1QCO

CRYSTAL STRUCTURE OF FUMARYLACETOACETATE HYDROLASE COMPLEXED WITH FUMARATE AND ACETOACETATE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.159 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Crystal structure and mechanism of a carbon-carbon bond hydrolase.

Timm, D.E.Mueller, H.A.Bhanumoorthy, P.Harp, J.M.Bunick, G.J.

(1999) Structure 7: 1023-1033

  • DOI: https://doi.org/10.1016/s0969-2126(99)80170-1
  • Primary Citation of Related Structures:  
    1QCN, 1QCO, 1QQJ

  • PubMed Abstract: 

    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. 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. 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.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology Indiana University School of Medicine 635 Barnhill Drive, Indianapolis, Indiana 46202, USA. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FUMARYLACETOACETATE HYDROLASE
A, B
423Mus musculusMutation(s): 0 
EC: 3.7.1.2
UniProt & NIH Common Fund Data Resources
Find proteins for P35505 (Mus musculus)
Explore P35505 
Go to UniProtKB:  P35505
IMPC:  MGI:95482
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35505
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FUM
Query on FUM

Download Ideal Coordinates CCD File 
E [auth A],
L [auth B]
FUMARIC ACID
C4 H4 O4
VZCYOOQTPOCHFL-OWOJBTEDSA-N
AAE
Query on AAE

Download Ideal Coordinates CCD File 
F [auth A],
M [auth B]
ACETOACETIC ACID
C4 H6 O3
WDJHALXBUFZDSR-UHFFFAOYSA-N
NI
Query on NI

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B],
I [auth B],
J [auth B],
K [auth B]
NICKEL (II) ION
Ni
VEQPNABPJHWNSG-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.159 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.64α = 90
b = 110.94β = 102.52
c = 67.81γ = 90
Software Package:
Software NamePurpose
AMoREphasing
X-PLORrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2000-06-07
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2022-12-21
    Changes: Database references, Derived calculations
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection