Abstract
Homogentisate dioxygenase (HGO) cleaves the aromatic ring during the metabolic degradation of Phe and Tyr. HGO deficiency causes alkaptonuria (AKU), the first human disease shown to be inherited as a recessive Mendelian trait. Crystal structures of apo-HGO and HGO containing an iron ion have been determined at 1.9 and 2.3 Å resolution, respectively. The HGO protomer, which contains a 280-residue N-terminal domain and a 140-residue C-terminal domain, associates as a hexamer arranged as a dimer of trimers. The active site iron ion is coordinated near the interface between subunits in the HGO trimer by a Glu and two His side chains. HGO represents a new structural class of dioxygenases. The largest group of AKU associated missense mutations affect residues located in regions of contact between subunits.
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Acknowledgements
We thank L.-J. Baker, J. Hamilton, T. Hurley and E. Harper for useful comments and discussion. We thank N. Steussy and H. Belamy for assistance collecting MAD data on the Stanford Synchrotron Radiation Laboratory beamline 1-5. This work was supported by the NIH, the Midwest Affiliate of the American Heart Association, and by the Spanish Comisión Interministerial de Ciencia y Tecnología and the Comunidad Autónoma de Madrid.
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Titus, G., Mueller, H., Burgner, J. et al. Crystal structure of human homogentisate dioxygenase. Nat Struct Mol Biol 7, 542–546 (2000). https://doi.org/10.1038/76756
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DOI: https://doi.org/10.1038/76756
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