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Database: UniProt
Entry: P00374
LinkDB: P00374
Original site: P00374 
ID   DYR_HUMAN               Reviewed;         187 AA.
AC   P00374; B4DDD2; Q14130; Q6IRW8;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 2.
DT   17-JUN-2020, entry version 215.
DE   RecName: Full=Dihydrofolate reductase;
DE            EC=1.5.1.3;
GN   Name=DHFR;
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 [GENOMIC DNA].
RX   PubMed=6323448;
RA   Chen M.-J., Shimada T., Moulton A.D., Cline A., Humphries R.K., Maizel J.,
RA   Nienhuis A.W.;
RT   "The functional human dihydrofolate reductase gene.";
RL   J. Biol. Chem. 259:3933-3943(1984).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX   PubMed=6687716; DOI=10.1016/0378-1119(83)90147-6;
RA   Masters J.N., Attardi G.;
RT   "The nucleotide sequence of the cDNA coding for the human dihydrofolic acid
RT   reductase.";
RL   Gene 21:59-63(1983).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=6235374; DOI=10.1016/0022-2836(84)90419-4;
RA   Yang J.K., Masters J.N., Attardi G.;
RT   "Human dihydrofolate reductase gene organization. Extensive conservation of
RT   the G + C-rich 5' non-coding sequence and strong intron size divergence
RT   from homologous mammalian genes.";
RL   J. Mol. Biol. 176:169-187(1984).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15372022; DOI=10.1038/nature02919;
RA   Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA   Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA   She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA   Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA   Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA   Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA   Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA   Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA   Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA   Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA   Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA   Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA   Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT   "The DNA sequence and comparative analysis of human chromosome 5.";
RL   Nature 431:268-274(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Eye;
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   [7]
RP   TISSUE SPECIFICITY, AND VARIANT DHFRD PHE-80.
RX   PubMed=21310276; DOI=10.1016/j.ajhg.2011.01.004;
RA   Banka S., Blom H.J., Walter J., Aziz M., Urquhart J., Clouthier C.M.,
RA   Rice G.I., de Brouwer A.P., Hilton E., Vassallo G., Will A., Smith D.E.,
RA   Smulders Y.M., Wevers R.A., Steinfeld R., Heales S., Crow Y.J.,
RA   Pelletier J.N., Jones S., Newman W.G.;
RT   "Identification and characterization of an inborn error of metabolism
RT   caused by dihydrofolate reductase deficiency.";
RL   Am. J. Hum. Genet. 88:216-225(2011).
RN   [8]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [9]
RP   CATALYTIC ACTIVITY, RNA-BINDING, AND BIOPHYSICOCHEMICAL PROPERTIES.
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   [10]
RP   FUNCTION.
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   [11]
RP   X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH FOLATE.
RX   PubMed=3383852; DOI=10.1111/j.1432-1033.1988.tb14108.x;
RA   Oefner C., D'Arcy A., Winkler F.K.;
RT   "Crystal structure of human dihydrofolate reductase complexed with
RT   folate.";
RL   Eur. J. Biochem. 174:377-385(1988).
RN   [12]
RP   X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEXES WITH FOLATE AND
RP   5-DEAZAFOLATE, AND SUBUNIT.
RX   PubMed=2248959; DOI=10.1021/bi00492a021;
RA   Davies J.F., Delcamp T.J., Prendergast N.J., Ashford V.A., Freisheim J.H.,
RA   Kraut J.;
RT   "Crystal structures of recombinant human dihydrofolate reductase complexed
RT   with folate and 5-deazafolate.";
RL   Biochemistry 29:9467-9479(1990).
RN   [13]
RP   STRUCTURE BY NMR.
RX   PubMed=1731871; DOI=10.1021/bi00116a031;
RA   Stockman B.J., Nirmala N.R., Wagner G., Delcamp T.J., Deyarman M.T.,
RA   Freisheim J.H.;
RT   "Sequence-specific 1H and 15N resonance assignments for human dihydrofolate
RT   reductase in solution.";
RL   Biochemistry 31:218-229(1992).
RN   [14]
RP   X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) IN COMPLEXES WITH NADPH; PIRITREXIM
RP   AND METOTHREXATE, AND MUTAGENESIS OF LEU-23.
RX   PubMed=7890613; DOI=10.1074/jbc.270.10.5057;
RA   Lewis W.S., Cody V., Galitsky N., Luft J.R., Pangborn W., Chunduru S.K.,
RA   Spencer H.T., Appleman J.R., Blakley R.L.;
RT   "Methotrexate-resistant variants of human dihydrofolate reductase with
RT   substitutions of leucine 22. Kinetics, crystallography, and potential as
RT   selectable markers.";
RL   J. Biol. Chem. 270:5057-5064(1995).
RN   [15]
RP   X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
RX   PubMed=9374868; DOI=10.1021/bi971711l;
RA   Cody V., Galitsky N., Luft J.R., Pangborn W., Blakley R.L., Gangjee A.;
RT   "Comparison of two independent crystal structures of human dihydrofolate
RT   reductase ternary complexes reduced with nicotinamide adenine dinucleotide
RT   phosphate and the very tight-binding inhibitor PT523.";
RL   Biochemistry 36:13897-13903(1997).
