ID   DYR2_HUMAN              Reviewed;         187 AA.
AC   Q86XF0; D3DN30; Q6P4I9;
DT   20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2003, sequence version 1.
DT   27-MAR-2024, entry version 151.
DE   RecName: Full=Dihydrofolate reductase 2, mitochondrial;
DE   AltName: Full=Dihydrofolate reductase, mitochondrial;
DE            EC=1.5.1.3;
DE   AltName: Full=Dihydrofolate reductase-like protein 1;
GN   Name=DHFR2 {ECO:0000312|HGNC:HGNC:27309}; Synonyms=DHFRL1, DHFRP4;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16641997; DOI=10.1038/nature04728;
RA   Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA   Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA   Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA   Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA   Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA   Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA   Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA   Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA   Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA   Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA   Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA   Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA   Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA   Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA   Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA   Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA   Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA   Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA   Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT   "The DNA sequence, annotation and analysis of human chromosome 3.";
RL   Nature 440:1194-1198(2006).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Melanoma;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ILE-166.
RC   TISSUE=Brain, and Muscle;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=21876188; DOI=10.1073/pnas.1103623108;
RA   Anderson D.D., Quintero C.M., Stover P.J.;
RT   "Identification of a de novo thymidylate biosynthesis pathway in mammalian
RT   mitochondria.";
RL   Proc. Natl. Acad. Sci. U.S.A. 108:15163-15168(2011).
RN   [6]
RP   FUNCTION, RNA-BINDING, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=21876184; DOI=10.1073/pnas.1103605108;
RA   McEntee G., Minguzzi S., O'Brien K., Ben Larbi N., Loscher C., O'Fagain C.,
RA   Parle-McDermott A.;
RT   "The former annotated human pseudogene dihydrofolate reductase-like 1
RT   (DHFRL1) is expressed and functional.";
RL   Proc. Natl. Acad. Sci. U.S.A. 108:15157-15162(2011).
RN   [7]
RP   PHYLOGENY.
RX   PubMed=25980602; DOI=10.1016/j.febslet.2015.05.017;
RA   Hughes L., Carton R., Minguzzi S., McEntee G., Deinum E.E., O'Connell M.J.,
RA   Parle-McDermott A.;
RT   "An active second dihydrofolate reductase enzyme is not a feature of rat
RT   and mouse, but they do have activity in their mitochondria.";
RL   FEBS Lett. 589:1855-1862(2015).
CC   -!- FUNCTION: Key enzyme in folate metabolism. Contributes to the de novo
CC       mitochondrial thymidylate biosynthesis pathway. Required to prevent
CC       uracil accumulation in mtDNA. Binds its own mRNA and that of DHFR.
CC       {ECO:0000269|PubMed:21876184, ECO:0000269|PubMed:21876188}.
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; Evidence={ECO:0000255|PROSITE-
CC         ProRule:PRU00660, ECO:0000269|PubMed:21876184};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=209 uM for dihydrofolate {ECO:0000269|PubMed:21876184};
CC         KM=20 uM for NADPH {ECO:0000269|PubMed:21876184};
CC   -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-
CC       tetrahydrofolate from 7,8-dihydrofolate: step 1/1.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:21876184,
CC       ECO:0000269|PubMed:21876188}. Mitochondrion matrix
CC       {ECO:0000269|PubMed:21876188}. Mitochondrion inner membrane
CC       {ECO:0000269|PubMed:21876188}.
CC   -!- TISSUE SPECIFICITY: Expressed in numerous cell lines.
CC       {ECO:0000269|PubMed:21876184}.
CC   -!- MISCELLANEOUS: Humans have acquired two dihydrofolate reductase enzymes
CC       during their evolution, DHFR and DHFR2. In contrast to human, mice and
CC       brown rats have just one. {ECO:0000269|PubMed:25980602}.
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; AL832912; CAH10617.1; -; mRNA.
DR   EMBL; AC130896; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471052; EAW79895.1; -; Genomic_DNA.
DR   EMBL; CH471052; EAW79896.1; -; Genomic_DNA.
DR   EMBL; BC045541; AAH45541.1; -; mRNA.
DR   EMBL; BC063379; AAH63379.1; -; mRNA.
DR   CCDS; CCDS2926.1; -.
DR   RefSeq; NP_001182572.1; NM_001195643.1.
DR   RefSeq; NP_789785.1; NM_176815.4.
DR   RefSeq; XP_011510839.1; XM_011512537.2.
DR   AlphaFoldDB; Q86XF0; -.
DR   SMR; Q86XF0; -.
DR   BioGRID; 128354; 292.
DR   IntAct; Q86XF0; 25.
DR   STRING; 9606.ENSP00000319170; -.
DR   DrugBank; DB02402; 5-(4-Methoxyphenoxy)-2,4-Quinazolinediamine.
DR   DrugBank; DB02001; 5-(4-Morpholin-4-Yl-Phenylsulfanyl)-2,4-Quinazolinediamine.
DR   DrugBank; DB04306; 5-[(4-Methylphenyl)Sulfanyl]-2,4-Quinazolinediamine.
DR   DrugBank; DB01958; 5-[4-Tert-Butylphenylsulfanyl]-2,4-Quinazolinediamine.
DR   DrugBank; DB01929; 5-Chloryl-2,4,6-quinazolinetriamine.
DR   DrugBank; DB04163; 5-Phenylsulfanyl-2,4-Quinazolinediamine.
DR   DrugBank; DB07862; 7-(1-ETHYL-PROPYL)-7H-PYRROLO-[3,2-F]QUINAZOLINE-1,3-DIAMINE.
DR   DrugBank; DB08203; 7-[2-METHOXY-1-(METHOXYMETHYL)ETHYL]-7H-PYRROLO[3,2-F] QUINAZOLINE-1,3-DIAMINE.
