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P00374

- DYR_HUMAN

UniProt

P00374 - DYR_HUMAN

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Protein

Dihydrofolate reductase

Gene

DHFR

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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 DHFRL1.2 Publications

Catalytic activityi

5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH.7 PublicationsPROSITE-ProRule annotation

Kineticsi

  1. KM=2.7 µM for dihydrofolate3 Publications
  2. KM=4.0 µM for NADPH3 Publications

Pathwayi

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei10 – 101NADP; via amide nitrogen and carbonyl oxygen3 Publications
Binding sitei65 – 651Substrate
Binding sitei71 – 711Substrate

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi16 – 227NADP3 Publications
Nucleotide bindingi55 – 573NADP3 Publications
Nucleotide bindingi77 – 793NADP3 Publications
Nucleotide bindingi117 – 1248NADP3 Publications

GO - Molecular functioni

  1. dihydrofolate reductase activity Source: UniProtKB
  2. drug binding Source: UniProtKB
  3. mRNA binding Source: UniProtKB
  4. NADP binding Source: InterPro

GO - Biological processi

  1. folic acid metabolic process Source: Reactome
  2. G1/S transition of mitotic cell cycle Source: Reactome
  3. glycine biosynthetic process Source: InterPro
  4. mitotic cell cycle Source: Reactome
  5. nitric oxide metabolic process Source: Reactome
  6. nucleotide biosynthetic process Source: InterPro
  7. one-carbon metabolic process Source: UniProtKB-KW
  8. regulation of nitric-oxide synthase activity Source: Reactome
  9. regulation of transcription involved in G1/S transition of mitotic cell cycle Source: Reactome
  10. response to methotrexate Source: UniProtKB-KW
  11. small molecule metabolic process Source: Reactome
  12. tetrahydrofolate biosynthetic process Source: UniProtKB-UniPathway
  13. tetrahydrofolate metabolic process Source: UniProtKB
  14. vitamin metabolic process Source: Reactome
  15. water-soluble vitamin metabolic process Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Keywords - Biological processi

Methotrexate resistance, One-carbon metabolism

Keywords - Ligandi

NADP, RNA-binding

Enzyme and pathway databases

ReactomeiREACT_111176. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
REACT_11167. Metabolism of folate and pterines.
REACT_471. E2F mediated regulation of DNA replication.
REACT_683. G1/S-Specific Transcription.
SABIO-RKP00374.
UniPathwayiUPA00077; UER00158.

Names & Taxonomyi

Protein namesi
Recommended name:
Dihydrofolate reductase (EC:1.5.1.3)
Gene namesi
Name:DHFR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 5

Organism-specific databases

HGNCiHGNC:2861. DHFR.

Subcellular locationi

GO - Cellular componenti

  1. cytosol Source: Reactome
  2. nucleoplasm Source: Reactome
Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]: An 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.2 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti80 – 801L → F in DHFRD. 1 Publication
VAR_065818
Natural varianti153 – 1531D → V in DHFRD. 1 Publication
VAR_065819

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi23 – 231L → F, W or Y: Decreases affinity for NADP and dihydrofolate over 10-fold. 2 Publications
Mutagenesisi23 – 231L → R: Strongly decreased affinity for methotrexate. Decreases catalytic rate constant 200-fold. Decreases affinity for NADP and dihydrofolate over 10-fold. 2 Publications
Mutagenesisi32 – 321F → R: Reduces catalytic rate 5-fold. Reduces affinity for dihydrofolate 9-fold; when associated with E-36. 1 Publication
Mutagenesisi36 – 361Q → E: Reduces catalytic rate 2-fold. Reduces affinity for dihydrofolate 9-fold; when associated with R-32. 3 Publications
Mutagenesisi36 – 361Q → K: Increases affinity for dihydrofolate about 3-fold. Reduces affinity for NADPH about 3-fold. 3 Publications
Mutagenesisi36 – 361Q → S: Increases affinity for dihydrofolate about 2-fold. No effect on affinity for NADPH. 3 Publications
Mutagenesisi65 – 651N → F: Increases affinity for dihydrofolate about 3-fold. No effect on affinity for NADPH. 2 Publications
Mutagenesisi65 – 651N → S: Increases affinity for dihydrofolate about 15-fold. No effect on affinity for NADPH. 2 Publications

Keywords - Diseasei

Disease mutation

Organism-specific databases

MIMi613839. phenotype.
Orphaneti319651. Constitutional megaloblastic anemia with severe neurologic disease.
PharmGKBiPA143.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 187186Dihydrofolate reductasePRO_0000186362Add
BLAST

Proteomic databases

MaxQBiP00374.
PaxDbiP00374.
PRIDEiP00374.

2D gel databases

UCD-2DPAGEP00374.

PTM databases

PhosphoSiteiP00374.

Expressioni

Tissue specificityi

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.1 Publication

Gene expression databases

BgeeiP00374.
CleanExiHS_DHFR.
ExpressionAtlasiP00374. baseline and differential.
GenevestigatoriP00374.

Organism-specific databases

HPAiCAB037129.
HPA051465.

Interactioni

Subunit structurei

Homodimer.7 Publications

Protein-protein interaction databases

BioGridi108065. 9 interactions.
MINTiMINT-5002355.
STRINGi9606.ENSP00000396308.

Structurei

Secondary structure

1
187
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi5 – 117
Beta strandi16 – 194
Beta strandi24 – 263
Helixi29 – 4012
Beta strandi43 – 464
Beta strandi48 – 547
Helixi55 – 606
Helixi63 – 653
Beta strandi71 – 766
Beta strandi88 – 936
Helixi94 – 1018
Turni104 – 1096
Beta strandi110 – 1156
Helixi119 – 1268
Beta strandi128 – 1303
Beta strandi132 – 14110
Beta strandi146 – 1483
Turni154 – 1563
Beta strandi157 – 1593
Beta strandi161 – 1633
Beta strandi171 – 1733
Beta strandi176 – 18510

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1BOZX-ray2.10A2-187[»]
1DHFX-ray2.30A/B2-187[»]
1DLRX-ray2.30A2-187[»]
1DLSX-ray2.30A2-187[»]
1DRFX-ray2.00A2-187[»]
1HFPX-ray2.10A2-187[»]
1HFQX-ray2.10A2-187[»]
1HFRX-ray2.10A2-187[»]
1KMSX-ray1.09A2-187[»]
1KMVX-ray1.05A2-187[»]
1MVSX-ray1.90A1-187[»]
1MVTX-ray1.80A1-187[»]
1OHJX-ray2.50A2-187[»]
1OHKX-ray2.50A2-187[»]
1PD8X-ray2.10A2-187[»]
1PD9X-ray2.20A2-187[»]
1PDBX-ray2.20A2-187[»]
1S3UX-ray2.50A2-187[»]
1S3VX-ray1.80A2-187[»]
1S3WX-ray1.90A2-187[»]
1U71X-ray2.20A2-187[»]
1U72X-ray1.90A2-187[»]
1YHONMR-A2-187[»]
2C2SX-ray1.40A/B2-187[»]
2C2TX-ray1.50A/B2-187[»]
2DHFX-ray2.30A/B2-187[»]
2W3AX-ray1.50A/B1-187[»]
2W3BX-ray1.27A/B1-187[»]
2W3MX-ray1.60A/B1-187[»]
3EIGX-ray1.70A2-187[»]
3F8YX-ray1.45A1-187[»]
3F8ZX-ray2.01A1-187[»]
3F91X-ray1.90A1-187[»]
3FS6X-ray1.23A1-187[»]
3GHCX-ray1.30A2-187[»]
3GHVX-ray1.30A2-187[»]
3GHWX-ray1.24A2-187[»]
3GI2X-ray1.53A1-187[»]
3GYFX-ray1.70A1-187[»]
3L3RX-ray2.00A2-187[»]
3N0HX-ray1.92A2-187[»]
3NTZX-ray1.35A2-187[»]
3NU0X-ray1.35A2-187[»]
3NXOX-ray1.35A2-187[»]
3NXRX-ray1.35A2-187[»]
3NXTX-ray1.70A2-187[»]
3NXVX-ray1.90A2-187[»]
3NXXX-ray1.35A2-187[»]
3NXYX-ray1.90A2-187[»]
3NZDX-ray1.80A2-187[»]
3OAFX-ray1.70A2-187[»]
3S3VX-ray1.53A2-187[»]
3S7AX-ray1.80A2-187[»]
4DDRX-ray2.05A2-187[»]
4G95X-ray1.35A2-187[»]
4KAKX-ray1.80A/B2-187[»]
4KBNX-ray1.84A/B2-187[»]
4KD7X-ray2.72A/B2-187[»]
4KEBX-ray1.45A/B2-187[»]
4KFJX-ray1.76A/B2-187[»]
4M6JX-ray1.20A1-187[»]
4M6KX-ray1.40A1-187[»]
4M6LX-ray1.70A1-187[»]
ProteinModelPortaliP00374.
SMRiP00374. Positions 2-186.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP00374.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini4 – 185182DHFRPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni31 – 366Substrate binding

