DYR_HUMAN
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 03-AUG-2022, entry version 225.
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; DOI=10.1016/s0021-9258(17)43186-3;
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 variants 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";
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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; 5SD6; X-ray; 2.15 A; A=1-187.
DR PDB; 5SD7; X-ray; 1.80 A; A=1-187.
DR PDB; 5SD8; X-ray; 2.05 A; A=1-187.
DR PDB; 5SD9; X-ray; 2.10 A; A=1-187.
DR PDB; 5SDA; X-ray; 2.45 A; A=1-187.
DR PDB; 5SDB; X-ray; 1.55 A; A/B=1-187.
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 PDB; 6VCJ; X-ray; 2.34 A; A/B/C/D=1-187.
DR PDB; 7ESE; X-ray; 1.85 A; A=1-187.
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; 5SD6; -.
DR PDBsum; 5SD7; -.
DR PDBsum; 5SD8; -.
DR PDBsum; 5SD9; -.
DR PDBsum; 5SDA; -.
DR PDBsum; 5SDB; -.
DR PDBsum; 6A7C; -.
DR PDBsum; 6A7E; -.
DR PDBsum; 6DAV; -.
DR PDBsum; 6DE4; -.
DR PDBsum; 6VCJ; -.
DR PDBsum; 7ESE; -.
DR AlphaFoldDB; P00374; -.
DR BMRB; P00374; -.
DR SMR; P00374; -.
DR BioGRID; 108065; 149.
DR IntAct; P00374; 12.
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; 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; 315 antibodies from 32 providers.
DR DNASU; 1719; -.
DR Ensembl; ENST00000439211.7; ENSP00000396308.2; ENSG00000228716.7. [P00374-1]
DR Ensembl; ENST00000504396.1; ENSP00000421334.1; ENSG00000228716.7. [P00374-2]
DR Ensembl; ENST00000505337.5; ENSP00000426474.1; ENSG00000228716.7. [P00374-1]
DR GeneID; 1719; -.
DR KEGG; hsa:1719; -.
DR MANE-Select; ENST00000439211.7; ENSP00000396308.2; NM_000791.4; NP_000782.1.
DR UCSC; uc003kgy.2; human. [P00374-1]
DR CTD; 1719; -.
DR DisGeNET; 1719; -.
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 VEuPathDB; HostDB:ENSG00000228716; -.
DR eggNOG; KOG1324; Eukaryota.
DR GeneTree; ENSGT00390000010283; -.
DR HOGENOM; CLU_043966_2_3_1; -.
DR InParanoid; P00374; -.
DR OMA; RDNQLPW; -.
DR PhylomeDB; P00374; -.
DR TreeFam; TF317636; -.
DR BioCyc; MetaCyc:HS09699-MON; -.
DR BRENDA; 1.5.1.3; 2681.
DR PathwayCommons; P00374; -.
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 SignaLink; P00374; -.
DR SIGNOR; P00374; -.
DR UniPathway; UPA00077; UER00158.
DR BioGRID-ORCS; 1719; 581 hits in 1085 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 209 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:0005542; F:folic acid binding; IDA:BHF-UCL.
DR GO; GO:0003729; F:mRNA binding; IDA:UniProtKB.
DR GO; GO:0000900; F:mRNA regulatory element binding translation repressor activity; IDA:CAFA.
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: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:0006545; P:glycine biosynthetic process; IEA:InterPro.
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: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:0031427; P:response to methotrexate; IEA:UniProtKB-KW.
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; 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 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant;
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 BINDING 10
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:15039552,
FT ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT BINDING 16..22
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:15039552,
FT ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT BINDING 31..36
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:2248959"
FT BINDING 55..57
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:15039552,
FT ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT BINDING 65
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:2248959"
FT BINDING 71
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:2248959"
FT BINDING 77..79
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:15039552,
FT ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
FT BINDING 117..124
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:15039552,
FT ECO:0000269|PubMed:16222560, ECO:0000269|PubMed:19478082"
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:0007829|PDB:1KMV"
FT STRAND 16..19
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 24..26
FT /evidence="ECO:0007829|PDB:5HVE"
FT HELIX 29..40
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 43..46
FT /evidence="ECO:0007829|PDB:5HQY"
FT STRAND 48..54
FT /evidence="ECO:0007829|PDB:1KMV"
FT HELIX 55..60
FT /evidence="ECO:0007829|PDB:1KMV"
FT HELIX 63..65
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 71..76
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 88..93
FT /evidence="ECO:0007829|PDB:1KMV"
FT HELIX 94..101
FT /evidence="ECO:0007829|PDB:1KMV"
FT TURN 104..109
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 110..115
FT /evidence="ECO:0007829|PDB:1KMV"
FT HELIX 119..126
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 128..130
FT /evidence="ECO:0007829|PDB:4M6K"
FT STRAND 132..141
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 146..148
FT /evidence="ECO:0007829|PDB:1KMV"
FT TURN 154..156
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 157..159
FT /evidence="ECO:0007829|PDB:1KMS"
FT STRAND 161..163
FT /evidence="ECO:0007829|PDB:3S7A"
FT STRAND 171..173
FT /evidence="ECO:0007829|PDB:1KMV"
FT STRAND 176..185
FT /evidence="ECO:0007829|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
