Download MendeleyCrystal Structure of Dihydropyrimidine Dehydrogenase, a Major Determinant of the Pharmacokinetics of the Anti-Cancer Drug 5-Fluorouracil
Dobritzsch, D., Schneider, G., Schnackerz, K.D., Lindqvist, Y.(2001) EMBO J 20: 650
- PubMed: 11179210
- DOI: https://doi.org/10.1093/emboj/20.4.650
- Primary Citation of Related Structures:
1H7W, 1H7X - 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.
Organizational Affiliation:
Division of Molecular Structural Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