Sequence similaritiesi

Belongs to the dihydrofolate reductase family.Curated
Contains 1 DHFR (dihydrofolate reductase) domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0262.
GeneTreeiENSGT00390000010283.
HOGENOMiHOG000040235.
HOVERGENiHBG000773.
InParanoidiP00374.
KOiK00287.
OMAiLPWHPIR.
OrthoDBiEOG7V1FS3.
PhylomeDBiP00374.
TreeFamiTF317636.

Family and domain databases

Gene3Di3.40.430.10. 1 hit.
InterProiIPR012259. DHFR.
IPR024072. DHFR-like_dom.
IPR017925. DHFR_CS.
IPR001796. DHFR_dom.
[Graphical view]
PfamiPF00186. DHFR_1. 1 hit.
[Graphical view]
PRINTSiPR00070. DHFR.
SUPFAMiSSF53597. SSF53597. 1 hit.
PROSITEiPS00075. DHFR_1. 1 hit.
PS51330. DHFR_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: P00374-1) [UniParc]FASTAAdd to Basket

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.

« Hide

        10         20         30         40         50
MVGSLNCIVA VSQNMGIGKN GDLPWPPLRN EFRYFQRMTT TSSVEGKQNL
60 70 80 90 100
VIMGKKTWFS IPEKNRPLKG RINLVLSREL KEPPQGAHFL SRSLDDALKL
110 120 130 140 150
TEQPELANKV DMVWIVGGSS VYKEAMNHPG HLKLFVTRIM QDFESDTFFP
160 170 180
EIDLEKYKLL PEYPGVLSDV QEEKGIKYKF EVYEKND
Length:187
Mass (Da):21,453
Last modified:January 23, 2007 - v2
Checksum:iEBDF3D1EC73E1566
GO
Isoform 2 (identifier: P00374-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-52: Missing.

Note: No experimental confirmation available.

Show »
Length:135
Mass (Da):15,672
Checksum:i92704AAABEE1EF40
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti113 – 1131V → L in AAH70280. (PubMed:15489334)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti80 – 801L → F in DHFRD. 1 Publication
VAR_065818
Natural varianti153 – 1531D → V in DHFRD. 1 Publication
VAR_065819

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 5252Missing in isoform 2. 1 PublicationVSP_056352Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
J00140 mRNA. Translation: AAA58485.1.
V00507 mRNA. Translation: CAA23765.1.
J00139
, K01612, K01613, J00138, K01614 Genomic DNA. Translation: AAA58484.1.
X00855
, X00856, X00857, X00858, X00859 Genomic DNA. Translation: CAA25409.1.
AK293146 mRNA. Translation: BAG56693.1.
AC008434 Genomic DNA. No translation available.
AC010270 Genomic DNA. No translation available.
BC000192 mRNA. Translation: AAH00192.1.
BC003584 mRNA. Translation: AAH03584.2.
BC070280 mRNA. Translation: AAH70280.1.
BC071996 mRNA. Translation: AAH71996.1.
CCDSiCCDS47240.1. [P00374-1]
PIRiA22551. RDHUD.
RefSeqiNP_000782.1. NM_000791.3.
NP_001277283.1. NM_001290354.1.
UniGeneiHs.592364.
Hs.648635.

