What question did this study set out to answer?

Determine the structural basis of catalytic electron transport and mechanism-based inhibition in dihydropyrimidine dehydrogenase using ternary enzyme complexes.

April 1, 2002Journal of Biological ChemistryOpen Access

Crystal Structure of the Productive Ternary Complex of Dihydropyrimidine Dehydrogenase with NADPH and 5-Iodouracil

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Authors

DDDoreen DobritzschUppsala University SRStéfano RicagnoUniversity of Milan GSG. SchneiderKarolinska Institutet

Discussion

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Implication

Crystallographic study reveals the 56-Ångström electron transfer pathway in dihydropyrimidine dehydrogenase, indicating how 5-iodouracil acts as a mechanism-based covalent inhibitor.

Key Points

Determine the structural basis of catalytic electron transport and mechanism-based inhibition in dihydropyrimidine dehydrogenase using ternary enzyme complexes.
Determined the three-dimensional crystal structure of dihydropyrimidine dehydrogenase in a binary complex with 5-iodouracil using X-ray crystallography.
Solved ternary complex crystal structures of the enzyme bound to NADPH and either 5-iodouracil or uracil-4-acetic acid.
Mapped a 56 Å electron transfer pathway extending from NADPH to the substrate via FAD, four [Fe-S] clusters, and FMN.
Identified a pH-dependent active-site loop closure triggered by pyrimidine binding that positions a critical cysteine near the substrate, which is sterically blocked by uracil-4-acetic acid.
Demonstrated that 5-iodouracil acts as a mechanism-based inhibitor by covalently modifying active-site residue Cys-671 into S-(hexahydro-2,4-dioxo-5-pyrimidinyl)cysteine.

Cite This Study

Dobritzsch et al. (2002) studied this question.

synapsesocial.com/papers/6aa36cb5e0a56e090ff424e2 https://doi.org/10.1074/jbc.m111877200

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April 1, 2002Journal of Biological ChemistryOpen Access

Crystal Structure of the Productive Ternary Complex of Dihydropyrimidine Dehydrogenase with NADPH and 5-Iodouracil

View Full Paper

Ask AI

Bookmark

Authors

DDDoreen DobritzschUppsala University SRStéfano RicagnoUniversity of Milan GSG. SchneiderKarolinska Institutet

Discussion

Member takes

Implication

Crystallographic study reveals the 56-Ångström electron transfer pathway in dihydropyrimidine dehydrogenase, indicating how 5-iodouracil acts as a mechanism-based covalent inhibitor.

Key Points

Determine the structural basis of catalytic electron transport and mechanism-based inhibition in dihydropyrimidine dehydrogenase using ternary enzyme complexes.
Determined the three-dimensional crystal structure of dihydropyrimidine dehydrogenase in a binary complex with 5-iodouracil using X-ray crystallography.
Solved ternary complex crystal structures of the enzyme bound to NADPH and either 5-iodouracil or uracil-4-acetic acid.
Mapped a 56 Å electron transfer pathway extending from NADPH to the substrate via FAD, four [Fe-S] clusters, and FMN.
Identified a pH-dependent active-site loop closure triggered by pyrimidine binding that positions a critical cysteine near the substrate, which is sterically blocked by uracil-4-acetic acid.
Demonstrated that 5-iodouracil acts as a mechanism-based inhibitor by covalently modifying active-site residue Cys-671 into S-(hexahydro-2,4-dioxo-5-pyrimidinyl)cysteine.

Cite This Study

Dobritzsch et al. (2002) studied this question.

synapsesocial.com/papers/6aa36cb5e0a56e090ff424e2 https://doi.org/10.1074/jbc.m111877200

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