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Published online before print March 7, 2006, 10.1110/ps.051967906
Protein Science (2006), 15:761-773. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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Crystal structure of 3-hydroxyanthranilic acid 3,4-dioxygenase from Saccharomyces cerevisiae: A special subgroup of the type III extradiol dioxygenases

Xiaowu Li1,2, Min Guo1,2, Jun Fan1,2, Wenying Tang1,2, Deqiang Wang1,2, Honghua Ge1,2, Hui Rong1,2, Maikun Teng1,2, Liwen Niu1,2, Qun Liu3 and Quan Hao3

1 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China, Hefei, Anhui 230027, China
2 Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230027, China
3 MacCHESS, Cornell High Energy Synchrotron Source, Cornell University, Ithaca, New York 14853, USA

(RECEIVED November 13, 2005; FINAL REVISION December 7, 2005; ACCEPTED December 13, 2005)

3-Hydroxyanthranilic acid 3,4-dioxygenase (3HAO) is a non-heme ferrous extradiol dioxygenase in the kynurenine pathway from tryptophan. It catalyzes the conversion of 3-hydroxyanthranilate (HAA) to quinolinic acid (QUIN), an endogenous neurotoxin, via the activation of N-methyl-D-aspartate (NMDA) receptors and the precursor of NAD+ biosynthesis. The crystal structure of 3HAO from S. cerevisiae at 2.4 Å resolution shows it to be a member of the functionally diverse cupin superfamily. The structure represents the first eukaryotic 3HAO to be resolved. The enzyme forms homodimers, with two nickel binding sites per molecule. One of the bound nickel atoms occupies the proposed ferrous-coordinated active site, which is located in a conserved double-strand beta-helix domain. Examination of the structure reveals the participation of a series of residues in catalysis different from other extradiol dioxygenases. Together with two iron-binding residues (His49 and Glu55), Asp120, Asn51, Glu111, and Arg114 form a hydrogen-bonding network; this hydrogen-bond network is key to the catalysis of 3HAO. Residues Arg101, Gln59, and the substrate-binding hydrophobic pocket are crucial for substrate specificity. Structure comparison with 3HAO from Ralstonia metallidurans reveals similarities at the active site and suggests the same catalytic mechanism in prokaryotic and eukaryotic 3HAO. Based on sequence comparison, we suggest that bicupin of human 3HAO is the first example of evolution from a monocupin dimer to bicupin monomer in the diverse cupin superfamilies. Based on the model of the substrate HAA at the active site of Y3HAO, we propose a mechanism of catalysis for 3HAO.

Keywords: X-ray crystallography; kynurenine pathway; extradiol dioxygenase; cupin superfamily; 2-His-1-carboxylate facial triad; MAD; 3-hydroxyanthranilic acid 3,4-dioxygenase


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