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Protein

Dihydrofolate reductase

Gene

Dhfr

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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.

Catalytic activityi

5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH.PROSITE-ProRule annotation1 Publication

Pathwayi: tetrahydrofolate biosynthesis

This protein is involved in step 1 of the subpathway that synthesizes 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate.
Proteins known to be involved in this subpathway in this organism are:
  1. Dihydrofolate reductase (Dhfr)
This subpathway is part of the pathway tetrahydrofolate biosynthesis, which is itself part of Cofactor biosynthesis.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate, the pathway tetrahydrofolate biosynthesis and in Cofactor biosynthesis.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei10NADP; via amide nitrogen and carbonyl oxygen2 Publications1
Binding sitei65Substrate1 Publication1
Binding sitei71Substrate1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi16 – 22NADP2 Publications7
Nucleotide bindingi55 – 57NADP2 Publications3
Nucleotide bindingi77 – 79NADP2 Publications3
Nucleotide bindingi117 – 124NADP2 Publications8

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Keywords - Biological processi

Methotrexate resistance, One-carbon metabolism

Keywords - Ligandi

NADP, RNA-binding

Enzyme and pathway databases

BRENDAi1.5.1.3. 3474.
ReactomeiR-MMU-113510. E2F mediated regulation of DNA replication.
R-MMU-1474151. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
R-MMU-196757. Metabolism of folate and pterines.
R-MMU-69205. G1/S-Specific Transcription.
SABIO-RKP00375.
UniPathwayiUPA00077; UER00158.

Names & Taxonomyi

Protein namesi
Recommended name:
Dihydrofolate reductase (EC:1.5.1.3)
Gene namesi
Name:Dhfr
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:94890. Dhfr.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL4564.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved1 Publication
ChainiPRO_00001863642 – 187Dihydrofolate reductaseAdd BLAST186

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei33N6-acetyllysine; alternateCombined sources1
Modified residuei33N6-succinyllysine; alternateCombined sources1

Keywords - PTMi

Acetylation

Proteomic databases

EPDiP00375.
PaxDbiP00375.
PeptideAtlasiP00375.
PRIDEiP00375.

PTM databases

iPTMnetiP00375.
PhosphoSitePlusiP00375.

Expressioni

Gene expression databases

BgeeiENSMUSG00000021707.
CleanExiMM_DHFR.
ExpressionAtlasiP00375. baseline and differential.
GenevisibleiP00375. MM.

Interactioni

Subunit structurei

Homodimer.By similarity

Protein-protein interaction databases

IntActiP00375. 2 interactors.
MINTiMINT-4093753.
STRINGi10090.ENSMUSP00000022218.

Chemistry databases

BindingDBiP00375.

Structurei

Secondary structure

1187
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi4 – 11Combined sources8
Beta strandi15 – 19Combined sources5
Beta strandi24 – 26Combined sources3
Helixi29 – 40Combined sources12
Beta strandi43 – 46Combined sources4
Beta strandi50 – 54Combined sources5
Helixi55 – 60Combined sources6
Helixi63 – 65Combined sources3
Beta strandi71 – 76Combined sources6
Beta strandi88 – 93Combined sources6
Helixi94 – 101Combined sources8
Helixi104 – 109Combined sources6
Beta strandi113 – 115Combined sources3
Helixi119 – 126Combined sources8
Beta strandi128 – 130Combined sources3
Beta strandi132 – 139Combined sources8
Beta strandi146 – 148Combined sources3
Turni154 – 156Combined sources3
Beta strandi157 – 159Combined sources3
Beta strandi171 – 173Combined sources3
Beta strandi176 – 185Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1U70X-ray2.50A2-187[»]
2FZJX-ray2.00A2-187[»]
3D80X-ray1.40A2-187[»]
3D84X-ray1.90X2-187[»]
3K45X-ray1.60A2-187[»]
3K47X-ray2.05A2-187[»]
ProteinModelPortaliP00375.
SMRiP00375.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP00375.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini4 – 185DHFRPROSITE-ProRule annotationAdd BLAST182

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni31 – 36Substrate binding1 Publication6

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiKOG1324. Eukaryota.
COG0262. LUCA.
GeneTreeiENSGT00390000010283.
HOGENOMiHOG000040235.
HOVERGENiHBG000773.
InParanoidiP00375.
KOiK00287.
OMAiNIETIWN.
OrthoDBiEOG091G0PRK.
PhylomeDBiP00375.
TreeFamiTF317636.

Family and domain databases

CDDicd00209. DHFR. 1 hit.
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]

Sequencei

Sequence statusi: Complete.

