DYR2_HUMAN
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 03-AUG-2022, entry version 143.
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}.
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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; 291.
DR IntAct; Q86XF0; 25.
DR STRING; 9606.ENSP00000377768; -.
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; Q86XF0; -.
DR PeptideAtlas; Q86XF0; -.
DR PRIDE; Q86XF0; -.
DR ProteomicsDB; 70273; -.
DR TopDownProteomics; Q86XF0; -.
DR Antibodypedia; 32082; 122 antibodies from 19 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 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; 1489621at2759; -.
DR PhylomeDB; Q86XF0; -.
DR TreeFam; TF317636; -.
DR BioCyc; MetaCyc:ENSG00000178700-MON; -.
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; 379 hits in 1004 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 194 other tissues.
DR ExpressionAtlas; Q86XF0; baseline and differential.
DR Genevisible; Q86XF0; HS.
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; -; 1.
DR InterPro; IPR012259; DHFR.
DR InterPro; IPR024072; DHFR-like_dom_sf.
DR InterPro; IPR001796; DHFR_dom.
DR PANTHER; PTHR48069; PTHR48069; 1.
DR Pfam; PF00186; DHFR_1; 1.
DR SUPFAM; SSF53597; SSF53597; 1.
DR PROSITE; PS51330; DHFR_2; 1.
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