RN   [16]
RP   X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEXES WITH NADPH AND
RP   QUINAZOLINE INHIBITORS, AND CATALYTIC ACTIVITY.
RX   PubMed=9719595; DOI=10.1021/jm980081y;
RA   Gangjee A., Vidwans A.P., Vasudevan A., Queener S.F., Kisliuk R.L.,
RA   Cody V., Li R., Galitsky N., Luft J.R., Pangborn W.;
RT   "Structure-based design and synthesis of lipophilic 2,4-diamino-6-
RT   substituted quinazolines and their evaluation as inhibitors of
RT   dihydrofolate reductases and potential antitumor agents.";
RL   J. Med. Chem. 41:3426-3434(1998).
RN   [17]
RP   X-RAY CRYSTALLOGRAPHY (1.05 ANGSTROMS) IN COMPLEXES WITH NADP AND THE
RP   SYNTHETIC INHIBITORS SRI-9439 AND SRI-9662, FUNCTION, AND CATALYTIC
RP   ACTIVITY.
RX   PubMed=12096917; DOI=10.1016/s0022-2836(02)00469-2;
RA   Klon A.E., Heroux A., Ross L.J., Pathak V., Johnson C.A., Piper J.R.,
RA   Borhani D.W.;
RT   "Atomic structures of human dihydrofolate reductase complexed with NADPH
RT   and two lipophilic antifolates at 1.09 A and 1.05 A resolution.";
RL   J. Mol. Biol. 320:677-693(2002).
RN   [18]
RP   X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX   PubMed=12657784; DOI=10.1107/s0907444903001951;
RA   Cody V., Galitsky N., Luft J.R., Pangborn W., Gangjee A.;
RT   "Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10
RT   reversed-bridge antifolate binary complex with human dihydrofolate
RT   reductase.";
RL   Acta Crystallogr. D 59:654-661(2003).
RN   [19]
RP   X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX   PubMed=12925791; DOI=10.1107/s0907444903014963;
RA   Cody V., Luft J.R., Pangborn W., Gangjee A.;
RT   "Analysis of three crystal structure determinations of a 5-methyl-6-N-
RT   methylanilino pyridopyrimidine antifolate complex with human dihydrofolate
RT   reductase.";
RL   Acta Crystallogr. D 59:1603-1609(2003).
RN   [20]
RP   X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEX WITH NADPH AND INHIBITOR,
RP   MUTAGENESIS OF GLN-36 AND ASN-65, CATALYTIC ACTIVITY, AND
RP   BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=15039552; DOI=10.1107/s0907444904002094;
RA   Cody V., Luft J.R., Pangborn W., Gangjee A., Queener S.F.;
RT   "Structure determination of tetrahydroquinazoline antifolates in complex
RT   with human and Pneumocystis carinii dihydrofolate reductase: correlations
RT   between enzyme selectivity and stereochemistry.";
RL   Acta Crystallogr. D 60:646-655(2004).
RN   [21]
RP   X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEXES WITH NADP AND
RP   METHOTREXATE, AND MUTAGENESIS OF LEU-23.
RX   PubMed=15681865; DOI=10.1107/s0907444904030422;
RA   Cody V., Luft J.R., Pangborn W.;
RT   "Understanding the role of Leu22 variants in methotrexate resistance:
RT   comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate
RT   reductase ternary crystal complexes with methotrexate and NADPH.";
RL   Acta Crystallogr. D 61:147-155(2005).
RN   [22]
RP   STRUCTURE BY NMR IN COMPLEX WITH TRIMETHOPRIM AND NADPH.
RX   PubMed=16222560; DOI=10.1007/s10858-005-1475-z;
RA   Kovalevskaya N.V., Smurnyy Y.D., Polshakov V.I., Birdsall B.,
RA   Bradbury A.F., Frenkiel T., Feeney J.;
RT   "Solution structure of human dihydrofolate reductase in its complex with
RT   trimethoprim and NADPH.";
RL   J. Biomol. NMR 33:69-72(2005).
RN   [23]
RP   X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) IN COMPLEXES WITH NADP AND
RP   BORON-CONTAINING INHIBITORS, AND CATALYTIC ACTIVITY.
RX   PubMed=17569517; DOI=10.1021/jm0701977;
RA   Reynolds R.C., Campbell S.R., Fairchild R.G., Kisliuk R.L., Micca P.L.,
RA   Queener S.F., Riordan J.M., Sedwick W.D., Waud W.R., Leung A.K.,
RA   Dixon R.W., Suling W.J., Borhani D.W.;
RT   "Novel boron-containing, nonclassical antifolates: synthesis and
RT   preliminary biological and structural evaluation.";
RL   J. Med. Chem. 50:3283-3289(2007).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (1.23 ANGSTROMS) IN COMPLEXES WITH NADP AND THE
RP   SYNTHETIC INHIBITOR PY957, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP   PROPERTIES, AND MUTAGENESIS OF GLN-36 AND ASN-65.
RX   PubMed=19196009; DOI=10.1021/bi801960h;
RA   Cody V., Pace J., Makin J., Piraino J., Queener S.F., Rosowsky A.;
RT   "Correlations of inhibitor kinetics for Pneumocystis jirovecii and human
RT   dihydrofolate reductase with structural data for human active site mutant
RT   enzyme complexes.";
RL   Biochemistry 48:1702-1711(2009).
RN   [25]
RP   X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF MUTANT ARG-32/GLU-36 IN COMPLEX
RP   WITH METHOTREXATE AND NADP, MUTAGENESIS OF PHE-32 AND GLN-36, AND CATALYTIC
RP   ACTIVITY.
RX   PubMed=19478082; DOI=10.1074/jbc.m109.018010;
RA   Volpato J.P., Yachnin B.J., Blanchet J., Guerrero V., Poulin L.,
RA   Fossati E., Berghuis A.M., Pelletier J.N.;
RT   "Multiple conformers in active site of human dihydrofolate reductase
RT   F31R/Q35E double mutant suggest structural basis for methotrexate
RT   resistance.";
RL   J. Biol. Chem. 284:20079-20089(2009).
RN   [26]
RP   X-RAY CRYSTALLOGRAPHY (1.24 ANGSTROMS) OF 1-187.
RX   PubMed=19719239; DOI=10.1021/jm900490a;
RA   Gangjee A., Li W., Kisliuk R.L., Cody V., Pace J., Piraino J., Makin J.;
RT   "Design, synthesis, and X-ray crystal structure of classical and
RT   nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as
RT   dual thymidylate synthase and dihydrofolate reductase inhibitors and as
RT   potential antitumor agents.";
RL   J. Med. Chem. 52:4892-4902(2009).
RN   [27]
RP   VARIANT DHFRD VAL-153.
RX   PubMed=21310277; DOI=10.1016/j.ajhg.2011.01.007;
RA   Cario H., Smith D.E., Blom H., Blau N., Bode H., Holzmann K., Pannicke U.,
RA   Hopfner K.P., Rump E.M., Ayric Z., Kohne E., Debatin K.M., Smulders Y.,
RA   Schwarz K.;
RT   "Dihydrofolate reductase deficiency due to a homozygous DHFR mutation
RT   causes megaloblastic anemia and cerebral folate deficiency leading to
RT   severe neurologic disease.";
RL   Am. J. Hum. Genet. 88:226-231(2011).
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 and that of DHFR2.
CC       {ECO:0000269|PubMed:12096917, 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:12096917,
CC         ECO:0000269|PubMed:15039552, ECO:0000269|PubMed:17569517,
CC         ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:19478082,
CC         ECO:0000269|PubMed:21876184, ECO:0000269|PubMed:9719595};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=2.7 uM for dihydrofolate {ECO:0000269|PubMed:15039552,
CC         ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:21876184};
CC         KM=4.0 uM for NADPH {ECO:0000269|PubMed:15039552,
CC         ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:21876184};
CC   -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-
CC       tetrahydrofolate from 7,8-dihydrofolate: step 1/1.
CC   -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:12657784,
CC       ECO:0000269|PubMed:12925791, ECO:0000269|PubMed:15039552,
CC       ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082,
CC       ECO:0000269|PubMed:2248959, ECO:0000269|PubMed:3383852}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P00375}.
CC       Cytoplasm {ECO:0000250|UniProtKB:P00375}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P00374-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P00374-2; Sequence=VSP_056352;
CC   -!- TISSUE SPECIFICITY: Widely expressed in fetal and adult tissues,
CC       including throughout the fetal and adult brains and whole blood.
CC       Expression is higher in the adult brain than in the fetal brain.
CC       {ECO:0000269|PubMed:21310276}.
CC   -!- DISEASE: Megaloblastic anemia due to dihydrofolate reductase deficiency
CC       (DHFRD) [MIM:613839]: An inborn error of metabolism, characterized by
CC       megaloblastic anemia and/or pancytopenia, severe cerebral folate
CC       deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical
CC       features include variable neurologic symptoms, ranging from severe
CC       developmental delay and generalized seizures in infancy, to childhood
CC       absence epilepsy with learning difficulties, to lack of symptoms.
CC       {ECO:0000269|PubMed:21310276, ECO:0000269|PubMed:21310277}. Note=The
CC       disease is caused by mutations affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the dihydrofolate reductase family.
CC       {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Dihydrofolate reductase entry;
CC       URL="https://en.wikipedia.org/wiki/Dihydrofolate_reductase";
DR   EMBL; J00140; AAA58485.1; -; mRNA.
DR   EMBL; V00507; CAA23765.1; -; mRNA.
DR   EMBL; J00139; AAA58484.1; -; Genomic_DNA.
DR   EMBL; K01612; AAA58484.1; JOINED; Genomic_DNA.
DR   EMBL; K01613; AAA58484.1; JOINED; Genomic_DNA.
DR   EMBL; J00138; AAA58484.1; JOINED; Genomic_DNA.
DR   EMBL; K01614; AAA58484.1; JOINED; Genomic_DNA.
DR   EMBL; X00855; CAA25409.1; -; Genomic_DNA.
DR   EMBL; X00856; CAA25409.1; JOINED; Genomic_DNA.
DR   EMBL; X00857; CAA25409.1; JOINED; Genomic_DNA.
DR   EMBL; X00858; CAA25409.1; JOINED; Genomic_DNA.
DR   EMBL; X00859; CAA25409.1; JOINED; Genomic_DNA.
DR   EMBL; AK293146; BAG56693.1; -; mRNA.
DR   EMBL; AC008434; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC010270; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC000192; AAH00192.1; -; mRNA.
DR   EMBL; BC003584; AAH03584.2; -; mRNA.
DR   EMBL; BC070280; AAH70280.1; -; mRNA.
DR   EMBL; BC071996; AAH71996.1; -; mRNA.
DR   CCDS; CCDS47240.1; -. [P00374-1]
DR   CCDS; CCDS78028.1; -. [P00374-2]
DR   PIR; A22551; RDHUD.
DR   RefSeq; NP_000782.1; NM_000791.3. [P00374-1]
DR   RefSeq; NP_001277283.1; NM_001290354.1. [P00374-2]
DR   PDB; 1BOZ; X-ray; 2.10 A; A=2-187.
DR   PDB; 1DHF; X-ray; 2.30 A; A/B=2-187.
DR   PDB; 1DLR; X-ray; 2.30 A; A=2-187.
DR   PDB; 1DLS; X-ray; 2.30 A; A=2-187.
DR   PDB; 1DRF; X-ray; 2.00 A; A=2-187.
DR   PDB; 1HFP; X-ray; 2.10 A; A=2-187.
DR   PDB; 1HFQ; X-ray; 2.10 A; A=2-187.
DR   PDB; 1HFR; X-ray; 2.10 A; A=2-187.
DR   PDB; 1KMS; X-ray; 1.09 A; A=2-187.
DR   PDB; 1KMV; X-ray; 1.05 A; A=2-187.
DR   PDB; 1MVS; X-ray; 1.90 A; A=1-187.
DR   PDB; 1MVT; X-ray; 1.80 A; A=1-187.
DR   PDB; 1OHJ; X-ray; 2.50 A; A=2-187.
DR   PDB; 1OHK; X-ray; 2.50 A; A=2-187.
DR   PDB; 1PD8; X-ray; 2.10 A; A=2-187.
DR   PDB; 1PD9; X-ray; 2.20 A; A=2-187.
DR   PDB; 1PDB; X-ray; 2.20 A; A=2-187.
DR   PDB; 1S3U; X-ray; 2.50 A; A=2-187.
DR   PDB; 1S3V; X-ray; 1.80 A; A=2-187.
DR   PDB; 1S3W; X-ray; 1.90 A; A=2-187.
DR   PDB; 1U71; X-ray; 2.20 A; A=2-187.
DR   PDB; 1U72; X-ray; 1.90 A; A=2-187.
DR   PDB; 1YHO; NMR; -; A=2-187.
DR   PDB; 2C2S; X-ray; 1.40 A; A/B=2-187.
DR   PDB; 2C2T; X-ray; 1.50 A; A/B=2-187.
DR   PDB; 2DHF; X-ray; 2.30 A; A/B=2-187.
DR   PDB; 2W3A; X-ray; 1.50 A; A/B=1-187.
DR   PDB; 2W3B; X-ray; 1.27 A; A/B=1-187.
DR   PDB; 2W3M; X-ray; 1.60 A; A/B=1-187.
DR   PDB; 3EIG; X-ray; 1.70 A; A=2-187.
DR   PDB; 3F8Y; X-ray; 1.45 A; A=1-187.
DR   PDB; 3F8Z; X-ray; 2.01 A; A=1-187.
DR   PDB; 3F91; X-ray; 1.90 A; A=1-187.
DR   PDB; 3FS6; X-ray; 1.23 A; A=1-187.
DR   PDB; 3GHC; X-ray; 1.30 A; A=2-187.
DR   PDB; 3GHV; X-ray; 1.30 A; A=2-187.
DR   PDB; 3GHW; X-ray; 1.24 A; A=2-187.
DR   PDB; 3GI2; X-ray; 1.53 A; A=1-187.
DR   PDB; 3GYF; X-ray; 1.70 A; A=1-187.
DR   PDB; 3L3R; X-ray; 2.00 A; A=2-187.
DR   PDB; 3N0H; X-ray; 1.92 A; A=2-187.
DR   PDB; 3NTZ; X-ray; 1.35 A; A=2-187.
DR   PDB; 3NU0; X-ray; 1.35 A; A=2-187.
DR   PDB; 3NXO; X-ray; 1.35 A; A=2-187.
DR   PDB; 3NXR; X-ray; 1.35 A; A=2-187.
DR   PDB; 3NXT; X-ray; 1.70 A; A=2-187.
DR   PDB; 3NXV; X-ray; 1.90 A; A=2-187.
DR   PDB; 3NXX; X-ray; 1.35 A; A=2-187.
DR   PDB; 3NXY; X-ray; 1.90 A; A=2-187.
DR   PDB; 3NZD; X-ray; 1.80 A; A=2-187.
DR   PDB; 3OAF; X-ray; 1.70 A; A=2-187.
DR   PDB; 3S3V; X-ray; 1.53 A; A=2-187.
DR   PDB; 3S7A; X-ray; 1.80 A; A=2-187.
DR   PDB; 4DDR; X-ray; 2.05 A; A=2-187.