Genome annotation databases

EnsembliENST00000439211; ENSP00000396308; ENSG00000228716. [P00374-1]
ENST00000504396; ENSP00000421334; ENSG00000228716. [P00374-2]
ENST00000505337; ENSP00000426474; ENSG00000228716. [P00374-1]
GeneIDi1719.
KEGGihsa:1719.
UCSCiuc003kgy.1. human. [P00374-1]

Polymorphism databases

DMDMi118992.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Web resourcesi

Wikipedia

Dihydrofolate reductase entry

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
J00140 mRNA. Translation: AAA58485.1 .
V00507 mRNA. Translation: CAA23765.1 .
J00139
, K01612 , K01613 , J00138 , K01614 Genomic DNA. Translation: AAA58484.1 .
X00855
, X00856 , X00857 , X00858 , X00859 Genomic DNA. Translation: CAA25409.1 .
AK293146 mRNA. Translation: BAG56693.1 .
AC008434 Genomic DNA. No translation available.
AC010270 Genomic DNA. No translation available.
BC000192 mRNA. Translation: AAH00192.1 .
BC003584 mRNA. Translation: AAH03584.2 .
BC070280 mRNA. Translation: AAH70280.1 .
BC071996 mRNA. Translation: AAH71996.1 .
CCDSi CCDS47240.1. [P00374-1 ]
PIRi A22551. RDHUD.
RefSeqi NP_000782.1. NM_000791.3.
NP_001277283.1. NM_001290354.1.
UniGenei Hs.592364.
Hs.648635.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1BOZ X-ray 2.10 A 2-187 [» ]
1DHF X-ray 2.30 A/B 2-187 [» ]
1DLR X-ray 2.30 A 2-187 [» ]
1DLS X-ray 2.30 A 2-187 [» ]
1DRF X-ray 2.00 A 2-187 [» ]
1HFP X-ray 2.10 A 2-187 [» ]
1HFQ X-ray 2.10 A 2-187 [» ]
1HFR X-ray 2.10 A 2-187 [» ]
1KMS X-ray 1.09 A 2-187 [» ]
1KMV X-ray 1.05 A 2-187 [» ]
1MVS X-ray 1.90 A 1-187 [» ]
1MVT X-ray 1.80 A 1-187 [» ]
1OHJ X-ray 2.50 A 2-187 [» ]
1OHK X-ray 2.50 A 2-187 [» ]
1PD8 X-ray 2.10 A 2-187 [» ]
1PD9 X-ray 2.20 A 2-187 [» ]
1PDB X-ray 2.20 A 2-187 [» ]
1S3U X-ray 2.50 A 2-187 [» ]
1S3V X-ray 1.80 A 2-187 [» ]
1S3W X-ray 1.90 A 2-187 [» ]
1U71 X-ray 2.20 A 2-187 [» ]
1U72 X-ray 1.90 A 2-187 [» ]
1YHO NMR - A 2-187 [» ]
2C2S X-ray 1.40 A/B 2-187 [» ]
2C2T X-ray 1.50 A/B 2-187 [» ]
2DHF X-ray 2.30 A/B 2-187 [» ]
2W3A X-ray 1.50 A/B 1-187 [» ]
2W3B X-ray 1.27 A/B 1-187 [» ]
2W3M X-ray 1.60 A/B 1-187 [» ]
3EIG X-ray 1.70 A 2-187 [» ]
3F8Y X-ray 1.45 A 1-187 [» ]
3F8Z X-ray 2.01 A 1-187 [» ]
3F91 X-ray 1.90 A 1-187 [» ]
3FS6 X-ray 1.23 A 1-187 [» ]
3GHC X-ray 1.30 A 2-187 [» ]
3GHV X-ray 1.30 A 2-187 [» ]
3GHW X-ray 1.24 A 2-187 [» ]
3GI2 X-ray 1.53 A 1-187 [» ]
3GYF X-ray 1.70 A 1-187 [» ]
3L3R X-ray 2.00 A 2-187 [» ]
3N0H X-ray 1.92 A 2-187 [» ]
3NTZ X-ray 1.35 A 2-187 [» ]
3NU0 X-ray 1.35 A 2-187 [» ]
3NXO X-ray 1.35 A 2-187 [» ]
3NXR X-ray 1.35 A 2-187 [» ]
3NXT X-ray 1.70 A 2-187 [» ]
3NXV X-ray 1.90 A 2-187 [» ]
3NXX X-ray 1.35 A 2-187 [» ]
3NXY X-ray 1.90 A 2-187 [» ]
3NZD X-ray 1.80 A 2-187 [» ]
3OAF X-ray 1.70 A 2-187 [» ]
3S3V X-ray 1.53 A 2-187 [» ]
3S7A X-ray 1.80 A 2-187 [» ]
4DDR X-ray 2.05 A 2-187 [» ]
4G95 X-ray 1.35 A 2-187 [» ]
4KAK X-ray 1.80 A/B 2-187 [» ]
4KBN X-ray 1.84 A/B 2-187 [» ]
4KD7 X-ray 2.72 A/B 2-187 [» ]
4KEB X-ray 1.45 A/B 2-187 [» ]
4KFJ X-ray 1.76 A/B 2-187 [» ]
4M6J X-ray 1.20 A 1-187 [» ]
4M6K X-ray 1.40 A 1-187 [» ]
4M6L X-ray 1.70 A 1-187 [» ]
ProteinModelPortali P00374.
SMRi P00374. Positions 2-186.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 108065. 9 interactions.
MINTi MINT-5002355.
STRINGi 9606.ENSP00000396308.

