1H7W

Dihydropyrimidine dehydrogenase (DPD) from pig

Summary for 1H7W

• Entry DOI: 10.2210/pdb1h7w/pdb
• Related: 1H7X
• Descriptor: DIHYDROPYRIMIDINE DEHYDROGENASE, IRON/SULFUR CLUSTER, FLAVIN MONONUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: electron transfer, flavin, iron-sulfur clusters, pyrimidine catabolism, oxidoreductase
• Biological source: SUS SCROFA (WILD BOAR)
• Total number of polymer chains: 4
• Total formula weight: 457007.19

Authors

Dobritzsch, D.,Schneider, G.,Schnackerz, K.D.,Lindqvist, Y. (deposition date: 2001-01-19, release date: 2001-02-23, Last modification date: 2024-05-08)

Primary citation

Dobritzsch, D.,Schneider, G.,Schnackerz, K.D.,Lindqvist, Y.
Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil.
EMBO J., 20:650-660, 2001

PubMed 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, two FMN and eight [4Fe-4S] 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.

PubMed: 11179210
DOI: 10.1093/emboj/20.4.650

Experimental method

X-RAY DIFFRACTION (1.9 Å)