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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1h7x
Original Entry
Title:
Electron transfer
Compound:
Dihydropyrimidine dehydrogenase
Mutant:
Yes
UniProt/Swiss-Prot:
Q28943-DPYD_PIG
EC Class:
1.3.1.2
Other CSA Entries:
Overview of all sites for 1h7x
Homologues of 1h7x
Entries for UniProt/Swiss-Prot: Q28943
Entries for EC: 1.3.1.2
Other Databases:
PDB entry: 1h7x
PDBsum entry: 1h7x
UniProt/Swiss-Prot: Q28943
IntEnz entry: 1.3.1.2
Literature Report:
Introduction:
Mammalian 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.
Mechanism:
The 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.
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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ALAA 671 671Sidechain
Acid/baseSubstrate
Ats as general acid base to protonate the transient carbanion formed after hydride transfer to the uracil.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11179210 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 9860876 Current protein Mutagenesis of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
FMND1030 0
Electron donor/acceptorSubstrate
Electron donor/acceptorCofactor
Substrate
Acts as nucleophile to transfer a hydride ion to the substrate, thus reducing it. This means that it acts as an electron donor/acceptor, shuttling electrons from FADH2 to the uracil substrate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11179210 Current protein Ligand is essential for catalysis
PubMed ID 11179210 Current protein Residue is positioned appropriately (ligand position known)
References:
1
Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil.
D. Dobritzsch and G. Schneider and K. D. Schnackerz and Y. Lindqvist
EMBO J 20, (4) 650-60, (2001).
11179210
2
Porcine recombinant dihydropyrimidine dehydrogenase: comparison of the spectroscopic and catalytic properties of the wild-type and C671A mutant enzymes.
K. Rosenbaum and K. Jahnke and B. Curti and W. R. Hagen and K. D. Schnackerz and M. A. Vanoni
Biochemistry 37, (50) 17598-609, (1998).
9860876
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