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Protein

Dihydrofolate reductase

Gene

DHFR

Organism
Mesocricetus auratus (Golden hamster)
Status
Reviewed-Annotation score: Annotation score: 4 out of 5-Experimental evidence at transcript 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 (By similarity).By similarity

Catalytic activityi

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

Pathway: 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 oxygenBy similarity
Binding sitei71 – 711SubstrateBy similarity
Binding sitei137 – 1371MethotrexateCurated

Regions

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

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

UniPathwayiUPA00077; UER00158.

Names & Taxonomyi

Protein namesi
Recommended name:
Dihydrofolate reductase (EC:1.5.1.3)
Gene namesi
Name:DHFR
OrganismiMesocricetus auratus (Golden hamster)
Taxonomic identifieri10036 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaCricetidaeCricetinaeMesocricetus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 187186Dihydrofolate reductasePRO_0000186363Add
BLAST

Amino acid modifications

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

Keywords - PTMi

Acetylation

Interactioni

Subunit structurei

Homodimer.By similarity

Structurei

3D structure databases

ProteinModelPortaliP04753.
SMRiP04753. Positions 2-186.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

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

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni8 – 3730Involved in methotrexate bindingCuratedAdd
BLAST
Regioni31 – 366Substrate bindingBy similarity
Regioni60 – 7011Involved in methotrexate bindingCuratedAdd
BLAST

Sequence similaritiesi

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

Phylogenomic databases

HOVERGENiHBG000773.

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]

Sequencei

Sequence statusi: Complete.

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

P04753-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVRPLNCIVA VSQNMGIGKN GDFPWPMLRN EFKYFQRMTT TSSVEGKQNL
60 70 80 90 100
VIMGRKTWFS IPEKNRPLKD RINIVLSREL KEPPQGAHFL AKSLDDALKL
110 120 130 140 150
IEQPELADKV DMVWIVGGSS VYKEAMNQPG HLRLFVTRIM QEFESDTFFP
160 170 180
EIDLEKYKLL PEYPGVLSEV QEEKGIKYKF EVYEKKG
Length:187
Mass (Da):21,660
Last modified:January 23, 2007 - v4
Checksum:iA91F85A74658C6F3
GO

Polymorphismi

The sequence shown is that of A3-35. The two clones A3-35 and MQ19-97 represent allelic forms. They differ in their drug sensitivities, possibly because of the difference at position 22.

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti23 – 231F → L in MQ19-97.
Natural varianti96 – 961D → N in MQ19-97.

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K01164 mRNA. Translation: AAA36974.1.
K01165 mRNA. Translation: AAA36976.1.
M19869 mRNA. Translation: AAA36970.1.
PIRiS42445.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K01164 mRNA. Translation: AAA36974.1.
K01165 mRNA. Translation: AAA36976.1.
M19869 mRNA. Translation: AAA36970.1.
PIRiS42445.

3D structure databases

ProteinModelPortaliP04753.
SMRiP04753. Positions 2-186.
ModBaseiSearch...
MobiDBiSearch...

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Phylogenomic databases

HOVERGENiHBG000773.

Enzyme and pathway databases

UniPathwayiUPA00077; UER00158.

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]
ProtoNetiSearch...

Publicationsi

  1. "Antifolate-resistant Chinese hamster cells. Molecular basis for the biochemical and structural heterogeneity among dihydrofolate reductases produced by drug-sensitive and drug-resistant cell lines."
    Melera P.W., Davide J.P., Oen H.
    J. Biol. Chem. 263:1978-1990(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  2. "Phenotypic expression in Escherichia coli and nucleotide sequence of two Chinese hamster lung cell cDNAs encoding different dihydrofolate reductases."
    Melera P.W., Davide J.P., Hession C.A., Scotto K.W.
    Mol. Cell. Biol. 4:38-48(1984) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Lung fibroblast.
  3. Erratum
    Melera P.W., Davide J.P., Hession C.A., Scotto K.W.
    Mol. Cell. Biol. 4:1001-1001(1984)

Entry informationi

Entry nameiDYR_MESAU
AccessioniPrimary (citable) accession number: P04753
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: January 23, 2007
Last modified: March 4, 2015
This is version 83 of the entry and version 4 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

Overexpression of the dihydrofolate gene (generally involving gene amplification) results in resistance to the antitumor antifolate drugs methotrexate (MTX) and methasquin.
Cell line DC-3F/A3 produces 90% of its dihydrofolate reductase in the 21k pI 6.5 form.
Cell line DC-3F/MQ19 produces 90% of its dihydrofolate reductase in the 20k pI 6.7 form (DHFR97).

Documents

  1. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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 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.