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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)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei10 – 101NADP; via amide nitrogen and carbonyl oxygen2 Publications
Binding sitei65 – 651Substrate1 Publication
Binding sitei71 – 711Substrate1 Publication

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi16 – 227NADP2 Publications
Nucleotide bindingi55 – 573NADP2 Publications
Nucleotide bindingi77 – 793NADP2 Publications
Nucleotide bindingi117 – 1248NADP2 Publications

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

ChEMBLiCHEMBL4564.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemoved1 Publication
Chaini2 – 187186Dihydrofolate reductasePRO_0000186364Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei33 – 331N6-acetyllysine; alternateCombined sources
Modified residuei33 – 331N6-succinyllysine; alternateCombined sources

Keywords - PTMi

Acetylation

Proteomic databases

EPDiP00375.
PaxDbiP00375.
PeptideAtlasiP00375.
PRIDEiP00375.

PTM databases

iPTMnetiP00375.
PhosphoSiteiP00375.

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 interactions.
MINTiMINT-4093753.
STRINGi10090.ENSMUSP00000022218.

Chemistry

BindingDBiP00375.

Structurei

Secondary structure

1
187
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi4 – 118Combined sources
Beta strandi15 – 195Combined sources
Beta strandi24 – 263Combined sources
Helixi29 – 4012Combined sources
Beta strandi43 – 464Combined sources
Beta strandi50 – 545Combined sources
Helixi55 – 606Combined sources
Helixi63 – 653Combined sources
Beta strandi71 – 766Combined sources
Beta strandi88 – 936Combined sources
Helixi94 – 1018Combined sources
Helixi104 – 1096Combined sources
Beta strandi113 – 1153Combined sources
Helixi119 – 1268Combined sources
Beta strandi128 – 1303Combined sources
Beta strandi132 – 1398Combined sources
Beta strandi146 – 1483Combined sources
Turni154 – 1563Combined sources
Beta strandi157 – 1593Combined sources
Beta strandi171 – 1733Combined sources
Beta strandi176 – 18510Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
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. Positions 2-187.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP00375.

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 binding1 Publication

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiKOG1324. Eukaryota.
COG0262. LUCA.
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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti4 – 41P → A in AAA37637 (PubMed:2982814).Curated
Sequence conflicti14 – 141N → D in CAA39544 (PubMed:2263462).Curated
Sequence conflicti123 – 1231Q → E AA sequence (PubMed:762074).Curated
Sequence conflicti123 – 1231Q → E in AAA37525 (PubMed:360074).Curated
Sequence conflicti124 – 1241E → Q AA sequence (PubMed:762074).Curated
Sequence conflicti128 – 1281Q → E AA sequence (PubMed:762074).Curated
Sequence conflicti174 – 1741K → D AA sequence (PubMed:762074).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti23 – 231L → R in a form with an abnormally low affinity for methotrexate. 1 Publication
Natural varianti32 – 321F → W in L-5178-Y cell line; methotrexate-resistant, requires 2 nucleotide substitutions.

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
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. Positions 2-187.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

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

Chemistry

BindingDBiP00375.
ChEMBLiCHEMBL4564.

PTM databases

iPTMnetiP00375.
PhosphoSiteiP00375.

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.
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: September 7, 2016
This is version 156 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.