ID   DYR_BOVIN               Reviewed;         187 AA.
AC   P00376; Q29RI1;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   02-SEP-2026, entry version 139.
DE   RecName: Full=Dihydrofolate reductase {ECO:0000250|UniProtKB:P00374};
DE            EC=1.5.1.3 {ECO:0000250|UniProtKB:P00374};
GN   Name=DHFR {ECO:0000250|UniProtKB:P00374};
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Hereford; TISSUE=Heart ventricle;
RG   NIH - Mammalian Gene Collection (MGC) project;
RL   Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   PROTEIN SEQUENCE OF 2-187.
RC   TISSUE=Liver;
RX   PubMed=7115669; DOI=10.1021/bi00257a006;
RA   Lai P.-H., Pan Y.-C.E., Gleisner J.M., Peterson D.L., Williams K.R.,
RA   Blakley R.L.;
RT   "Structure of dihydrofolate reductase: primary sequence of the bovine liver
RT   enzyme.";
RL   Biochemistry 21:3284-3294(1982).
CC   -!- FUNCTION: Catalyzes the reduction of 7,8-dihydrofolate (DHF) to
CC       5,6,7,8-tetrahydrofolate in a NADPH-dependent manner. Key enzyme in
CC       folate metabolism. Contributes to the nuclear and mitochondrial de novo
CC       thymidylate biosynthesis pathway. Catalyzes an essential reaction for
CC       de novo glycine and purine synthesis, and for DNA precursor synthesis.
CC       Binds its own mRNA and that of DHFR2. {ECO:0000250|UniProtKB:P00374}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6S)-5,6,7,8-tetrahydrofolate + NADP(+) = 7,8-dihydrofolate +
CC         NADPH + H(+); 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:P00374, ECO:0000255|PROSITE-
CC         ProRule:PRU00660};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15011;
CC         Evidence={ECO:0000250|UniProtKB:P00374};
CC   -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-
CC       tetrahydrofolate from 7,8-dihydrofolate: step 1/1.
CC       {ECO:0000250|UniProtKB:P00374}.
CC   -!- SUBUNIT: Homodimer. Part of the de novo thymidylate synthesis complex
CC       composed at least by SHMT1, DHFR and TYMS. Interacts with SHMT1; this
CC       interaction is DNA-dependent and mediates DHFR co-localization with
CC       LMNB1. {ECO:0000250|UniProtKB:P00374}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P00375}.
CC       Cytoplasm {ECO:0000250|UniProtKB:P00375}. Nucleus
CC       {ECO:0000250|UniProtKB:P00374}. Note=Localized to the nucleus during S
CC       and G2/M phases of the cell cycle. As a component of the de novo
CC       thymidylate synthesis complex, localizes specifically to replication
CC       forks during DNA synthesis. {ECO:0000250|UniProtKB:P00374}.
CC   -!- PTM: Sumoylated by UBE2I/UBC9. {ECO:0000250|UniProtKB:P00374}.
CC   -!- SIMILARITY: Belongs to the dihydrofolate reductase family.
CC       {ECO:0000305}.
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DR   EMBL; BC114162; AAI14163.1; -; mRNA.
DR   PIR; A00388; RDBOD.
DR   RefSeq; NP_001071351.1; NM_001077883.1.
DR   AlphaFoldDB; P00376; -.
DR   SMR; P00376; -.
DR   FunCoup; P00376; 714.
DR   STRING; 9913.ENSBTAP00000010103; -.
DR   BindingDB; P00376; -.
DR   ChEMBL; CHEMBL1075051; -.
DR   DrugCentral; P00376; -.
DR   PaxDb; 9913-ENSBTAP00000010103; -.
DR   PeptideAtlas; P00376; -.
DR   GeneID; 508809; -.
DR   KEGG; bta:508809; -.
DR   CTD; 1719; -.
DR   eggNOG; KOG1324; Eukaryota.
DR   HOGENOM; CLU_043966_2_3_1; -.
DR   InParanoid; P00376; -.
DR   OrthoDB; 4664297at2759; -.
DR   SABIO-RK; P00376; -.
DR   UniPathway; UPA00077; UER00158.
DR   PRO; PR:P00376; -.
DR   Proteomes; UP000009136; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR   GO; GO:0005634; C:nucleus; 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; IBA:GO_Central.
DR   GO; GO:0046452; P:dihydrofolate metabolic process; IBA:GO_Central.
DR   GO; GO:0046655; P:folic acid metabolic process; IBA:GO_Central.
DR   GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IBA:GO_Central.
DR   GO; GO:0046653; P:tetrahydrofolate metabolic process; ISS:UniProtKB.
DR   CDD; cd00209; DHFR; 1.
DR   FunFam; 3.40.430.10:FF:000002; Dihydrofolate reductase; 1.
DR   Gene3D; 3.40.430.10; Dihydrofolate Reductase, subunit A; 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; DIHYDROFOLATE REDUCTASE; 1.
DR   PANTHER; PTHR48069:SF6; DIHYDROFOLATE REDUCTASE; 1.
DR   Pfam; PF00186; DHFR_1; 1.
DR   PRINTS; PR00070; DHFR.
DR   SUPFAM; SSF53597; Dihydrofolate reductase-like; 1.
DR   PROSITE; PS00075; DHFR_1; 1.
DR   PROSITE; PS51330; DHFR_2; 1.
PE   1: Evidence at protein level;
KW   Cytoplasm; Direct protein sequencing; Methotrexate resistance;
KW   Mitochondrion; NADP; Nucleus; One-carbon metabolism; Oxidoreductase;
KW   Reference proteome; RNA-binding; Ubl conjugation.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:7115669"
FT   CHAIN           2..187
FT                   /note="Dihydrofolate reductase"
FT                   /id="PRO_0000186361"
FT   DOMAIN          4..185
FT                   /note="DHFR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00660"
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   CONFLICT        22
FT                   /note="D -> N (in Ref. 1; AAI14163)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        102
FT                   /note="E -> Q (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   187 AA;  21604 MW;  0727DD855C8A7CD8 CRC64;
     MVRPLNCIVA VSQNMGIGKN GDLPWPPLRN EFQYFQRMTT VSSVEGKQNL VIMGRKTWFS
     IPEKNRPLKD RINIVLSREL KEPPKGAHFL AKSLDDALEL IEDPELTNKV DVVWIVGGSS
     VYKEAMNKPG HVRLFVTRIM QEFESDAFFP EIDFEKYKLL PEYPGVPLDV QEEKGIKYKF
     EVYEKNN
//