title: 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 A 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Titus
authors.forename: H A
authors.initials: HA
authors.lastname: Mueller
authors.forename: J
authors.initials: J
authors.lastname: Burgner
authors.forename: S
authors.initials: S
authors.lastname: Rodríguez De Córdoba
authors.forename: M A
authors.initials: MA
authors.lastname: Peñalva
authors.forename: D E
authors.initials: DE
authors.lastname: Timm
mesh_terms: D000474:Alkaptonuria / Q000201:enzymology* / Q000235:genetics; D001051:Apoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D019281:Dimerization; D049308:Dioxygenases; D050560:Homogentisate 1,2-Dioxygenase; D006801:Humans; D007501:Iron / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D001051:Apoenzymes; D007501:Iron; D010105:Oxygenases; D049308:Dioxygenases; D050560:Homogentisate 1,2-Dioxygenase