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Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil.
EMBO J. 2001 Feb 15; 20(4):650-60.EJ

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.

Authors+Show Affiliations

Division of Molecular Structural Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11179210

Citation

Dobritzsch, D, et al. "Crystal Structure of Dihydropyrimidine Dehydrogenase, a Major Determinant of the Pharmacokinetics of the Anti-cancer Drug 5-fluorouracil." The EMBO Journal, vol. 20, no. 4, 2001, pp. 650-60.
Dobritzsch D, Schneider G, Schnackerz KD, et al. Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil. EMBO J. 2001;20(4):650-60.
Dobritzsch, D., Schneider, G., Schnackerz, K. D., & Lindqvist, Y. (2001). Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil. The EMBO Journal, 20(4), 650-60.
Dobritzsch D, et al. Crystal Structure of Dihydropyrimidine Dehydrogenase, a Major Determinant of the Pharmacokinetics of the Anti-cancer Drug 5-fluorouracil. EMBO J. 2001 Feb 15;20(4):650-60. PubMed PMID: 11179210.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil. AU - Dobritzsch,D, AU - Schneider,G, AU - Schnackerz,K D, AU - Lindqvist,Y, PY - 2001/2/17/pubmed PY - 2001/4/17/medline PY - 2001/2/17/entrez SP - 650 EP - 60 JF - The EMBO journal JO - EMBO J VL - 20 IS - 4 N2 - 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. SN - 0261-4189 UR - https://www.unboundmedicine.com/medline/citation/11179210/Crystal_structure_of_dihydropyrimidine_dehydrogenase_a_major_determinant_of_the_pharmacokinetics_of_the_anti_cancer_drug_5_fluorouracil_ L2 - https://doi.org/10.1093/emboj/20.4.650 DB - PRIME DP - Unbound Medicine ER -