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Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil
Karolinska Institutet. (Molecular Structural Biology)
2001 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 20, no 4, 650-660 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2001. Vol. 20, no 4, 650-660 p.
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Structural Biology
URN: urn:nbn:se:uu:diva-214444DOI: 10.1093/emboj/20.4.650ISI: 000167087200003PubMedID: 11179210OAI: oai:DiVA.org:uu-214444DiVA: diva2:684889
Available from: 2014-01-08 Created: 2014-01-08 Last updated: 2014-01-15Bibliographically approved

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