PDBsum entry 1qcn

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
Protein chains
417 a.a. *
ACT ×4
_CA ×2
Waters ×604
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of fumarylacetoacetate hydrolase
Structure: Fumarylacetoacetate hydrolase. Chain: a, b. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
1.90Å     R-factor:   0.191     R-free:   0.220
Authors: D.E.Timm,H.A.Mueller,P.Bhanumoorthy,J.M.Harp,G.J.Bunick
Key ref:
D.E.Timm et al. (1999). Crystal structure and mechanism of a carbon-carbon bond hydrolase. Structure, 7, 1023-1033. PubMed id: 10508789 DOI: 10.1016/S0969-2126(99)80170-1
14-May-99     Release date:   07-Jun-00    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P35505  (FAAA_MOUSE) -  Fumarylacetoacetase
419 a.a.
417 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.  - Fumarylacetoacetase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 4-fumarylacetoacetate + H2O = acetoacetate + fumarate
+ H(2)O
Bound ligand (Het Group name = ACT)
matches with 57.00% similarity
+ fumarate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular vesicular exosome   1 term 
  Biological process     metabolic process   5 terms 
  Biochemical function     catalytic activity     4 terms  


DOI no: 10.1016/S0969-2126(99)80170-1 Structure 7:1023-1033 (1999)
PubMed id: 10508789  
Crystal structure and mechanism of a carbon-carbon bond hydrolase.
D.E.Timm, H.A.Mueller, P.Bhanumoorthy, J.M.Harp, G.J.Bunick.
BACKGROUND: Fumarylacetoacetate hydrolase (FAH) catalyzes the final step of tyrosine and phenylalanine catabolism, the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate, to yield fumarate and acetoacetate. FAH has no known sequence homologs and functions by an unknown mechanism. Carbon-carbon hydrolysis reactions are essential for the human metabolism of aromatic amino acids. FAH deficiency causes the fatal metabolic disease hereditary tyrosinemia type I. Carbon-carbon bond hydrolysis is also important in the microbial metabolism of aromatic compounds as part of the global carbon cycle. RESULTS: The FAH crystal structure has been determined by rapid, automated analysis of multiwavelength anomalous diffraction data. The FAH polypeptide folds into a 120-residue N-terminal domain and a 300-residue C-terminal domain. The C-terminal domain defines an unusual beta-strand topology and a novel 'mixed beta-sandwich roll' structure. The structure of FAH complexed with its physiological products was also determined. This structure reveals fumarate binding near the entrance to the active site and acetoacetate binding to an octahedrally coordinated calcium ion located in close proximity to a Glu-His dyad. CONCLUSIONS: FAH represents the first structure of a hydrolase that acts specifically on carbon-carbon bonds. FAH also defines a new class of metalloenzymes characterized by a unique alpha/beta fold. A mechanism involving a Glu-His-water catalytic triad is suggested based on structural observations, sequence conservation and mutational analysis. The histidine imidazole group is proposed to function as a general base. The Ca(2+) is proposed to function in binding substrate, activating the nucleophile and stabilizing a carbanion leaving group. An oxyanion hole formed from sidechains is proposed to stabilize a tetrahedral alkoxide transition state. The proton transferred to the carbanion leaving group is proposed to originate from a lysine sidechain. The results also reveal the molecular basis for mutations causing the hereditary tyrosinemia type 1.
  Selected figure(s)  
Figure 2.
Figure 2. FAH structure, topology and HT1-associated mutations. (a) A stereo ribbon diagram illustrating the FAH subunit structure and position of point mutations causing hereditary tyrosinemia type I is shown. The N-terminal domain is located at the bottom of the figure. The mixed b-sandwich roll structure is centrally located in the figure. Helices are colored red; b strands are colored in shades of blue corresponding to the b sheet they form; the positions of point mutations are represented by green spheres; a calcium ion is colored yellow; acetate carbon and oxygen atoms are respectively colored orange and red (top of figure). (b) A topology diagram of the novel FAH b-strand arrangement is shown. b Strands are numbered in red according to their sequential occurrence in the polypeptide chain; residue numbering is in black. Sheets A, B and C are respectively colored in dark, light and medium shades of blue, as in (a). a Helices are represented by red rectangles. Figure 2, Figure 3 and Figure 4 and Figure 6b were generated using MOLSCRIPT [40].
