DYR_MESAU
ID DYR_MESAU Reviewed; 187 AA.
AC P04753;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 4.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=Dihydrofolate reductase;
DE EC=1.5.1.3;
GN Name=DHFR;
OS Mesocricetus auratus (Golden hamster).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Mesocricetus.
OX NCBI_TaxID=10036;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS LEU-23 AND ASN-96.
RX PubMed=3339001; DOI=10.1016/s0021-9258(19)77974-5;
RA Melera P.W., Davide J.P., Oen H.;
RT "Antifolate-resistant Chinese hamster cells. Molecular basis for the
RT biochemical and structural heterogeneity among dihydrofolate reductases
RT produced by drug-sensitive and drug-resistant cell lines.";
RL J. Biol. Chem. 263:1978-1990(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lung fibroblast;
RX PubMed=6366511; DOI=10.1128/mcb.4.1.38-48.1984;
RA Melera P.W., Davide J.P., Hession C.A., Scotto K.W.;
RT "Phenotypic expression in Escherichia coli and nucleotide sequence of two
RT Chinese hamster lung cell cDNAs encoding different dihydrofolate
RT reductases.";
RL Mol. Cell. Biol. 4:38-48(1984).
RN [3]
RP ERRATUM OF PUBMED:6366511.
RA Melera P.W., Davide J.P., Hession C.A., Scotto K.W.;
RL Mol. Cell. Biol. 4:1001-1001(1984).
CC -!- FUNCTION: Key enzyme in folate metabolism. Contributes to the de novo
CC mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential
CC reaction for de novo glycine and purine synthesis, and for DNA
CC precursor synthesis. Binds its own mRNA (By similarity).
CC {ECO:0000250|UniProtKB:P00374}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5,6,7,8-tetrahydrofolate + NADP(+) = 7,8-dihydrofolate +
CC H(+) + NADPH; Xref=Rhea:RHEA:15009, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57451, ChEBI:CHEBI:57453, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.5.1.3;
CC Evidence={ECO:0000250|UniProtKB:P00375, ECO:0000255|PROSITE-
CC ProRule:PRU00660};
CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-
CC tetrahydrofolate from 7,8-dihydrofolate: step 1/1.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P00374}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P00375}.
CC Cytoplasm {ECO:0000250|UniProtKB:P00375}.
CC -!- POLYMORPHISM: The sequence shown is that of A3-35. The two clones A3-35
CC and MQ19-97 represent allelic forms. They differ in their drug
CC sensitivities, possibly because of the difference at position 22.
CC {ECO:0000269|PubMed:3339001, ECO:0000269|PubMed:6366511}.
CC -!- MISCELLANEOUS: Overexpression of the dihydrofolate gene (generally
CC involving gene amplification) results in resistance to the antitumor
CC antifolate drugs methotrexate (MTX) and methasquin.
CC {ECO:0000305|PubMed:3339001}.
CC -!- SIMILARITY: Belongs to the dihydrofolate reductase family.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; K01164; AAA36974.1; -; mRNA.
DR EMBL; K01165; AAA36976.1; -; mRNA.
DR EMBL; M19869; AAA36970.1; -; mRNA.
DR PIR; S42445; S42445.
DR AlphaFoldDB; P04753; -.
DR SMR; P04753; -.
DR STRING; 10036.XP_005065719.1; -.
DR eggNOG; KOG1324; Eukaryota.
DR UniPathway; UPA00077; UER00158.
DR Proteomes; UP000189706; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0004146; F:dihydrofolate reductase activity; ISS:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
DR GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR GO; GO:0006545; P:glycine biosynthetic process; IEA:InterPro.
DR GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0031427; P:response to methotrexate; IEA:UniProtKB-KW.
DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0046653; P:tetrahydrofolate metabolic process; ISS:UniProtKB.
DR CDD; cd00209; DHFR; 1.
DR Gene3D; 3.40.430.10; -; 1.
DR InterPro; IPR012259; DHFR.
DR InterPro; IPR024072; DHFR-like_dom_sf.
DR InterPro; IPR017925; DHFR_CS.
DR InterPro; IPR001796; DHFR_dom.
DR PANTHER; PTHR48069; PTHR48069; 1.
DR Pfam; PF00186; DHFR_1; 1.
DR SUPFAM; SSF53597; SSF53597; 1.
DR PROSITE; PS00075; DHFR_1; 1.
DR PROSITE; PS51330; DHFR_2; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Cytoplasm; Methotrexate resistance; Mitochondrion; NADP;
KW One-carbon metabolism; Oxidoreductase; Reference proteome; RNA-binding.
FT CHAIN 1..187
FT /note="Dihydrofolate reductase"
FT /id="PRO_0000186363"
FT DOMAIN 4..185
FT /note="DHFR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00660"
FT REGION 8..37
FT /note="Involved in methotrexate binding"
FT /evidence="ECO:0000305"
FT REGION 60..70
FT /note="Involved in methotrexate binding"
FT /evidence="ECO:0000305"
FT BINDING 10
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P00374"
FT BINDING 16..22
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P00374"
FT BINDING 31..36
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00374"
FT BINDING 55..57
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P00374"
FT BINDING 71
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00374"
FT BINDING 77..79
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P00374"
FT BINDING 117..124
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P00374"
FT BINDING 137
FT /ligand="methotrexate"
FT /ligand_id="ChEBI:CHEBI:50681"
FT /evidence="ECO:0000305"
FT MOD_RES 33
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P00375"
FT MOD_RES 33
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P00375"
FT VARIANT 23
FT /note="F -> L (in MQ19-97)"
FT /evidence="ECO:0000269|PubMed:3339001"
FT VARIANT 96
FT /note="D -> N (in MQ19-97)"
FT /evidence="ECO:0000269|PubMed:3339001"
SQ SEQUENCE 187 AA; 21660 MW; A91F85A74658C6F3 CRC64;
MVRPLNCIVA VSQNMGIGKN GDFPWPMLRN EFKYFQRMTT TSSVEGKQNL VIMGRKTWFS
IPEKNRPLKD RINIVLSREL KEPPQGAHFL AKSLDDALKL IEQPELADKV DMVWIVGGSS
VYKEAMNQPG HLRLFVTRIM QEFESDTFFP EIDLEKYKLL PEYPGVLSEV QEEKGIKYKF
EVYEKKG