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

P00375-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVRPLNCIVA VSQNMGIGKN GDLPWPPLRN EFKYFQRMTT TSSVEGKQNL
60 70 80 90 100
VIMGRKTWFS IPEKNRPLKD RINIVLSREL KEPPRGAHFL AKSLDDALRL
110 120 130 140 150
IEQPELASKV DMVWIVGGSS VYQEAMNQPG HLRLFVTRIM QEFESDTFFP
160 170 180
EIDLGKYKLL PEYPGVLSEV QEEKGIKYKF EVYEKKD
Length:187
Mass (Da):21,606
Last modified:January 23, 2007 - v3
Checksum:i47AEF15F879B119C
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti4P → A in AAA37637 (PubMed:2982814).Curated1
Sequence conflicti14N → D in CAA39544 (PubMed:2263462).Curated1
Sequence conflicti123Q → E AA sequence (PubMed:762074).Curated1
Sequence conflicti123Q → E in AAA37525 (PubMed:360074).Curated1
Sequence conflicti124E → Q AA sequence (PubMed:762074).Curated1
Sequence conflicti128Q → E AA sequence (PubMed:762074).Curated1
Sequence conflicti174K → D AA sequence (PubMed:762074).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti23L → R in a form with an abnormally low affinity for methotrexate. 1 Publication1
Natural varianti32F → W in L-5178-Y cell line; methotrexate-resistant, requires 2 nucleotide substitutions. 1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
V00734 mRNA. Translation: CAA24112.1.
X56066 mRNA. Translation: CAA39544.1.
BC005796 mRNA. Translation: AAH05796.1.
M10071 Genomic DNA. Translation: AAA37637.1.
L26316 mRNA. Translation: AAA37523.1.
J00387
, J00382, J00383, J00384, J00385, J00386 Genomic DNA. Translation: AAA37638.1.
V00731 mRNA. Translation: CAB43539.2.
M10722 mRNA. Translation: AAA37524.1.
M10811 mRNA. Translation: AAA37525.1.
V00733 Genomic DNA. Translation: CAA24111.1.
CCDSiCCDS26680.1.
PIRiS13096. RDMSD.
RefSeqiNP_034179.1. NM_010049.3.
UniGeneiMm.23695.

Genome annotation databases

EnsembliENSMUST00000022218; ENSMUSP00000022218; ENSMUSG00000021707.
GeneIDi13361.
KEGGimmu:13361.
UCSCiuc007rkl.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
V00734 mRNA. Translation: CAA24112.1.
X56066 mRNA. Translation: CAA39544.1.
BC005796 mRNA. Translation: AAH05796.1.
M10071 Genomic DNA. Translation: AAA37637.1.
L26316 mRNA. Translation: AAA37523.1.
J00387
, J00382, J00383, J00384, J00385, J00386 Genomic DNA. Translation: AAA37638.1.
V00731 mRNA. Translation: CAB43539.2.
M10722 mRNA. Translation: AAA37524.1.
M10811 mRNA. Translation: AAA37525.1.
V00733 Genomic DNA. Translation: CAA24111.1.
CCDSiCCDS26680.1.
PIRiS13096. RDMSD.
RefSeqiNP_034179.1. NM_010049.3.
UniGeneiMm.23695.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1U70X-ray2.50A2-187[»]
2FZJX-ray2.00A2-187[»]
3D80X-ray1.40A2-187[»]
3D84X-ray1.90X2-187[»]
3K45X-ray1.60A2-187[»]
3K47X-ray2.05A2-187[»]
ProteinModelPortaliP00375.
SMRiP00375.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP00375. 2 interactors.
MINTiMINT-4093753.
STRINGi10090.ENSMUSP00000022218.

Chemistry databases

BindingDBiP00375.
ChEMBLiCHEMBL4564.

PTM databases

iPTMnetiP00375.
PhosphoSitePlusiP00375.

Proteomic databases

EPDiP00375.
PaxDbiP00375.
PeptideAtlasiP00375.
PRIDEiP00375.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000022218; ENSMUSP00000022218; ENSMUSG00000021707.
GeneIDi13361.
KEGGimmu:13361.
UCSCiuc007rkl.1. mouse.

Organism-specific databases

CTDi1719.
MGIiMGI:94890. Dhfr.

Phylogenomic databases

eggNOGiKOG1324. Eukaryota.
COG0262. LUCA.
GeneTreeiENSGT00390000010283.
HOGENOMiHOG000040235.
HOVERGENiHBG000773.
InParanoidiP00375.
KOiK00287.
OMAiNIETIWN.
OrthoDBiEOG091G0PRK.
PhylomeDBiP00375.
TreeFamiTF317636.

Enzyme and pathway databases

UniPathwayiUPA00077; UER00158.
BRENDAi1.5.1.3. 3474.
ReactomeiR-MMU-113510. E2F mediated regulation of DNA replication.
R-MMU-1474151. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
R-MMU-196757. Metabolism of folate and pterines.
R-MMU-69205. G1/S-Specific Transcription.
SABIO-RKP00375.

Miscellaneous databases

ChiTaRSiDhfr. mouse.
EvolutionaryTraceiP00375.
PROiP00375.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000021707.
CleanExiMM_DHFR.
ExpressionAtlasiP00375. baseline and differential.
GenevisibleiP00375. MM.

Family and domain databases

CDDicd00209. DHFR. 1 hit.
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]
ProtoNetiSearch...

Entry informationi

Entry nameiDYR_MOUSE
AccessioniPrimary (citable) accession number: P00375
Secondary accession number(s): P70693
, Q61485, Q61487, Q61579
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: January 23, 2007
Last modified: November 2, 2016
This is version 158 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.