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PDBsum entry 1h7x

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protein ligands Protein-protein interface(s) links
Electron transfer PDB id
1h7x
Jmol
Contents
Protein chains
1016 a.a. *
Ligands
SF4 ×16
FMN ×4
FAD ×4
NDP ×4
URF ×4
Waters ×4289
* Residue conservation analysis
PDB id:
1h7x
Name: Electron transfer
Title: Dihydropyrimidine dehydrogenase (dpd) from pig, ternary complex of a mutant enzyme (c671a), NADPH and 5-fluorouracil
Structure: Dihydropyrimidine dehydrogenase. Chain: a, b, c, d. Synonym: dihydrouracil dehydrogenase, dihydrothymine dehydrogenase. Engineered: yes. Mutation: yes
Source: Sus scrofa. Wild boar. Organism_taxid: 9823. Cellular_location: cytoplasm. Gene: dpyd. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Homo-Dimer (from PDB file)
Resolution:
2.01Å     R-factor:   0.171     R-free:   0.192
Authors: D.Dobritzsch,G.Schneider,K.D.Schnackerz,Y.Lindqvist
Key ref:
D.Dobritzsch et al. (2001). Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil. EMBO J, 20, 650-660. PubMed id: 11179210 DOI: 10.1093/emboj/20.4.650
Date:
19-Jan-01     Release date:   23-Feb-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q28943  (DPYD_PIG) -  Dihydropyrimidine dehydrogenase [NADP(+)]
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1025 a.a.
1016 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.3.1.2  - Dihydropyrimidine dehydrogenase (NADP(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 5,6-dihydrouracil + NADP+ = uracil + NADPH
5,6-dihydrouracil
Bound ligand (Het Group name = URF)
matches with 88.00% similarity
+
NADP(+)
Bound ligand (Het Group name = NDP)
corresponds exactly
= uracil
+ NADPH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     oxidation-reduction process   5 terms 
  Biochemical function     catalytic activity     13 terms  

 

 
    reference    
 
 
DOI no: 10.1093/emboj/20.4.650 EMBO J 20:650-660 (2001)
PubMed id: 11179210  
 
 
Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil.
D.Dobritzsch, G.Schneider, K.D.Schnackerz, Y.Lindqvist.
 
  ABSTRACT  
 
Dihydropyrimidine dehydrogenase catalyzes the first step in pyrimidine degradation: the NADPH-dependent reduction of uracil and thymine to the corresponding 5,6-dihydropyrimidines. Its controlled inhibition has become an adjunct target for cancer therapy, since the enzyme is also responsible for the rapid breakdown of the chemotherapeutic drug 5-fluorouracil. The crystal structure of the homodimeric pig liver enzyme (2x 111 kDa) determined at 1.9 A resolution reveals a highly modular subunit organization, consisting of five domains with different folds. Dihydropyrimidine dehydrogenase contains two FAD, clusters, arranged in two electron transfer chains that pass the dimer interface twice. Two of the Fe-S clusters show a hitherto unobserved coordination involving a glutamine residue. The ternary complex of an inactive mutant of the enzyme with bound NADPH and 5-fluorouracil reveals the architecture of the substrate-binding sites and residues responsible for recognition and binding of the drug.
 
  Selected figure(s)  
 