DR   PDB; 4G95; X-ray; 1.35 A; A=2-187.
DR   PDB; 4KAK; X-ray; 1.80 A; A/B=2-187.
DR   PDB; 4KBN; X-ray; 1.84 A; A/B=2-187.
DR   PDB; 4KD7; X-ray; 2.72 A; A/B=2-187.
DR   PDB; 4KEB; X-ray; 1.45 A; A/B=2-187.
DR   PDB; 4KFJ; X-ray; 1.76 A; A/B=2-187.
DR   PDB; 4M6J; X-ray; 1.20 A; A=1-187.
DR   PDB; 4M6K; X-ray; 1.40 A; A=1-187.
DR   PDB; 4M6L; X-ray; 1.70 A; A=1-187.
DR   PDB; 4QHV; X-ray; 1.61 A; A=2-187.
DR   PDB; 4QJC; X-ray; 1.62 A; A=2-187.
DR   PDB; 5HPB; X-ray; 1.65 A; A=2-187.
DR   PDB; 5HQY; X-ray; 1.46 A; A=2-187.
DR   PDB; 5HQZ; X-ray; 1.46 A; A=2-187.
DR   PDB; 5HSR; X-ray; 1.21 A; A=2-187.
DR   PDB; 5HSU; X-ray; 1.46 A; A=2-187.
DR   PDB; 5HT4; X-ray; 1.60 A; A=2-187.
DR   PDB; 5HT5; X-ray; 1.90 A; A=2-187.
DR   PDB; 5HUI; X-ray; 1.46 A; A=2-187.
DR   PDB; 5HVB; X-ray; 1.60 A; A=2-187.
DR   PDB; 5HVE; X-ray; 1.46 A; A=2-187.
DR   PDB; 6A7C; X-ray; 2.06 A; A=2-187.
DR   PDB; 6A7E; X-ray; 1.85 A; A=2-187.
DR   PDB; 6DAV; X-ray; 1.55 A; A/B=1-187.
DR   PDB; 6DE4; X-ray; 2.41 A; A/B=2-187.
DR   PDBsum; 1BOZ; -.
DR   PDBsum; 1DHF; -.
DR   PDBsum; 1DLR; -.
DR   PDBsum; 1DLS; -.
DR   PDBsum; 1DRF; -.
DR   PDBsum; 1HFP; -.
DR   PDBsum; 1HFQ; -.
DR   PDBsum; 1HFR; -.
DR   PDBsum; 1KMS; -.
DR   PDBsum; 1KMV; -.
DR   PDBsum; 1MVS; -.
DR   PDBsum; 1MVT; -.
DR   PDBsum; 1OHJ; -.
DR   PDBsum; 1OHK; -.
DR   PDBsum; 1PD8; -.
DR   PDBsum; 1PD9; -.
DR   PDBsum; 1PDB; -.
DR   PDBsum; 1S3U; -.
DR   PDBsum; 1S3V; -.
DR   PDBsum; 1S3W; -.
DR   PDBsum; 1U71; -.
DR   PDBsum; 1U72; -.
DR   PDBsum; 1YHO; -.
DR   PDBsum; 2C2S; -.
DR   PDBsum; 2C2T; -.
DR   PDBsum; 2DHF; -.
DR   PDBsum; 2W3A; -.
DR   PDBsum; 2W3B; -.
DR   PDBsum; 2W3M; -.
DR   PDBsum; 3EIG; -.
DR   PDBsum; 3F8Y; -.
DR   PDBsum; 3F8Z; -.
DR   PDBsum; 3F91; -.
DR   PDBsum; 3FS6; -.
DR   PDBsum; 3GHC; -.
DR   PDBsum; 3GHV; -.
DR   PDBsum; 3GHW; -.
DR   PDBsum; 3GI2; -.
DR   PDBsum; 3GYF; -.
DR   PDBsum; 3L3R; -.
DR   PDBsum; 3N0H; -.
DR   PDBsum; 3NTZ; -.
DR   PDBsum; 3NU0; -.
DR   PDBsum; 3NXO; -.
DR   PDBsum; 3NXR; -.
DR   PDBsum; 3NXT; -.
DR   PDBsum; 3NXV; -.
DR   PDBsum; 3NXX; -.
DR   PDBsum; 3NXY; -.
DR   PDBsum; 3NZD; -.
DR   PDBsum; 3OAF; -.
DR   PDBsum; 3S3V; -.
DR   PDBsum; 3S7A; -.
DR   PDBsum; 4DDR; -.
DR   PDBsum; 4G95; -.
DR   PDBsum; 4KAK; -.
DR   PDBsum; 4KBN; -.
DR   PDBsum; 4KD7; -.
DR   PDBsum; 4KEB; -.
DR   PDBsum; 4KFJ; -.
DR   PDBsum; 4M6J; -.
DR   PDBsum; 4M6K; -.
DR   PDBsum; 4M6L; -.
DR   PDBsum; 4QHV; -.
DR   PDBsum; 4QJC; -.
DR   PDBsum; 5HPB; -.
DR   PDBsum; 5HQY; -.
DR   PDBsum; 5HQZ; -.
DR   PDBsum; 5HSR; -.
