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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 1h7x

E.C. namedihydropyrimidine dehydrogenase (NADP+)
SpeciesSus scrofa (Pig)
E.C. Number (IntEnz) 1.3.1.2
CSA Homologues of 1h7xThere are 52 Homologs
CSA Entries With UniProtID Q28943
CSA Entries With EC Number 1.3.1.2
PDBe Entry 1h7x
PDBSum Entry 1h7x
MACiE Entry 1h7x

Literature Report

IntroductionMammalian dihydropyrimidine dehydrogenase catalyses the reduction of uracil or thymine to dihydrouracil or dihydrothymine respectively. This reaction represents an important step in the pathway of pyrimidine degradation in cells, but is particularly important to medicine because the anticancer drug 5flourouracil, though shown to be effective, is also a substrate for this enzyme, thus its effectiveness is reduced. The development of specific inhibitors is therefore paramount in order to reduce the cost and side effects of treatment with this drug.
MechansimThe enzyme uses electrons from NADPH to reduce the uracil substrate. However, the electrons are not passed directly to uracil but instead are transferred from NADPH to FAD and then from FAD to FMN. Finally the FMN acts as a nucleophile to transfer a hydride ion to the double bond of the uracil. This creates a transient carbanion at the second carbon of the double bond, allowing protonation by Cys 671 to occur, completing the reaction.
Reaction

Catalytic Sites for 1h7x

Annotated By Reference To The Literature - Site 5 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AlaA671671macie:sideChainAts as general acid base to protonate the transient carbanion formed after hydride transfer to the uracil.

Annotated By Reference To The Literature - Site 6 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AlaB671671macie:sideChainAts as general acid base to protonate the transient carbanion formed after hydride transfer to the uracil.

Annotated By Reference To The Literature - Site 7 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AlaC671671macie:sideChainAts as general acid base to protonate the transient carbanion formed after hydride transfer to the uracil.

Annotated By Reference To The Literature - Site 8 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AlaD671671macie:sideChainAts as general acid base to protonate the transient carbanion formed after hydride transfer to the uracil.

Literature References

Notes:
Dobritzsch D
Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil.
EMBO J 2001 20 650-660
PubMed: 11179210
Rosenbaum K
Porcine recombinant dihydropyrimidine dehydrogenase: comparison of the spectroscopic and catalytic properties of the wild-type and C671A mutant enzymes.
Biochemistry 1998 37 17598-17609
PubMed: 9860876
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