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Catalytic Site Atlas

CSA LITERATURE entry for 1d3g

E.C. namedihydroorotate dehydrogenase (quinone)
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz)
CSA Homologues of 1d3gThere are 23 Homologs
CSA Entries With UniProtID Q02127
CSA Entries With EC Number
PDBe Entry 1d3g
PDBSum Entry 1d3g
MACiE Entry M0109

Literature Report

IntroductionDihydroororate reductase in humans catalyses a key step in the synthesis of pyrimidines, as it is able to convert dihydroororate into ororate, using FMN and Ubiquinone as cofactors for the reaction. The human enzyme is part of family 2, with homology to other mammalian dihydroororate reductases and to the equivalent enzymes in bacteria which are clustered in family 1. The enzyme is particularly important in T cells because of their high nucleotide turnover through new DNA synthesis.
MechansimThe reaction proceeds via initial abstraction of a proton from dihydroororate by Ser 215 which is activated to act as an acid base by Thr 218 and Phe 149. This creates a carbanion which transfers a hydride ion to FMN to form FMNH2, assisted by protonation of the FMN by Lys 255, forming the product. The hydride ion is then transferred to Ubiquinone which associates with the inner mitochondrial membrane and thus contributes to the electron transfer chain.

Catalytic Sites for 1d3g

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
SerA215214macie:sideChainActs to remove proton from the dihydroororate substrate, thus allowing the carbanion to form which can transfer a hydride to the FMN cofactor.
ThrA218217macie:sideChainThrough electrostatic contacts, is able to lower the pKa of Ser 215 to allow it to act as a general base.
PheA149148macie:sideChainThrough contacts between the pi electron ring and the OH group of Ser 215, is able to lower the pKa of Ser 215 sufficiently for it to act as a general base.
LysA255254macie:sideChainActs as an acid, donating a proton to FMN to allow its reduction to be completed after the transfer of a hydride ion.

Literature References

Notes:A complete understanding of the mechanism requires further work.
Liu S
Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents.
Structure 2000 8 25-33
PubMed: 10673429