok,
Pozharski Edwin,
Molloy John L.,
Michel Sarah L. J.,
Toth Eric A.
Publication year - 2017
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.374
H-Index - 138
ISSN - 2059-7983
DOI - 10.1107/s2059798317002029
Subject(s) - chemistry , active site , dioxygenase , kynurenine pathway , electron paramagnetic resonance , tryptophan , metabolite , stereochemistry , heme , quinolinic acid , kynurenine , binding site , fluorescence spectroscopy , biochemistry , enzyme , fluorescence , amino acid , nuclear magnetic resonance , physics , quantum mechanics
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 the addition of both atoms of O 2 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 pharmacological downregulation. Here, the first crystal structure of human 3HAO with the native iron bound in its active site is presented, together with an additional structure with zinc (a known inhibitor of human 3HAO) bound in the active site. The metal‐binding environment is examined both structurally and via inductively coupled plasma mass spectrometry (ICP‐MS), X‐ray fluorescence spectroscopy (XRF) and electron paramagnetic resonance spectroscopy (EPR). The studies identified Met35 as the source of potential new interactions with substrates and inhibitors, which may prove useful in future therapeutic efforts.