Chemistry

BindingDBi P00374.
ChEMBLi CHEMBL202.
DrugBanki DB00563. Methotrexate.
DB00642. Pemetrexed.
DB06813. Pralatrexate.
DB01131. Proguanil.
DB00205. Pyrimethamine.
DB00440. Trimethoprim.
DB01157. Trimetrexate.
GuidetoPHARMACOLOGYi 2603.

PTM databases

PhosphoSitei P00374.

Polymorphism databases

DMDMi 118992.

2D gel databases

UCD-2DPAGE P00374.

Proteomic databases

MaxQBi P00374.
PaxDbi P00374.
PRIDEi P00374.

Protocols and materials databases

DNASUi 1719.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000439211 ; ENSP00000396308 ; ENSG00000228716 . [P00374-1 ]
ENST00000504396 ; ENSP00000421334 ; ENSG00000228716 . [P00374-2 ]
ENST00000505337 ; ENSP00000426474 ; ENSG00000228716 . [P00374-1 ]
GeneIDi 1719.
KEGGi hsa:1719.
UCSCi uc003kgy.1. human. [P00374-1 ]

Organism-specific databases

CTDi 1719.
GeneCardsi GC05M079922.
HGNCi HGNC:2861. DHFR.
HPAi CAB037129.
HPA051465.
MIMi 126060. gene.
613839. phenotype.
neXtProti NX_P00374.
Orphaneti 319651. Constitutional megaloblastic anemia with severe neurologic disease.
PharmGKBi PA143.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG0262.
GeneTreei ENSGT00390000010283.
HOGENOMi HOG000040235.
HOVERGENi HBG000773.
InParanoidi P00374.
KOi K00287.
OMAi LPWHPIR.
OrthoDBi EOG7V1FS3.
PhylomeDBi P00374.
TreeFami TF317636.

Enzyme and pathway databases

UniPathwayi UPA00077 ; UER00158 .
Reactomei REACT_111176. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
REACT_11167. Metabolism of folate and pterines.
REACT_471. E2F mediated regulation of DNA replication.
REACT_683. G1/S-Specific Transcription.
SABIO-RK P00374.

