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| The EMBO Journal
(2001) 20, 650–660, doi:10.1093/emboj/20.4.650 |
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| Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil |
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| Doreen Dobritzsch1, Gunter Schneider1, Klaus D. Schnackerz2, 3 and Ylva Lindqvist1 |
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1 Division of Molecular Structural Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden 2 Theodor-Boveri-Institut für Biowissenschaften, Physiologische Chemie I, Am Hubland, Würzburg, Germany 3 Present adress: School of Chemistry, University of Birmingham, Birmingham, UK To whom correspondence should be addressed Gunter Schneider, gunter@alfa.mbb.ki.se Ylva Lindqvist, ylva@alfa.mbb.ki.se Received 13 November 2000; Revised 2 January 2001; Accepted 2 January 2001. |
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| Abstract |
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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 (2 111 kDa) determined at 1.9 Å 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. |
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| Keywords: electron transfer, flavin, iron–sulfur clusters, protein crystallography, pyrimidine metabolism |
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