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

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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 (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.