DR   DrugBank; DB12116; Epigallocatechin gallate.
DR   iPTMnet; Q86XF0; -.
DR   PhosphoSitePlus; Q86XF0; -.
DR   BioMuta; DHFR2; -.
DR   DMDM; 74727819; -.
DR   jPOST; Q86XF0; -.
DR   MassIVE; Q86XF0; -.
DR   MaxQB; Q86XF0; -.
DR   PaxDb; 9606-ENSP00000377768; -.
DR   PeptideAtlas; Q86XF0; -.
DR   ProteomicsDB; 70273; -.
DR   TopDownProteomics; Q86XF0; -.
DR   Antibodypedia; 32082; 142 antibodies from 20 providers.
DR   DNASU; 200895; -.
DR   Ensembl; ENST00000314636.3; ENSP00000319170.2; ENSG00000178700.9.
DR   Ensembl; ENST00000394221.3; ENSP00000377768.2; ENSG00000178700.9.
DR   Ensembl; ENST00000461173.5; ENSP00000418415.1; ENSG00000178700.9.
DR   Ensembl; ENST00000619045.1; ENSP00000480823.1; ENSG00000178700.9.
DR   GeneID; 200895; -.
DR   KEGG; hsa:200895; -.
DR   MANE-Select; ENST00000314636.3; ENSP00000319170.2; NM_176815.5; NP_789785.1.
DR   UCSC; uc003dri.3; human.
DR   AGR; HGNC:27309; -.
DR   CTD; 200895; -.
DR   DisGeNET; 200895; -.
DR   GeneCards; DHFR2; -.
DR   HGNC; HGNC:27309; DHFR2.
DR   HPA; ENSG00000178700; Low tissue specificity.
DR   MIM; 616588; gene.
DR   neXtProt; NX_Q86XF0; -.
DR   OpenTargets; ENSG00000178700; -.
DR   PharmGKB; PA134889916; -.
DR   VEuPathDB; HostDB:ENSG00000178700; -.
DR   eggNOG; KOG1324; Eukaryota.
DR   GeneTree; ENSGT00390000010283; -.
DR   InParanoid; Q86XF0; -.
DR   OMA; AMSQNMG; -.
DR   OrthoDB; 1118873at2759; -.
DR   PhylomeDB; Q86XF0; -.
DR   TreeFam; TF317636; -.
DR   BioCyc; MetaCyc:ENSG00000178700-MONOMER; -.
DR   BRENDA; 1.5.1.3; 2681.
DR   PathwayCommons; Q86XF0; -.
DR   Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR   SignaLink; Q86XF0; -.
DR   SIGNOR; Q86XF0; -.
DR   UniPathway; UPA00077; UER00158.
DR   BioGRID-ORCS; 200895; 381 hits in 1077 CRISPR screens.
DR   ChiTaRS; DHFR2; human.
DR   GenomeRNAi; 200895; -.
DR   Pharos; Q86XF0; Tbio.
DR   PRO; PR:Q86XF0; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; Q86XF0; Protein.
DR   Bgee; ENSG00000178700; Expressed in buccal mucosa cell and 196 other cell types or tissues.
DR   ExpressionAtlas; Q86XF0; baseline and differential.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IMP:UniProtKB.
DR   GO; GO:0005759; C:mitochondrial matrix; IMP:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0004146; F:dihydrofolate reductase activity; IMP:UniProtKB.
DR   GO; GO:0033560; F:folate reductase activity; TAS:Reactome.
DR   GO; GO:0003729; F:mRNA binding; IDA: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:0006545; P:glycine biosynthetic process; IEA:InterPro.
DR   GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IBA:GO_Central.
DR   GO; GO:0046653; P:tetrahydrofolate metabolic process; IDA:UniProtKB.
DR   GO; GO:0046105; P:thymidine biosynthetic process; IDA:UniProtKB.
DR   CDD; cd00209; DHFR; 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; IPR001796; DHFR_dom.
DR   PANTHER; PTHR48069; DIHYDROFOLATE REDUCTASE; 1.
DR   PANTHER; PTHR48069:SF1; DIHYDROFOLATE REDUCTASE 2, MITOCHONDRIAL; 1.
DR   Pfam; PF00186; DHFR_1; 1.
DR   PRINTS; PR00070; DHFR.
DR   SUPFAM; SSF53597; Dihydrofolate reductase-like; 1.
DR   PROSITE; PS51330; DHFR_2; 1.
DR   Genevisible; Q86XF0; HS.
PE   1: Evidence at protein level;
KW   Membrane; Mitochondrion; Mitochondrion inner membrane; NADP;
KW   One-carbon metabolism; Oxidoreductase; Reference proteome.
FT   CHAIN           1..187
FT                   /note="Dihydrofolate reductase 2, mitochondrial"
FT                   /id="PRO_0000186368"
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"
FT   BINDING         16..22
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   BINDING         31..36
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         55..57
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   BINDING         71
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         77..79
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   BINDING         117..124
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   VARIANT         166
FT                   /note="V -> I (in dbSNP:rs17855824)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_061135"
SQ   SEQUENCE   187 AA;  21620 MW;  BA6548FB0F576FF7 CRC64;
     MFLLLNCIVA VSQNMGIGKN GDLPRPPLRN EFRYFQRMTT TSSVEGKQNL VIMGRKTWFS
     IPEKNRPLKD RINLVLSREL KEPPQGAHFL ARSLDDALKL TERPELANKV DMIWIVGGSS
     VYKEAMNHLG HLKLFVTRIM QDFESDTFFS EIDLEKYKLL PEYPGVLSDV QEGKHIKYKF
     EVCEKDD
//