DR   PDBsum; 5HSU; -.
DR   PDBsum; 5HT4; -.
DR   PDBsum; 5HT5; -.
DR   PDBsum; 5HUI; -.
DR   PDBsum; 5HVB; -.
DR   PDBsum; 5HVE; -.
DR   PDBsum; 6A7C; -.
DR   PDBsum; 6A7E; -.
DR   PDBsum; 6DAV; -.
DR   PDBsum; 6DE4; -.
DR   SMR; P00374; -.
DR   BioGRID; 108065; 27.
DR   IntAct; P00374; 9.
DR   MINT; P00374; -.
DR   STRING; 9606.ENSP00000396308; -.
DR   BindingDB; P00374; -.
DR   ChEMBL; CHEMBL202; -.
DR   DrugBank; DB08642; (2R,6S)-6-{[methyl(3,4,5-trimethoxyphenyl)amino]methyl}-1,2,5,6,7,8-hexahydroquinazoline-2,4-diamine.
DR   DrugBank; DB08448; (4aS)-5-[(2,4-diaminopteridin-6-yl)methyl]-4a,5-dihydro-2H-dibenzo[b,f]azepin-8-ol.
DR   DrugBank; DB03125; 2,4-Diamino-5-(3,4,5-Trimethoxy-Benzyl)-Pyrimidin-1-Ium.
DR   DrugBank; DB02104; 2,4-Diamino-5-Methyl-6-[(3,4,5-Trimethoxy-N-Methylanilino)Methyl]Pyrido[2,3-D]Pyrimidine.
DR   DrugBank; DB02427; 2,4-Diamino-6-[N-(2',5'-Dimethoxybenzyl)-N-Methylamino]Quinazoline.
DR   DrugBank; DB02919; 2,4-Diamino-6-[N-(3',4',5'-Trimethoxybenzyl)-N-Methylamino]Pyrido[2,3-D]Pyrimidine.
DR   DrugBank; DB03987; 2,4-Diamino-6-[N-(3',5'-Dimethoxybenzyl)-N-Methylamino]Pyrido[2,3-D]Pyrimidine.
DR   DrugBank; DB07144; 5-[(3R)-3-(5-methoxy-2',6'-dimethylbiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine.
DR   DrugBank; DB07142; 5-[(3R)-3-(5-methoxy-3',5'-dimethylbiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine.
DR   DrugBank; DB07141; 5-[(3R)-3-(5-methoxy-4'-methylbiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine.
DR   DrugBank; DB07140; 5-[(3R)-3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine.
DR   DrugBank; DB08234; 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine.
DR   DrugBank; DB02559; 6-(Octahydro-1h-Indol-1-Ylmethyl)Decahydroquinazoline-2,4-Diamine.
DR   DrugBank; DB08406; [N-(2,4-DIAMINOPTERIDIN-6-YL)-METHYL]-DIBENZ[B,F]AZEPINE.
DR   DrugBank; DB08878; Aminopterin.
DR   DrugBank; DB03886; Biopterin.
DR   DrugBank; DB00158; Folic acid.
DR   DrugBank; DB00798; Gentamicin.
DR   DrugBank; DB06358; Iclaprim.
DR   DrugBank; DB00555; Lamotrigine.
DR   DrugBank; DB00563; Methotrexate.
DR   DrugBank; DB02583; N6-(2,5-Dimethoxy-Benzyl)-N6-Methyl-Pyrido[2,3-D]Pyrimidine-2,4,6-Triamine.
DR   DrugBank; DB00157; NADH.
DR   DrugBank; DB03461; Nicotinamide adenine dinucleotide phosphate.
DR   DrugBank; DB00642; Pemetrexed.
DR   DrugBank; DB03695; Piritrexim.
DR   DrugBank; DB06813; Pralatrexate.
DR   DrugBank; DB01131; Proguanil.
DR   DrugBank; DB00205; Pyrimethamine.
DR   DrugBank; DB03351; Sri-9439.
DR   DrugBank; DB03060; Sri-9662.
DR   DrugBank; DB00440; Trimethoprim.
DR   DrugBank; DB01157; Trimetrexate.
DR   DrugCentral; P00374; -.
DR   GuidetoPHARMACOLOGY; 2603; -.
DR   MoonProt; P00374; -.
DR   iPTMnet; P00374; -.
DR   PhosphoSitePlus; P00374; -.
DR   SwissPalm; P00374; -.
DR   BioMuta; DHFR; -.
DR   DMDM; 118992; -.
DR   UCD-2DPAGE; P00374; -.
DR   EPD; P00374; -.
DR   jPOST; P00374; -.
DR   MassIVE; P00374; -.
DR   MaxQB; P00374; -.
DR   PaxDb; P00374; -.
DR   PeptideAtlas; P00374; -.
DR   PRIDE; P00374; -.
DR   ProteomicsDB; 3847; -.
DR   ProteomicsDB; 51237; -. [P00374-1]
DR   Antibodypedia; 24646; 294 antibodies.
DR   DNASU; 1719; -.
