PDBsum entry: 1eyb

Oxidoreductase

PDB id: 1eyb

Contents

Protein chain

419 a.a. *

Waters ×483

* Residue conservation analysis

PDB id:

1eyb

Name:

Oxidoreductase

Title:

Crystal structure of apo human homogentisate dioxygenase

Structure:

Homogentisate 1,2-dioxygenase. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: liver. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Hexamer (from PDB file)

Resolution:

1.90Å R-factor: 0.192 R-free: 0.222

Authors:

D.E.Timm,G.P.Titus,M.A.Penalva,H.A.Mueller,S.M.De Cordoba

Key ref:

G.P.Titus et al. (2000). Crystal structure of human homogentisate dioxygenase. Nat Struct Biol, 7, 542-546. PubMed id: 10876237 DOI: 10.1038/76756

Date:

05-May-00 Release date: 05-Nov-00

Protein chain

Q93099  (HGD_HUMAN) -  Homogentisate 1,2-dioxygenase

Seq: 445 a.a.

Struc: 419 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.1.13.11.5 - Homogentisate 1,2-dioxygenase.
• Reaction: Homogentisate + O₂ = 4-maleylacetoacetate
• Cofactor: Iron

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: cytosol (1 term)
• Biological process: oxidation-reduction process (6 terms)
• Biochemical function: oxidoreductase activity (4 terms)

reference

DOI no: 10.1038/76756

Nat Struct Biol 7:542-546 (2000)

PubMed id: 10876237

Crystal structure of human homogentisate dioxygenase.

G.P.Titus, H.A.Mueller, J.Burgner, S.Rodríguez De Córdoba, M.A.Peñalva, D.E.Timm.

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.

Selected figure(s)

Figure 2.
Figure 2. AKU associated mutations and the HGO quaternary structure. a, Stereo ribbon diagram of the HGO protomer with the central -sandwich colored in dark blue, the C-terminal active site domain in green and the strands of the intersubunit -sheet in light blue. The positions of 20 mutations causing AKU are indicated by the numbered side chains shown in red (see refs 6, 7, 8, 9, 10 and citations therein). The view is similar to that of Fig. 1b, with the position of the active site is indicated by the H371 label. The knot between N-terminal and C-terminal domains occurs near Trp 97. A dashed line indicates the inferred path of a disordered section of polypeptide between residues 418 and 430. b, The HGO trimer is viewed along a three-fold axis. The positions of side chains affected by the AKU mutations L25P, E42A, W60G, Y62C, A122D, E168K, I216T, R225H, D291E, M368V, and H317R are indicated by side chains modeled as ball and sticks. These mutations affect residues located in the interfaces between subunits in the HGO hexamer. The foreground surface forms the interface between trimers in the HGO hexamer. Residues Leu 25, Trp 60, Ile 216, Arg 225 and Asp 291 have solvent accessible surface areas that decrease by 40, 90, 100, 85 and 85%, respectively, in the hexamer relative to the trimer. Individual subunits are colored light blue with red side chains, dark blue with light blue side chains and red with dark blue side chains. The iron cofactor in each subunit is drawn as a green sphere. c, Analytical ultracentrifugation data. Absorbance distribution profiles (Abs[obs]) for HGO at 0.7 M subunit concentration equilibrated at 4,000, 6,000, and 8,500, r.p.m. are shown with solid lines representing values derived from the global fit of data obtained at three rotor speeds and two protein concentrations (A[calc]). Samples were equilibrated for 28 -36 h at each rotor speed with approach to equilibrium monitored every 4 h. Residuals of the fit are shown inset above (A[diff]).

Figure 4.
Figure 4. The HGO catalytic mechanism. Key steps in the proposed catalytic mechanism for HGO are shown with the flow of electrons indicated by arrows. The mechanism is a modified version of those previously proposed for gentisate dioxygenase^11, 12.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2000, 7, 542-546) copyright 2000.

Figures were selected by an automated process.