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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1d3g
Original Entry
Title:
Oxidoreductase
Compound:
Dihydroorotate dehydrogenase
Mutant:
No
UniProt/Swiss-Prot:
Q02127-PYRD_HUMAN
EC Class:
1.3.3.1
Other CSA Entries:
Overview of all sites for 1d3g
Homologues of 1d3g
Entries for UniProt/Swiss-Prot: Q02127
Entries for EC: 1.3.3.1
Other Databases:
PDB entry: 1d3g
PDBsum entry: 1d3g
UniProt/Swiss-Prot: Q02127
IntEnz entry: 1.3.3.1
Literature Report:
Introduction:
Dihydroororate 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.
Mechanism:
The 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.
Sites:

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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
398 0
Substrate
Acts to accept a hydride from the carbanion created by the conjugate base of dihydroororate, thus allows its reduction to ororate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10673429 Current protein Residue is positioned appropriately
PubMed ID 10673429 Current protein Ligand is essential for catalysis

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
PHEA 149 148Sidechain
ElectrostaticResidue
Through 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.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10673429 Current protein Conservation of residue
PubMed ID 10673429 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
SERA 215 214Sidechain
Acid/baseSubstrate
Acts to remove proton from the dihydroororate substrate, thus allowing the carbanion to form which can transfer a hydride to the FMN cofactor.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10673429 Current protein Structural similarity to homologue of known mechanism
PubMed ID 10673429 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10673429 Current protein Conservation of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
THRA 218 217Sidechain
ElectrostaticResidue
Through electrostatic contacts, is able to lower the pKa of Ser 215 to allow it to act as a general base.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10673429 Current protein Conservation of residue
PubMed ID 10673429 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
LYSA 255 254Sidechain
Acid/baseCofactor
Acts as an acid, donating a proton to FMN to allow its reduction to be completed after the transfer of a hydride ion.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10673429 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10673429 Current protein Conservation of residue
Notes:
A complete understanding of the mechanism requires further work.
References:
1
Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents.
S. Liu and E. A. Neidhardt and T. H. Grossman and T. Ocain and J. Clardy
Structure Fold Des 8, (1) 25-33, (2000).
10673429
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