1H7X

Dihydropyrimidine dehydrogenase (DPD) from pig, ternary complex of a mutant enzyme (C671A), NADPH and 5-fluorouracil

Summary for 1H7X

• Entry DOI: 10.2210/pdb1h7x/pdb
• Related: 1H7W
• Descriptor: DIHYDROPYRIMIDINE DEHYDROGENASE, IRON/SULFUR CLUSTER, FLAVIN MONONUCLEOTIDE, ... (7 entities in total)
• Functional Keywords: electron transfer, flavin, iron-sulfur clusters, pyrimidine catabolism, 5-fluorouracil degradation, oxidoreductase
• Biological source: SUS SCROFA (WILD BOAR)
• Cellular location: Cytoplasm: Q28943
• Total number of polymer chains: 4
• Total formula weight: 460380.93

Authors

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

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-, 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 (2.01 Å)