Miscellaneous databases

ChiTaRSi DHFR. human.
EvolutionaryTracei P00374.
GeneWikii Dihydrofolate_reductase.
GenomeRNAii 1719.
NextBioi 35470906.
PROi P00374.
SOURCEi Search...

Gene expression databases

Bgeei P00374.
CleanExi HS_DHFR.
ExpressionAtlasi P00374. baseline and differential.
Genevestigatori P00374.

Family and domain databases

Gene3Di 3.40.430.10. 1 hit.
InterProi IPR012259. DHFR.
IPR024072. DHFR-like_dom.
IPR017925. DHFR_CS.
IPR001796. DHFR_dom.
[Graphical view ]
Pfami PF00186. DHFR_1. 1 hit.
[Graphical view ]
PRINTSi PR00070. DHFR.
SUPFAMi SSF53597. SSF53597. 1 hit.
PROSITEi PS00075. DHFR_1. 1 hit.
PS51330. DHFR_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "The functional human dihydrofolate reductase gene."
    Chen M.-J., Shimada T., Moulton A.D., Cline A., Humphries R.K., Maizel J., Nienhuis A.W.
    J. Biol. Chem. 259:3933-3943(1984) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  2. "The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase."
    Masters J.N., Attardi G.
    Gene 21:59-63(1983) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
  3. "Human dihydrofolate reductase gene organization. Extensive conservation of the G + C-rich 5' non-coding sequence and strong intron size divergence from homologous mammalian genes."
    Yang J.K., Masters J.N., Attardi G.
    J. Mol. Biol. 176:169-187(1984) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  4. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
  5. "The DNA sequence and comparative analysis of human chromosome 5."
    Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.
    , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
    Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Eye.
  7. Cited for: TISSUE SPECIFICITY, VARIANT DHFRD PHE-80.
  8. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  9. "The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional."
    McEntee G., Minguzzi S., O'Brien K., Ben Larbi N., Loscher C., O'Fagain C., Parle-McDermott A.
    Proc. Natl. Acad. Sci. U.S.A. 108:15157-15162(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: CATALYTIC ACTIVITY, RNA-BINDING, BIOPHYSICOCHEMICAL PROPERTIES.
  10. "Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria."
    Anderson D.D., Quintero C.M., Stover P.J.
    Proc. Natl. Acad. Sci. U.S.A. 108:15163-15168(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  11. "Crystal structure of human dihydrofolate reductase complexed with folate."
    Oefner C., D'Arcy A., Winkler F.K.
    Eur. J. Biochem. 174:377-385(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH FOLATE.
  12. "Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate."
    Davies J.F., Delcamp T.J., Prendergast N.J., Ashford V.A., Freisheim J.H., Kraut J.
    Biochemistry 29:9467-9479(1990) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEXES WITH FOLATE AND 5-DEAZAFOLATE, SUBUNIT.
  13. "Sequence-specific 1H and 15N resonance assignments for human dihydrofolate reductase in solution."
    Stockman B.J., Nirmala N.R., Wagner G., Delcamp T.J., Deyarman M.T., Freisheim J.H.
    Biochemistry 31:218-229(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: STRUCTURE BY NMR.
  14. "Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers."
    Lewis W.S., Cody V., Galitsky N., Luft J.R., Pangborn W., Chunduru S.K., Spencer H.T., Appleman J.R., Blakley R.L.
    J. Biol. Chem. 270:5057-5064(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) IN COMPLEXES WITH NADPH; PIRITREXIM AND METOTHREXATE, MUTAGENESIS OF LEU-23.
  15. "Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523."
    Cody V., Galitsky N., Luft J.R., Pangborn W., Blakley R.L., Gangjee A.
    Biochemistry 36:13897-13903(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
  16. "Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents."
    Gangjee A., Vidwans A.P., Vasudevan A., Queener S.F., Kisliuk R.L., Cody V., Li R., Galitsky N., Luft J.R., Pangborn W.
    J. Med. Chem. 41:3426-3434(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEXES WITH NADPH AND QUINAZOLINE INHIBITORS, CATALYTIC ACTIVITY.