DR   Ensembl; ENST00000439211; ENSP00000396308; ENSG00000228716. [P00374-1]
DR   Ensembl; ENST00000504396; ENSP00000421334; ENSG00000228716. [P00374-2]
DR   Ensembl; ENST00000505337; ENSP00000426474; ENSG00000228716. [P00374-1]
DR   GeneID; 1719; -.
DR   KEGG; hsa:1719; -.
DR   UCSC; uc003kgy.2; human. [P00374-1]
DR   CTD; 1719; -.
DR   DisGeNET; 1719; -.
DR   EuPathDB; HostDB:ENSG00000228716.6; -.
DR   GeneCards; DHFR; -.
DR   HGNC; HGNC:2861; DHFR.
DR   HPA; ENSG00000228716; Low tissue specificity.
DR   MalaCards; DHFR; -.
DR   MIM; 126060; gene.
DR   MIM; 613839; phenotype.
DR   neXtProt; NX_P00374; -.
DR   OpenTargets; ENSG00000228716; -.
DR   Orphanet; 319651; Constitutional megaloblastic anemia with severe neurologic disease.
DR   PharmGKB; PA143; -.
DR   eggNOG; KOG1324; Eukaryota.
DR   eggNOG; COG0262; LUCA.
DR   GeneTree; ENSGT00390000010283; -.
DR   HOGENOM; CLU_043966_2_3_1; -.
DR   InParanoid; P00374; -.
DR   KO; K00287; -.
DR   OMA; RDNQLPW; -.
DR   PhylomeDB; P00374; -.
DR   TreeFam; TF317636; -.
DR   BioCyc; MetaCyc:HS09699-MONOMER; -.
DR   BRENDA; 1.5.1.3; 2681.
DR   Reactome; R-HSA-1474151; Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
DR   Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR   Reactome; R-HSA-69205; G1/S-Specific Transcription.
DR   SABIO-RK; P00374; -.
DR   SIGNOR; P00374; -.
DR   UniPathway; UPA00077; UER00158.
DR   BioGRID-ORCS; 1719; 541 hits in 785 CRISPR screens.
DR   ChiTaRS; DHFR; human.
DR   EvolutionaryTrace; P00374; -.
DR   GeneWiki; Dihydrofolate_reductase; -.
DR   GenomeRNAi; 1719; -.
DR   Pharos; P00374; Tclin.
DR   PRO; PR:P00374; -.
DR   Proteomes; UP000005640; Chromosome 5.
DR   RNAct; P00374; protein.
DR   Bgee; ENSG00000228716; Expressed in buccal mucosa cell and 231 other tissues.
DR   ExpressionAtlas; P00374; baseline and differential.
DR   Genevisible; P00374; HS.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR   GO; GO:0004146; F:dihydrofolate reductase activity; IDA:UniProtKB.
DR   GO; GO:0008144; F:drug binding; IDA:UniProtKB.
DR   GO; GO:0005542; F:folic acid binding; IDA:BHF-UCL.
DR   GO; GO:0051870; F:methotrexate binding; IDA:BHF-UCL.
DR   GO; GO:0003729; F:mRNA binding; IDA:UniProtKB.
DR   GO; GO:0050661; F:NADP binding; IBA:GO_Central.
DR   GO; GO:0070402; F:NADPH binding; IDA:BHF-UCL.
DR   GO; GO:1990825; F:sequence-specific mRNA binding; IDA:CAFA.
DR   GO; GO:0000900; F:translation repressor activity, mRNA regulatory element binding; IDA:CAFA.
DR   GO; GO:0031103; P:axon regeneration; ISS:BHF-UCL.
DR   GO; GO:0046452; P:dihydrofolate metabolic process; IDA:BHF-UCL.
DR   GO; GO:0046655; P:folic acid metabolic process; ISS:BHF-UCL.
DR   GO; GO:0017148; P:negative regulation of translation; IDA:CAFA.
DR   GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0055114; P:oxidation-reduction process; IDA:BHF-UCL.
DR   GO; GO:0051000; P:positive regulation of nitric-oxide synthase activity; ISS:BHF-UCL.
DR   GO; GO:2000121; P:regulation of removal of superoxide radicals; ISS:BHF-UCL.
DR   GO; GO:0000083; P:regulation of transcription involved in G1/S transition of mitotic cell cycle; TAS:Reactome.
DR   GO; GO:0031427; P:response to methotrexate; ISS:BHF-UCL.
DR   GO; GO:0006729; P:tetrahydrobiopterin biosynthetic process; IMP:BHF-UCL.
DR   GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IDA:BHF-UCL.
DR   GO; GO:0046653; P:tetrahydrofolate metabolic process; IDA:UniProtKB.
DR   CDD; cd00209; DHFR; 1.
DR   Gene3D; 3.40.430.10; -; 1.
DR   InterPro; IPR024072; DHFR-like_dom_sf.
DR   InterPro; IPR017925; DHFR_CS.
DR   InterPro; IPR001796; DHFR_dom.
DR   Pfam; PF00186; DHFR_1; 1.
DR   SUPFAM; SSF53597; SSF53597; 1.
DR   PROSITE; PS00075; DHFR_1; 1.
DR   PROSITE; PS51330; DHFR_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cytoplasm; Disease mutation;
KW   Methotrexate resistance; Mitochondrion; NADP; One-carbon metabolism;
KW   Oxidoreductase; Reference proteome; RNA-binding.
