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Crystal structure of the productive ternary complex of dihydropyrimidine dehydrogenase with NADPH and 5-iodouracil. Implications for mechanism of inhibition and electron transfer.

Dobritzsch D, Ricagno S, Schneider G, Schnackerz KD, Lindqvist Y
J Biol Chem 277 13155-66 (2002)
Related entries: 1gte, 1gth

Cited: 25 times
EuropePMC logo PMID: 11796730

Abstract

Dihydroprymidine dehydrogenase catalyzes the first and rate-limiting step in pyrimidine degradation by converting pyrimidines to the corresponding 5,6- dihydro compounds. The three-dimensional structures of a binary complex with the inhibitor 5-iodouracil and two ternary complexes with NADPH and the inhibitors 5-iodouracil and uracil-4-acetic acid were determined by x-ray crystallography. In the ternary complexes, NADPH is bound in a catalytically competent fashion, with the nicotinamide ring in a position suitable for hydride transfer to FAD. The structures provide a complete picture of the electron transfer chain from NADPH to the substrate, 5-iodouracil, spanning a distance of 56 A and involving FAD, four [Fe-S] clusters, and FMN as cofactors. The crystallographic analysis further reveals that pyrimidine binding triggers a conformational change of a flexible active-site loop in the alpha/beta-barrel domain, resulting in placement of a catalytically crucial cysteine close to the bound substrate. Loop closure requires physiological pH, which is also necessary for correct binding of NADPH. Binding of the voluminous competitive inhibitor uracil-4-acetic acid prevents loop closure due to steric hindrance. The three-dimensional structure of the ternary complex enzyme-NADPH-5-iodouracil supports the proposal that this compound acts as a mechanism-based inhibitor, covalently modifying the active-site residue Cys-671, resulting in S-(hexahydro-2,4-dioxo-5-pyrimidinyl)cysteine.

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  1. Bioinformatics and variability in drug response: a protein structural perspective. Lahti JL, Tang GW, Capriotti E, Liu T, Altman RB. J R Soc Interface 9 1409-1437 (2012)

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  1. Gene-Specific Variant Classifier (DPYD-Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase. Shrestha S, Zhang C, Jerde CR, Nie Q, Li H, Offer SM, Diasio RB. Clin Pharmacol Ther 104 709-718 (2018)


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  1. Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Ezzeldin H, Diasio R. Clin Colorectal Cancer 4 181-189 (2004)
  2. Structure--function studies on the iron-sulfur flavoenzyme glutamate synthase: an unexpectedly complex self-regulated enzyme. Vanoni MA, Curti B. Arch Biochem Biophys 433 193-211 (2005)
  3. Regulation of human dihydropyrimidine dehydrogenase: implications in the pharmacogenetics of 5-FU-based chemotherapy. Zhang X, Diasio RB. Pharmacogenomics 8 257-265 (2007)
  4. In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase. Hishinuma E, Gutiérrez Rico E, Hiratsuka M. J Clin Med 9 E2342 (2020)

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  2. 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)
  3. Biochemical fossils of the ancient transition from geoenergetics to bioenergetics in prokaryotic one carbon compound metabolism. Sousa FL, Martin WF. Biochim Biophys Acta 1837 964-981 (2014)
  4. The active conformation of glutamate synthase and its binding to ferredoxin. van den Heuvel RH, Svergun DI, Petoukhov MV, Coda A, Curti B, Ravasio S, Vanoni MA, Mattevi A. J Mol Biol 330 113-128 (2003)
  5. Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences. Maekawa K, Saeki M, Saito Y, Ozawa S, Kurose K, Kaniwa N, Kawamoto M, Kamatani N, Kato K, Hamaguchi T, Yamada Y, Shirao K, Shimada Y, Muto M, Doi T, Ohtsu A, Yoshida T, Matsumura Y, Saijo N, Sawada JI. J Hum Genet 52 804-819 (2007)
  6. Structural analysis of metal sites in proteins: non-heme iron sites as a case study. Andreini C, Bertini I, Cavallaro G, Najmanovich RJ, Thornton JM. J Mol Biol 388 356-380 (2009)
  7. Molecular evolution of dihydrouridine synthases. Kasprzak JM, Czerwoniec A, Bujnicki JM. BMC Bioinformatics 13 153 (2012)
  8. Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression. Edwards L, Gupta R, Filipp FV. Mol Cancer Res 14 196-206 (2016)
  9. A hidden metabolic pathway exposed. Osterman A. Proc Natl Acad Sci U S A 103 5637-5638 (2006)
  10. Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals. Hishinuma E, Narita Y, Saito S, Maekawa M, Akai F, Nakanishi Y, Yasuda J, Nagasaki M, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M. Drug Metab Dispos 46 1083-1090 (2018)
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  12. Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population. Hishinuma E, Narita Y, Obuchi K, Ueda A, Saito S, Tadaka S, Kinoshita K, Maekawa M, Mano N, Hirasawa N, Hiratsuka M. Front Pharmacol 13 930470 (2022)
  13. Purification and characterization of dihydropyrimidine dehydrogenase enzyme from sheep liver and determination of the effects of some anaesthetic and antidepressant drugs on the enzyme activity. Camadan Y, Özdemir H, Gulcin İ. J Enzyme Inhib Med Chem 31 1335-1341 (2016)
  14. 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)
  15. 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)
  16. Thiation of 2'-deoxy-5,6-dihydropyrimidine nucleosides with Lawesson's reagent: characterisation of oxathiaphosphepane intermediates. Peyrane F, Fourrey JL, Clivio P. Chem Commun (Camb) 736-737 (2003)
  17. 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)
  18. A ferredoxin-dependent dihydropyrimidine dehydrogenase in Clostridium chromiireducens. Wang F, Wei Y, Lu Q, Ang EL, Zhao H, Zhang Y. Biosci Rep 40 BSR20201642 (2020)
  19. Ligand-Enabled Copper-Mediated Radioiodination of Arenes. McErlain H, Andrews MJ, Watson AJB, Pimlott SL, Sutherland A. Org Lett 26 1528-1532 (2024)


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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