  17. "Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 A and 1.05 A resolution."
    Klon A.E., Heroux A., Ross L.J., Pathak V., Johnson C.A., Piper J.R., Borhani D.W.
    J. Mol. Biol. 320:677-693(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.05 ANGSTROMS) IN COMPLEXES WITH NADP AND THE SYNTHETIC INHIBITORS SRI-9439 AND SRI-9662, FUNCTION, CATALYTIC ACTIVITY.
  18. "Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase."
    Cody V., Galitsky N., Luft J.R., Pangborn W., Gangjee A.
    Acta Crystallogr. D 59:654-661(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
  19. "Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase."
    Cody V., Luft J.R., Pangborn W., Gangjee A.
    Acta Crystallogr. D 59:1603-1609(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
  20. "Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry."
    Cody V., Luft J.R., Pangborn W., Gangjee A., Queener S.F.
    Acta Crystallogr. D 60:646-655(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEX WITH NADPH AND INHIBITOR, MUTAGENESIS OF GLN-36 AND ASN-65, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
  21. "Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH."
    Cody V., Luft J.R., Pangborn W.
    Acta Crystallogr. D 61:147-155(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEXES WITH NADP AND METHOTREXATE, MUTAGENESIS OF LEU-23.
  22. "Solution structure of human dihydrofolate reductase in its complex with trimethoprim and NADPH."
    Kovalevskaya N.V., Smurnyy Y.D., Polshakov V.I., Birdsall B., Bradbury A.F., Frenkiel T., Feeney J.
    J. Biomol. NMR 33:69-72(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: STRUCTURE BY NMR IN COMPLEX WITH TRIMETHOPRIM AND NADPH.
  23. "Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation."
    Reynolds R.C., Campbell S.R., Fairchild R.G., Kisliuk R.L., Micca P.L., Queener S.F., Riordan J.M., Sedwick W.D., Waud W.R., Leung A.K., Dixon R.W., Suling W.J., Borhani D.W.
    J. Med. Chem. 50:3283-3289(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) IN COMPLEXES WITH NADP AND BORON-CONTAINING INHIBITORS, CATALYTIC ACTIVITY.
  24. "Correlations of inhibitor kinetics for Pneumocystis jirovecii and human dihydrofolate reductase with structural data for human active site mutant enzyme complexes."
    Cody V., Pace J., Makin J., Piraino J., Queener S.F., Rosowsky A.
    Biochemistry 48:1702-1711(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.23 ANGSTROMS) IN COMPLEXES WITH NADP AND THE SYNTHETIC INHIBITOR PY957, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF GLN-36 AND ASN-65.
  25. "Multiple conformers in active site of human dihydrofolate reductase F31R/Q35E double mutant suggest structural basis for methotrexate resistance."
    Volpato J.P., Yachnin B.J., Blanchet J., Guerrero V., Poulin L., Fossati E., Berghuis A.M., Pelletier J.N.
    J. Biol. Chem. 284:20079-20089(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF MUTANT ARG-32/GLU-36 IN COMPLEX WITH METHOTREXATE AND NADP, MUTAGENESIS OF PHE-32 AND GLN-36, CATALYTIC ACTIVITY.
  26. "Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents."
    Gangjee A., Li W., Kisliuk R.L., Cody V., Pace J., Piraino J., Makin J.
    J. Med. Chem. 52:4892-4902(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.24 ANGSTROMS) OF 1-187.
  27. "Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease."
    Cario H., Smith D.E., Blom H., Blau N., Bode H., Holzmann K., Pannicke U., Hopfner K.P., Rump E.M., Ayric Z., Kohne E., Debatin K.M., Smulders Y., Schwarz K.
    Am. J. Hum. Genet. 88:226-231(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT DHFRD VAL-153.

Entry informationi

Entry nameiDYR_HUMAN
AccessioniPrimary (citable) accession number: P00374
Secondary accession number(s): B4DDD2, Q14130, Q6IRW8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: January 23, 2007
Last modified: October 29, 2014
This is version 166 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3