PDBsum entry 1ey2

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protein metals links
Oxidoreductase PDB id
Protein chain
419 a.a. *
Waters ×232
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Human homogentisate dioxygenase with fe(ii)
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)
2.30Å     R-factor:   0.193     R-free:   0.242
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
05-May-00     Release date:   05-Nov-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q93099  (HGD_HUMAN) -  Homogentisate 1,2-dioxygenase
445 a.a.
419 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Homogentisate 1,2-dioxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Homogentisate + O2 = 4-maleylacetoacetate
+ O(2)
= 4-maleylacetoacetate
      Cofactor: Fe cation
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular vesicular exosome   2 terms 
  Biological process     small molecule metabolic process   7 terms 
  Biochemical function     oxidoreductase activity     4 terms  


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.
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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21458406 M.Wang, Y.Wang, J.Wang, L.Lin, H.Hong, and D.Wang (2011).
Proteome profiles in medaka (Oryzias melastigma) liver and brain experimentally exposed to acute inorganic mercury.
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21246129 N.Anitha, and M.Palaniandavar (2011).
Mononuclear iron(III) complexes of 3N ligands in organized assemblies: spectral and redox properties and attainment of regioselective extradiol dioxygenase activity.
  Dalton Trans, 40, 1888-1901.  
19478949 G.Agarwal, M.Rajavel, B.Gopal, and N.Srinivasan (2009).
Structure-based phylogeny as a diagnostic for functional characterization of proteins with a cupin fold.
  PLoS One, 4, e5736.  
19300822 M.Brivio, J.Schlosrich, M.Ahmad, C.Tolond, and T.D.Bugg (2009).
Investigation of acid-base catalysis in the extradiol and intradiol catechol dioxygenase reactions using a broad specificity mutant enzyme and model chemistry.
  Org Biomol Chem, 7, 1368-1373.  
19888216 Q.Zhong, N.Simonis, Q.R.Li, B.Charloteaux, F.Heuze, N.Klitgord, S.Tam, H.Yu, K.Venkatesan, D.Mou, V.Swearingen, M.A.Yildirim, H.Yan, A.Dricot, D.Szeto, C.Lin, T.Hao, C.Fan, S.Milstein, D.Dupuy, R.Brasseur, D.E.Hill, M.E.Cusick, and M.Vidal (2009).
Edgetic perturbation models of human inherited disorders.
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19754880 S.Leitgeb, G.D.Straganz, and B.Nidetzky (2009).
Functional characterization of an orphan cupin protein from Burkholderia xenovorans reveals a mononuclear nonheme Fe2+-dependent oxygenase that cleaves beta-diketones.
  FEBS J, 276, 5983-5997.  
19862842 T.Vilboux, M.Kayser, W.Introne, P.Suwannarat, I.Bernardini, R.Fischer, K.O'Brien, R.Kleta, M.Huizing, and W.A.Gahl (2009).
Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.
  Hum Mutat, 30, 1611-1619.  
18227072 A.L.Fisher, K.E.Page, G.J.Lithgow, and L.Nash (2008).
The Caenorhabditis elegans K10C2.4 gene encodes a member of the fumarylacetoacetate hydrolase family: a Caenorhabditis elegans model of type I tyrosinemia.
  J Biol Chem, 283, 9127-9135.  
18850300 C.R.Scriver (2008).
Garrod's Croonian Lectures (1908) and the charter 'Inborn Errors of Metabolism': albinism, alkaptonuria, cystinuria, and pentosuria at age 100 in 2008.
  J Inherit Metab Dis, 31, 580-598.  
19050788 K.Sundaravel, T.Dhanalakshmi, E.Suresh, and M.Palaniandavar (2008).
Synthesis, structure, spectra and reactivity of iron(III) complexes of facially coordinating and sterically hindering 3N ligands as models for catechol dioxygenases.
  Dalton Trans, (), 7012-7025.  
18502868 M.J.Moonen, N.M.Kamerbeek, A.H.Westphal, S.A.Boeren, D.B.Janssen, M.W.Fraaije, and W.J.van Berkel (2008).
Elucidation of the 4-hydroxyacetophenone catabolic pathway in Pseudomonas fluorescens ACB.
  J Bacteriol, 190, 5190-5198.  
18502867 M.J.Moonen, S.A.Synowsky, W.A.van den Berg, A.H.Westphal, A.J.Heck, R.H.van den Heuvel, M.W.Fraaije, and W.J.van Berkel (2008).
Hydroquinone dioxygenase from pseudomonas fluorescens ACB: a novel member of the family of nonheme-iron(II)-dependent dioxygenases.
  J Bacteriol, 190, 5199-5209.  
18019494 C.A.Joseph, and M.J.Maroney (2007).
Cysteine dioxygenase: structure and mechanism.
  Chem Commun (Camb), (), 3338-3349.  
