Crystal structure of human homogentisate dioxygenase

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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Figure 1: Electron density and Cα trace for HGO.
Figure 2: AKU associated mutations and the HGO quaternary structure.
Figure 3: Side chains close to the active site of HGO.
Figure 4: The HGO catalytic mechanism.

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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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Correspondence to David E. Timm.

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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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