FT   CHAIN           1..187
FT                   /note="Dihydrofolate reductase"
FT                   /id="PRO_0000186362"
FT   DOMAIN          4..185
FT                   /note="DHFR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00660"
FT   NP_BIND         16..22
FT                   /note="NADP"
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT   NP_BIND         55..57
FT                   /note="NADP"
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT   NP_BIND         77..79
FT                   /note="NADP"
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT   NP_BIND         117..124
FT                   /note="NADP"
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT   REGION          31..36
FT                   /note="Substrate binding"
FT                   /evidence="ECO:0000305|PubMed:2248959"
FT   BINDING         10
FT                   /note="NADP; via amide nitrogen and carbonyl oxygen"
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT   BINDING         65
FT                   /note="Substrate"
FT                   /evidence="ECO:0000305|PubMed:2248959"
FT   BINDING         71
FT                   /note="Substrate"
FT                   /evidence="ECO:0000305|PubMed:2248959"
FT   VAR_SEQ         1..52
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_056352"
FT   VARIANT         80
FT                   /note="L -> F (in DHFRD; dbSNP:rs387906619)"
FT                   /evidence="ECO:0000269|PubMed:21310276"
FT                   /id="VAR_065818"
FT   VARIANT         153
FT                   /note="D -> V (in DHFRD; dbSNP:rs121913223)"
FT                   /evidence="ECO:0000269|PubMed:21310277"
FT                   /id="VAR_065819"
FT   MUTAGEN         23
FT                   /note="L->F,W,Y: Decreases affinity for NADP and
FT                   dihydrofolate over 10-fold."
FT                   /evidence="ECO:0000269|PubMed:15681865,
FT                   ECO:0000269|PubMed:7890613"
FT   MUTAGEN         23
FT                   /note="L->R: Strongly decreased affinity for methotrexate.
FT                   Decreases catalytic rate constant 200-fold. Decreases
FT                   affinity for NADP and dihydrofolate over 10-fold."
FT                   /evidence="ECO:0000269|PubMed:15681865,
FT                   ECO:0000269|PubMed:7890613"
FT   MUTAGEN         32
FT                   /note="F->R: Reduces catalytic rate 5-fold. Reduces
FT                   affinity for dihydrofolate 9-fold; when associated with E-
FT                   36."
FT                   /evidence="ECO:0000269|PubMed:19478082"
FT   MUTAGEN         36
FT                   /note="Q->E: Reduces catalytic rate 2-fold. Reduces
FT                   affinity for dihydrofolate 9-fold; when associated with R-
FT                   32."
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:19478082"
FT   MUTAGEN         36
FT                   /note="Q->K: Increases affinity for dihydrofolate about 3-
FT                   fold. Reduces affinity for NADPH about 3-fold."
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:19478082"
FT   MUTAGEN         36
FT                   /note="Q->S: Increases affinity for dihydrofolate about 2-
FT                   fold. No effect on affinity for NADPH."
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:19478082"
FT   MUTAGEN         65
FT                   /note="N->F: Increases affinity for dihydrofolate about 3-
FT                   fold. No effect on affinity for NADPH."
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:19196009"
FT   MUTAGEN         65
FT                   /note="N->S: Increases affinity for dihydrofolate about 15-
FT                   fold. No effect on affinity for NADPH."
FT                   /evidence="ECO:0000269|PubMed:15039552,
FT                   ECO:0000269|PubMed:19196009"
FT   CONFLICT        113
FT                   /note="V -> L (in Ref. 6; AAH70280)"
FT                   /evidence="ECO:0000305"
FT   STRAND          5..11
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          16..19
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          24..26
FT                   /evidence="ECO:0000244|PDB:5HVE"
FT   HELIX           29..40
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          43..46
FT                   /evidence="ECO:0000244|PDB:5HQY"
FT   STRAND          48..54
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   HELIX           55..60
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   HELIX           63..65
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          71..76
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          88..93
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   HELIX           94..101
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   TURN            104..109
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          110..115
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   HELIX           119..126
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          128..130
FT                   /evidence="ECO:0000244|PDB:4M6K"
FT   STRAND          132..141
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          146..148
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   TURN            154..156
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          157..159
FT                   /evidence="ECO:0000244|PDB:1KMS"
FT   STRAND          161..163
FT                   /evidence="ECO:0000244|PDB:3S7A"
FT   STRAND          171..173
FT                   /evidence="ECO:0000244|PDB:1KMV"
FT   STRAND          176..185
FT                   /evidence="ECO:0000244|PDB:1KMV"
SQ   SEQUENCE   187 AA;  21453 MW;  EBDF3D1EC73E1566 CRC64;
     MVGSLNCIVA VSQNMGIGKN GDLPWPPLRN EFRYFQRMTT TSSVEGKQNL VIMGKKTWFS
     IPEKNRPLKG RINLVLSREL KEPPQGAHFL SRSLDDALKL TEQPELANKV DMVWIVGGSS
     VYKEAMNHPG HLKLFVTRIM QDFESDTFFP EIDLEKYKLL PEYPGVLSDV QEEKGIKYKF
     EVYEKND
//
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