17639604 M.A.Adams, M.D.Suits, J.Zheng, and Z.Jia (2007).
Piecing together the structure-function puzzle: experiences in structure-based functional annotation of hypothetical proteins.
  Proteomics, 7, 2920-2932.  
16492780 J.G.McCoy, L.J.Bailey, E.Bitto, C.A.Bingman, D.J.Aceti, B.G.Fox, and G.N.Phillips (2006).
Structure and mechanism of mouse cysteine dioxygenase.
  Proc Natl Acad Sci U S A, 103, 3084-3089.
PDB code: 2atf
16930152 M.A.Adams, V.K.Singh, B.O.Keller, and Z.Jia (2006).
Structural and biochemical characterization of gentisate 1,2-dioxygenase from Escherichia coli O157:H7.
  Mol Microbiol, 61, 1469-1484.
PDB code: 2d40
16920789 M.L.Neidig, A.Decker, O.W.Choroba, F.Huang, M.Kavana, G.R.Moran, J.B.Spencer, and E.I.Solomon (2006).
Spectroscopic and electronic structure studies of aromatic electrophilic attack and hydrogen-atom abstraction by non-heme iron enzymes.
  Proc Natl Acad Sci U S A, 103, 12966-12973.  
16522801 X.Li, M.Guo, J.Fan, W.Tang, D.Wang, H.Ge, H.Rong, M.Teng, L.Niu, Q.Liu, and Q.Hao (2006).
Crystal structure of 3-hydroxyanthranilic acid 3,4-dioxygenase from Saccharomyces cerevisiae: a special subgroup of the type III extradiol dioxygenases.
  Protein Sci, 15, 761-773.  
16077096 A.Teplyakov, G.Obmolova, J.Toedt, M.Y.Galperin, and G.L.Gilliland (2005).
Crystal structure of the bacterial YhcH protein indicates a role in sialic acid catabolism.
  J Bacteriol, 187, 5520-5527.
PDB code: 1s4c
15739104 K.D.Koehntop, J.P.Emerson, and L.Que (2005).
The 2-His-1-carboxylate facial triad: a versatile platform for dioxygen activation by mononuclear non-heme iron(II) enzymes.
  J Biol Inorg Chem, 10, 87-93.  
16317455 M.L.Neidig, and E.I.Solomon (2005).
Structure-function correlations in oxygen activating non-heme iron enzymes.
  Chem Commun (Camb), (), 5843-5863.  
15716432 T.Hansen, B.Schlichting, M.Felgendreher, and P.Schönheit (2005).
Cupin-type phosphoglucose isomerases (Cupin-PGIs) constitute a novel metal-dependent PGI family representing a convergent line of PGI evolution.
  J Bacteriol, 187, 1621-1631.  
15220336 J.P.Hintner, T.Reemtsma, and A.Stolz (2004).
Biochemical and molecular characterization of a ring fission dioxygenase with the ability to oxidize (substituted) salicylate(s) from Pseudaminobacter salicylatoxidans.
  J Biol Chem, 279, 37250-37260.  
12630963 A.Zatkova, A.Chmelikova, H.Polakova, E.Ferakova, and L.Kadasi (2003).
Rapid detection methods for five HGO gene mutations causing alkaptonuria.
  Clin Genet, 63, 145-149.  
12039004 M.J.Ryle, and R.P.Hausinger (2002).
Non-heme iron oxygenases.
  Curr Opin Chem Biol, 6, 193-201.  
12056897 R.Anand, P.C.Dorrestein, C.Kinsland, T.P.Begley, and S.E.Ealick (2002).
Structure of oxalate decarboxylase from Bacillus subtilis at 1.75 A resolution.
  Biochemistry, 41, 7659-7669.
PDB codes: 1j58 1l3j
12192069 S.Chakraborty, N.Chakraborty, D.Jain, D.M.Salunke, and A.Datta (2002).
Active site geometry of oxalate decarboxylase from Flammulina velutipes: Role of histidine-coordinated manganese in substrate recognition.
  Protein Sci, 11, 2138-2147.  
11546787 A.Tanner, L.Bowater, S.A.Fairhurst, and S.Bornemann (2001).
Oxalate decarboxylase requires manganese and dioxygen for activity. Overexpression and characterization of Bacillus subtilis YvrK and YoaN.
  J Biol Chem, 276, 43627-43634.  
11578928 T.D.Bugg (2001).
Oxygenases: mechanisms and structural motifs for O(2) activation.
  Curr Opin Chem Biol, 5, 550-555.  
  11017803 A.Zatková, Bernabé, H.Poláková, M.Zvarík, E.Feráková, V.Bosák, V.Ferák, L.Kádasi, and Córdoba (2000).
High frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple mutations in HGO involving different mutational hot spots.
  Am J Hum Genet, 67, 1333-1339.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.