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

Dobritzsch D, Schneider G, Schnackerz KD, Lindqvist Y
EMBO J 20 650-60 (2001)
Cited: 57 times
EuropePMC logo PMID: 11179210

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.

Articles - 1h7x mentioned but not cited (3)

  1. Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil. Dobritzsch D, Schneider G, Schnackerz KD, Lindqvist Y. EMBO J. 20 650-660 (2001)
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  3. Force Field Parameters for Fe2+4S2-4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies. Tendwa MB, Chebon-Bore L, Lobb K, Musyoka TM, Tastan Bishop Ö. Molecules 26 2929 (2021)


Reviews citing this publication (11)

  1. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. van Kuilenburg AB. Eur. J. Cancer 40 939-950 (2004)
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  11. In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase. Hishinuma E, Gutiérrez Rico E, Hiratsuka M. J Clin Med 9 (2020)

Articles citing this publication (43)

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  11. Insights into Flavin-based Electron Bifurcation via the NADH-dependent Reduced Ferredoxin:NADP Oxidoreductase Structure. Demmer JK, Huang H, Wang S, Demmer U, Thauer RK, Ermler U. J. Biol. Chem. 290 21985-21995 (2015)
  12. A comparative analysis of translated dihydropyrimidine dehydrogenase cDNA; conservation of functional domains and relevance to genetic polymorphisms. Mattison LK, Johnson MR, Diasio RB. Pharmacogenetics 12 133-144 (2002)
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  16. Analysis of pyrimidine catabolism in Drosophila melanogaster using epistatic interactions with mutations of pyrimidine biosynthesis and beta-alanine metabolism. Rawls JM. Genetics 172 1665-1674 (2006)
  17. Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function. Van Kuilenburg AB, Meinsma R, Beke E, Bobba B, Boffi P, Enns GM, Witt DR, Dobritzsch D. Biol. Chem. 386 319-324 (2005)
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  19. Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio. Thomas F, Hennebelle I, Delmas C, Lochon I, Dhelens C, Garnier Tixidre C, Bonadona A, Penel N, Goncalves A, Delord JP, Toulas C, Chatelut E. Clin. Pharmacol. Ther. 99 235-242 (2016)
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  29. The unexpected structural role of glutamate synthase [4Fe-4S](+1,+2) clusters as demonstrated by site-directed mutagenesis of conserved C residues at the N-terminus of the enzyme beta subunit. Agnelli P, Dossena L, Colombi P, Mulazzi S, Morandi P, Tedeschi G, Negri A, Curti B, Vanoni MA. Arch. Biochem. Biophys. 436 355-366 (2005)
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  31. Novel Deleterious Dihydropyrimidine Dehydrogenase Variants May Contribute to 5-Fluorouracil Sensitivity in an East African Population. Elraiyah T, Jerde CR, Shrestha S, Wu R, Nie Q, Giama NH, Sarangi V, Roberts LR, Offer SM, Diasio RB. Clin. Pharmacol. Ther. 101 382-390 (2017)
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  35. Iron-sulfur flavoenzymes: the added value of making the most ancient redox cofactors and the versatile flavins work together. Vanoni MA. Open Biol 11 210010 (2021)
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  37. DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach. Villalvazo P, Marzal-Alfaro B, García-Alfonso P, Revuelta-Herrero JL, Thomas F, López-Tarruella S, García-González X, Calvo A, Yakoubi M, Salvador-Martín S, López-López F, Aguilar I, Sanjurjo-Sáez M, Martín M, López-Fernández LA. J Pers Med 11 792 (2021)
  38. Evolutionary Diversity of Dus2 Enzymes Reveals Novel Structural and Functional Features among Members of the RNA Dihydrouridine Synthases Family. Lombard M, Reed CJ, Pecqueur L, Faivre B, Toubdji S, Sudol C, Brégeon D, de Crécy-Lagard V, Hamdane D. Biomolecules 12 1760 (2022)
  39. Identification of fungal dihydrouracil-oxidase genes by expression in Saccharomyces cerevisiae. Bouwknegt J, Vos AM, Ortiz Merino RA, van Cuylenburg DC, Luttik MAH, Pronk JT. Antonie Van Leeuwenhoek 115 1363-1378 (2022)
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Related citations provided by authors (1)

  1. Crystallization and preliminary X-ray study of pig liver dihydropyrimidine dehydrogenase.. Dobritzsch D, Persson K, Schneider G, Lindqvist Y Acta Crystallogr D Biol Crystallogr 57 153-5 (2001)

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