Figure 1.
Figure 1 Structure of pig liver DPD. (A) Schematic view of the subunit of DPD with the domains in different colors. The cofactors are shown as ball-and-stick models, iron ions in magenta and sulfur atoms in green. (B) The DPD dimer. The color codes for the domains of the first subunit are the same as in (A), the corresponding domains in the second subunit are shown in light green, brown, cyan, pink and light blue.
Figure 6.
Figure 6 Electron transfer pathways in DPD. Distances between closest atoms of the cofactors are indicated. The nicotinamide ring of NADPH is shown at its assumed position during electron transfer.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 650-660) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20803296 A.B.van Kuilenburg, J.Meijer, A.N.Mul, R.Meinsma, V.Schmid, D.Dobritzsch, R.C.Hennekam, M.M.Mannens, M.Kiechle, M.C.Etienne-Grimaldi, H.J.Klümpen, J.G.Maring, V.A.Derleyn, E.Maartense, G.Milano, R.Vijzelaar, and E.Gross (2010).
Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity.
  Hum Genet, 128, 529-538.  
18160405 A.Karcher, A.Schele, and K.P.Hopfner (2008).
X-ray structure of the complete ABC enzyme ABCE1 from Pyrococcus abyssi.
  J Biol Chem, 283, 7962-7971.
PDB code: 3bk7
19104657 E.Gross, B.Busse, M.Riemenschneider, S.Neubauer, K.Seck, H.G.Klein, M.Kiechle, F.Lordick, and A.Meindl (2008).
Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients.
  PLoS ONE, 3, e4003.  
18421771 M.A.Vanoni, and B.Curti (2008).
Structure-function studies of glutamate synthases: a class of self-regulated iron-sulfur flavoenzymes essential for nitrogen assimilation.
  IUBMB Life, 60, 287-300.  
18199747 M.Cottevieille, E.Larquet, S.Jonic, M.V.Petoukhov, G.Caprini, S.Paravisi, D.I.Svergun, M.A.Vanoni, and N.Boisset (2008).
The subnanometer resolution structure of the glutamate synthase 1.2-MDa hexamer by cryoelectron microscopy and its oligomerization behavior in solution: functional implications.
  J Biol Chem, 283, 8237-8249.
PDB code: 2vdc
19094041 S.Jonić, C.O.Sorzano, and N.Boisset (2008).
Comparison of single-particle analysis and electron tomography approaches: an overview.
  J Microsc, 232, 562-579.  
17611751 C.O.Sorzano, S.Jonic, M.Cottevieille, E.Larquet, N.Boisset, and S.Marco (2007).
3D electron microscopy of biological nanomachines: principles and applications.
  Eur Biophys J, 36, 995.  
17324113 X.Zhang, and R.B.Diasio (2007).
Regulation of human dihydropyrimidine dehydrogenase: implications in the pharmacogenetics of 5-FU-based chemotherapy.
  Pharmacogenomics, 8, 257-265.  
17612628 X.Zhang, R.Soong, K.Wang, L.Li, J.R.Davie, V.Guarcello, and R.B.Diasio (2007).
Suppression of DPYD expression in RKO cells via DNA methylation in the regulatory region of the DPYD promoter: a potentially important epigenetic mechanism regulating DPYD expression.
  Biochem Cell Biol, 85, 337-346.  
16361227 J.M.Rawls (2006).
Analysis of pyrimidine catabolism in Drosophila melanogaster using epistatic interactions with mutations of pyrimidine biosynthesis and beta-alanine metabolism.
  Genetics, 172, 1665-1674.  
16603087 S.S.Krishna, R.I.Sadreyev, and N.V.Grishin (2006).
A tale of two ferredoxins: sequence similarity and structural differences.
  BMC Struct Biol, 6, 8.  
15899693 A.B.Van Kuilenburg, R.Meinsma, E.Beke, B.Bobba, P.Boffi, G.M.Enns, D.R.Witt, and D.Dobritzsch (2005).
Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function.
  Biol Chem, 386, 319-324.  
15842620 A.Somanchi, D.Barnes, and S.P.Mayfield (2005).
A nuclear gene of Chlamydomonas reinhardtii, Tba1, encodes a putative oxidoreductase required for translation of the chloroplast psbA mRNA.
  Plant J, 42, 341-352.  
16143853 M.A.Vanoni, L.Dossena, R.H.van den Heuvel, and B.Curti (2005).
Structure-function studies on the complex iron-sulfur flavoprotein glutamate synthase: the key enzyme of ammonia assimilation.
  Photosynth Res, 83, 219-238.  
14622288 M.H.Hefti, J.Vervoort, and W.J.van Berkel (2003).
Deflavination and reconstitution of flavoproteins.
  Eur J Biochem, 270, 4227-4242.  
12777402 M.V.Petoukhov, D.I.Svergun, P.V.Konarev, S.Ravasio, R.H.van den Heuvel, B.Curti, and M.A.Vanoni (2003).
Quaternary structure of Azospirillum brasilense NADPH-dependent glutamate synthase in solution as revealed by synchrotron radiation x-ray scattering.
  J Biol Chem, 278, 29933-29939.  
12840019 P.A.Hubbard, X.Liang, H.Schulz, and J.J.Kim (2003).
The crystal structure and reaction mechanism of Escherichia coli 2,4-dienoyl-CoA reductase.
  J Biol Chem, 278, 37553-37560.
PDB code: 1ps9
12192068 C.A.Bottoms, P.E.Smith, and J.J.Tanner (2002).
A structurally conserved water molecule in Rossmann dinucleotide-binding domains.
  Protein Sci, 11, 2125-2137.  
11796730 D.Dobritzsch, S.Ricagno, G.Schneider, K.D.Schnackerz, and Y.Lindqvist (2002).
Crystal structure of the productive ternary complex of dihydropyrimidine dehydrogenase with NADPH and 5-iodouracil. Implications for mechanism of inhibition and electron transfer.
  J Biol Chem, 277, 13155-13166.
PDB codes: 1gt8 1gte 1gth
11875367 L.K.Mattison, M.R.Johnson, and R.B.Diasio (2002).
A comparative analysis of translated dihydropyrimidine dehydrogenase cDNA; conservation of functional domains and relevance to genetic polymorphisms.
  Pharmacogenetics, 12, 133-144.  
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.