PDBsum entry 1h7w

Electron transfer

PDB id: 1h7w

Contents

Protein chains

1016 a.a. *

Ligands

SF4 ×16

FMN ×4

FAD ×4

Waters ×4639

* Residue conservation analysis

PDB id:

1h7w

Name:

Electron transfer

Title:

Dihydropyrimidine dehydrogenase (dpd) from pig

Structure:

Dihydropyrimidine dehydrogenase. Chain: a, b, c, d. Synonym: dihydrouracil dehydrogenase, dihydrothymine dehydrogenase. Engineered: yes

Source:

Sus scrofa. Wild boar. Organism_taxid: 9823. Cellular_location: cytoplasm. Gene: dpyd. Expressed in: escherichia coli dh5[alpha]. Expression_system_taxid: 668369.

Biol. unit:

Homo-Dimer (from PDB file)

Resolution:

1.90Å R-factor: 0.174 R-free: 0.196

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

Protein chains

Q28943  (DPYD_PIG) -  Dihydropyrimidine dehydrogenase [NADP(+)] from Sus scrofa

Seq: 1025 a.a.

Struc: 1016 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.1.3.1.2 - dihydropyrimidine dehydrogenase (NADP(+)).
• Reaction: 5,6-dihydrouracil + NADP⁺ = uracil + NADPH + H⁺

5,6-dihydrouracil + NADP(+) (Bound ligand (Het Group name = FAD) matches with 71.19% similarity) = uracil + NADPH + H(+)

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

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.