  The above figure is reprinted by permission from Cell Press: Structure (1999, 7, 1023-1033) copyright 1999.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19811085 M.Duhalde-Vega, J.L.Aparicio, and L.A.Retegui (2009).
Fine specificity of autoantibodies induced by mouse hepatitis virus A59.
  Viral Immunol, 22, 287-294.  
19187228 S.Watanabe, and K.Makino (2009).
Novel modified version of nonphosphorylated sugar metabolism--an alternative L-rhamnose pathway of Sphingomonas sp.
  FEBS J, 276, 1554-1567.  
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.  
  17768357 H.Mizutani, and N.Kunishima (2007).
Purification, crystallization and preliminary X-ray analysis of the fumarylacetoacetase family member TTHA0809 from Thermus thermophilus HB8.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 792-794.  
16704972 M.De, J.Bell, N.J.Blackburn, R.E.Mains, and B.A.Eipper (2006).
Role for an essential tyrosine in peptide amidation.
  J Biol Chem, 281, 20873-20882.  
15638932 N.Dreumont, A.Maresca, J.F.Boisclair-Lachance, A.Bergeron, and R.M.Tanguay (2005).
A minor alternative transcript of the fumarylacetoacetate hydrolase gene produces a protein despite being likely subjected to nonsense-mediated mRNA decay.
  BMC Mol Biol, 6, 1.  
15551868 B.A.Manjasetty, F.H.Niesen, H.Delbrück, F.Götz, V.Sievert, K.Büssow, J.Behlke, and U.Heinemann (2004).
X-ray structure of fumarylacetoacetate hydrolase family member Homo sapiens FLJ36880.
  Biol Chem, 385, 935-942.
PDB code: 1saw
15310761 I.Fujii, Y.Yasuoka, H.F.Tsai, Y.C.Chang, K.J.Kwon-Chung, and Y.Ebizuka (2004).
Hydrolytic polyketide shortening by ayg1p, a novel enzyme involved in fungal melanin biosynthesis.
  J Biol Chem, 279, 44613-44620.  
15020593 N.Leulliot, S.Quevillon-Cheruel, I.Sorel, M.Graille, P.Meyer, D.Liger, K.Blondeau, J.Janin, and H.van Tilbeurgh (2004).
Crystal structure of yeast allantoicase reveals a repeated jelly roll motif.
  J Biol Chem, 279, 23447-23452.
PDB code: 1sg3
15324930 P.A.Mathieu, K.A.Gómez, J.P.Coutelier, and L.A.Retegui (2004).
Sequence similarity and structural homologies are involved in the autoimmune response elicited by mouse hepatitis virus A59.
  J Autoimmun, 23, 117-126.  
14506266 J.K.McIninch, J.D.McIninch, and S.W.May (2003).
Catalysis, stereochemistry, and inhibition of ureidoglycolate lyase.
  J Biol Chem, 278, 50091-50100.  
12203990 J.A.Arranz, F.Piñol, L.Kozak, C.Pérez-Cerdá, B.Cormand, M.Ugarte, and E.Riudor (2002).
Splicing mutations, mainly IVS6-1(G>T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients.
  Hum Mutat, 20, 180-188.  
11863436 J.R.Tame, K.Namba, E.J.Dodson, and D.I.Roper (2002).
The crystal structure of HpcE, a bifunctional decarboxylase/isomerase with a multifunctional fold.
  Biochemistry, 41, 2982-2989.
PDB codes: 1gtt 1i7o
11418771 D.G.Levitt (2001).
A new software routine that automates the fitting of protein X-ray crystallographic electron-density maps.
  Acta Crystallogr D Biol Crystallogr, 57, 1013-1019.  
11476670 N.Dreumont, J.A.Poudrier, A.Bergeron, H.L.Levy, F.Baklouti, and R.M.Tanguay (2001).
A missense mutation (Q279R) in the fumarylacetoacetate hydrolase gene, responsible for hereditary tyrosinemia, acts as a splicing mutation.
  BMC Genet, 2, 9.  
11006535 S.E.Ealick (2000).
Advances in multiple wavelength anomalous diffraction crystallography.
  Curr Opin Chem Biol, 4, 495-499.  
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.