Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil

被引:103
作者
Dobritzsch, D
Schneider, G [1 ]
Schnackerz, KD
Lindqvist, Y
机构
[1] Karolinska Inst, Dept Med Biochem & Biophys, Div Mol Struct Biol, Stockholm, Sweden
[2] Theodor Boveri Inst Biowissensch, Wurzburg, Germany
关键词
electron transfer; flavin; iron-sulfur clusters; protein crystallography; pyrimidine metabolism;
D O I
10.1093/emboj/20.4.650
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 x 111 kDa) determined at 1.9 Angstrom 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.
引用
收藏
页码:650 / 660
页数:11
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