P00374 · DYR_HUMAN
- ProteinDihydrofolate reductase
- GeneDHFR
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids187 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2.
Catalytic activity
- (6S)-5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + H+ + NADPH
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
2.7 μM | dihydrofolate | |||||
4 μM | NADPH |
Pathway
Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate: step 1/1.
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 10 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: A | ||||||
Binding site | 16-22 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: GIGKNGD | ||||||
Binding site | 31-36 | substrate | ||||
Sequence: EFRYFQ | ||||||
Binding site | 55-57 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: KKT | ||||||
Binding site | 65 | substrate | ||||
Sequence: N | ||||||
Binding site | 71 | substrate | ||||
Sequence: R | ||||||
Binding site | 77-79 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: SRE | ||||||
Binding site | 117-124 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: GGSSVYKE |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytosol | |
Cellular Component | mitochondrion | |
Molecular Function | dihydrofolate reductase activity | |
Molecular Function | folic acid binding | |
Molecular Function | mRNA binding | |
Molecular Function | mRNA regulatory element binding translation repressor activity | |
Molecular Function | NADP binding | |
Molecular Function | NADPH binding | |
Molecular Function | sequence-specific mRNA binding | |
Biological Process | axon regeneration | |
Biological Process | dihydrofolate metabolic process | |
Biological Process | folic acid metabolic process | |
Biological Process | negative regulation of translation | |
Biological Process | one-carbon metabolic process | |
Biological Process | positive regulation of nitric-oxide synthase activity | |
Biological Process | regulation of removal of superoxide radicals | |
Biological Process | response to methotrexate | |
Biological Process | tetrahydrobiopterin biosynthetic process | |
Biological Process | tetrahydrofolate biosynthetic process | |
Biological Process | tetrahydrofolate metabolic process |
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameDihydrofolate reductase
- EC number
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP00374
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Involvement in disease
Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD)
- Note
- DescriptionAn inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.
- See alsoMIM:613839
Natural variants in DHFRD
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_065818 | 80 | L>F | in DHFRD; dbSNP:rs387906619 | |
VAR_065819 | 153 | D>V | in DHFRD; dbSNP:rs121913223 |
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 23 | Decreases affinity for NADP and dihydrofolate over 10-fold. | ||||
Sequence: L → F, W, or Y | ||||||
Mutagenesis | 23 | Strongly decreased affinity for methotrexate. Decreases catalytic rate constant 200-fold. Decreases affinity for NADP and dihydrofolate over 10-fold. | ||||
Sequence: L → R | ||||||
Mutagenesis | 32 | Reduces catalytic rate 5-fold. Reduces affinity for dihydrofolate 9-fold; when associated with E-36. | ||||
Sequence: F → R | ||||||
Mutagenesis | 36 | Reduces catalytic rate 2-fold. Reduces affinity for dihydrofolate 9-fold; when associated with R-32. | ||||
Sequence: Q → E | ||||||
Mutagenesis | 36 | Increases affinity for dihydrofolate about 3-fold. Reduces affinity for NADPH about 3-fold. | ||||
Sequence: Q → K | ||||||
Mutagenesis | 36 | Increases affinity for dihydrofolate about 2-fold. No effect on affinity for NADPH. | ||||
Sequence: Q → S | ||||||
Mutagenesis | 65 | Increases affinity for dihydrofolate about 3-fold. No effect on affinity for NADPH. | ||||
Sequence: N → F | ||||||
Mutagenesis | 65 | Increases affinity for dihydrofolate about 15-fold. No effect on affinity for NADPH. | ||||
Sequence: N → S | ||||||
Natural variant | VAR_065818 | 80 | in DHFRD; dbSNP:rs387906619 | |||
Sequence: L → F | ||||||
Natural variant | VAR_065819 | 153 | in DHFRD; dbSNP:rs121913223 | |||
Sequence: D → V |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 189 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000186362 | 1-187 | UniProt | Dihydrofolate reductase | |||
Sequence: MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFSIPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSSVYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKFEVYEKND | |||||||
Modified residue (large scale data) | 4 | PRIDE | Phosphoserine | ||||
Sequence: S |
Proteomic databases
PTM databases
Expression
Tissue specificity
Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain.
Gene expression databases
Organism-specific databases
Structure
Family & Domains
Features
Showing features for domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 4-185 | DHFR | ||||
Sequence: SLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFSIPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSSVYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKFEVYEK |
Sequence similarities
Belongs to the dihydrofolate reductase family.
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
P00374-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length187
- Mass (Da)21,453
- Last updated2007-01-23 v2
- ChecksumEBDF3D1EC73E1566
P00374-2
- Name2
- Differences from canonical
- 1-52: Missing
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
B4DM58 | B4DM58_HUMAN | DHFR | 129 |
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_056352 | 1-52 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 113 | in Ref. 6; AAH70280 | ||||
Sequence: V → L |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
J00140 EMBL· GenBank· DDBJ | AAA58485.1 EMBL· GenBank· DDBJ | mRNA | ||
V00507 EMBL· GenBank· DDBJ | CAA23765.1 EMBL· GenBank· DDBJ | mRNA | ||
J00139 EMBL· GenBank· DDBJ | AAA58484.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
K01612 EMBL· GenBank· DDBJ | AAA58484.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
K01613 EMBL· GenBank· DDBJ | AAA58484.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
J00138 EMBL· GenBank· DDBJ | AAA58484.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
K01614 EMBL· GenBank· DDBJ | AAA58484.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X00855 EMBL· GenBank· DDBJ | CAA25409.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X00856 EMBL· GenBank· DDBJ | CAA25409.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X00857 EMBL· GenBank· DDBJ | CAA25409.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X00858 EMBL· GenBank· DDBJ | CAA25409.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X00859 EMBL· GenBank· DDBJ | CAA25409.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AK293146 EMBL· GenBank· DDBJ | BAG56693.1 EMBL· GenBank· DDBJ | mRNA | ||
AC008434 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AC010270 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC000192 EMBL· GenBank· DDBJ | AAH00192.1 EMBL· GenBank· DDBJ | mRNA | ||
BC003584 EMBL· GenBank· DDBJ | AAH03584.2 EMBL· GenBank· DDBJ | mRNA | ||
BC070280 EMBL· GenBank· DDBJ | AAH70280.1 EMBL· GenBank· DDBJ | mRNA | ||
BC071996 EMBL· GenBank· DDBJ | AAH71996.1 EMBL· GenBank· DDBJ | mRNA |