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 02-SEP-2026, entry version 244. DE RecName: Full=Dihydrofolate reductase {ECO:0000305}; DE EC=1.5.1.3 {ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:15039552, ECO:0000269|PubMed:17569517, ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:19478082, ECO:0000269|PubMed:21876184, ECO:0000269|PubMed:9719595}; GN Name=DHFR {ECO:0000312|HGNC:HGNC:2861}; 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 SUMOYLATION. RX PubMed=18067453; DOI=10.1515/cclm.2007.355; RA Anderson D.D., Woeller C.F., Stover P.J.; RT "Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate RT synthase and dihydrofolate reductase."; RL Clin. Chem. Lab. Med. 45:1760-1763(2007). RN [8] 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 [9] 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 [10] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, RNA-BINDING, AND BIOPHYSICOCHEMICAL RP 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 [11] 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 [12] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SHMT1. RX PubMed=22235121; DOI=10.1074/jbc.m111.333120; RA Anderson D.D., Woeller C.F., Chiang E.P., Shane B., Stover P.J.; RT "Serine hydroxymethyltransferase anchors de novo thymidylate synthesis RT pathway to nuclear lamina for DNA synthesis."; RL J. Biol. Chem. 287:7051-7062(2012). RN [13] 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 [14] 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 [15] 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 [16] 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 [17] 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 [18] RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEXES WITH NADPH AND RP QUINAZOLINE INHIBITORS, FUNCTION, 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 [19] 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 [20] 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 [21] 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 [22] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEX WITH NADPH AND INHIBITOR, RP MUTAGENESIS OF GLN-36 AND ASN-65, FUNCTION, 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 [23] 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 [24] 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 [25] RP X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) IN COMPLEXES WITH NADP AND RP BORON-CONTAINING INHIBITORS, FUNCTION, 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 [26] RP X-RAY CRYSTALLOGRAPHY (1.23 ANGSTROMS) IN COMPLEXES WITH NADP AND THE RP SYNTHETIC INHIBITOR PY957, FUNCTION, 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 [27] 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, FUNCTION, AND RP CATALYTIC 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 [28] 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 [29] 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: Catalyzes the reduction of 7,8-dihydrofolate (DHF) to CC 5,6,7,8-tetrahydrofolate in a NADPH-dependent manner (PubMed:12096917, CC PubMed:15039552, PubMed:17569517, PubMed:19196009, PubMed:19478082, CC PubMed:21876184, PubMed:9719595). Key enzyme in folate metabolism. CC Contributes to the nuclear and mitochondrial de novo thymidylate CC biosynthesis pathway (PubMed:21876188, PubMed:22235121). Catalyzes an CC essential reaction for de novo glycine and purine synthesis, and for CC DNA precursor synthesis. Binds its own mRNA and that of DHFR2. CC {ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:15039552, CC ECO:0000269|PubMed:17569517, ECO:0000269|PubMed:19196009, CC ECO:0000269|PubMed:19478082, ECO:0000269|PubMed:21876184, CC ECO:0000269|PubMed:21876188, ECO:0000269|PubMed:22235121, CC ECO:0000269|PubMed:9719595}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(6S)-5,6,7,8-tetrahydrofolate + NADP(+) = 7,8-dihydrofolate + CC NADPH + H(+); Xref=Rhea:RHEA:15009, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:57451, ChEBI:CHEBI:57453, ChEBI:CHEBI:57783, CC ChEBI:CHEBI:58349; EC=1.5.1.3; 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 PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15011; CC Evidence={ECO:0000269|PubMed:21876184}; 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 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 {ECO:0000269|PubMed:21876184}. CC -!- SUBUNIT: Homodimer. Part of the de novo thymidylate synthesis complex CC composed at least by SHMT1, DHFR and TYMS (PubMed:22235121). Interacts CC with SHMT1; this interaction is DNA-dependent and mediates DHFR co- CC localization with LMNB1 (PubMed:22235121). CC {ECO:0000269|PubMed:12657784, ECO:0000269|PubMed:12925791, CC ECO:0000269|PubMed:15039552, ECO:0000269|PubMed:16222560, CC ECO:0000269|PubMed:19478082, ECO:0000269|PubMed:22235121, CC ECO:0000269|PubMed:2248959, ECO:0000269|PubMed:3383852}. CC -!- INTERACTION: CC P00374; Q86XF0: DHFR2; NbExp=2; IntAct=EBI-10039315, EBI-2807201; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P00375}. CC Cytoplasm {ECO:0000250|UniProtKB:P00375}. Nucleus CC {ECO:0000269|PubMed:22235121}. Note=Localized to the nucleus during S CC and G2/M phases of the cell cycle. As a component of the de novo CC thymidylate synthesis complex, localizes specifically to replication CC forks during DNA synthesis (PubMed:22235121). CC {ECO:0000269|PubMed:22235121}. 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 -!- PTM: Sumoylated by UBE2I/UBC9. {ECO:0000269|PubMed:18067453}. 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"; 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; 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_000791.4. [P00374-1] DR RefSeq; NP_001277283.1; NM_001290354.2. [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 PDB; 7XI7; X-ray; 1.65 A; A=1-187. DR PDB; 8WGN; X-ray; 2.00 A; A=1-187. DR AlphaFoldDB; P00374; -. DR BMRB; P00374; -. DR MDposit; P00374; -. DR MDRepo; P00374; -. DR SMR; P00374; -. DR BioGRID; 108065; 181. DR CORUM; P00374; -. DR FunCoup; P00374; 1273. DR IntAct; P00374; 103. DR MINT; P00374; -. DR NDEx; IQUERY-CP-DHFR; 17 NDEx IQuery Curated Pathways. 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; DB00233; Aminosalicylic acid. DR DrugBank; DB03886; Biopterin. DR DrugBank; DB19052; CH-1504 L-isomer. DR DrugBank; DB00158; Folic acid. DR DrugBank; DB06358; Iclaprim. DR DrugBank; DB00555; Lamotrigine. DR DrugBank; DB00650; Leucovorin. 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; DB00205; Pyrimethamine. DR DrugBank; DB16326; Sepiapterin. 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 jPOST; P00374; -. DR MassIVE; P00374; -. DR PaxDb; 9606-ENSP00000396308; -. DR PeptideAtlas; P00374; -. DR ProteomicsDB; 3847; -. DR ProteomicsDB; 51237; -. [P00374-1] DR Pumba; P00374; -. DR Antibodypedia; 24646; 327 antibodies from 35 providers. DR DNASU; 1719; -. DR Ensembl; ENST00000439211.7; ENSP00000396308.2; ENSG00000228716.8. [P00374-1] DR Ensembl; ENST00000504396.1; ENSP00000421334.1; ENSG00000228716.8. [P00374-2] DR Ensembl; ENST00000505337.5; ENSP00000426474.1; ENSG00000228716.8. [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 AGR; HGNC:2861; -. DR AGR; HGNC:2862; -. DR ClinPGx; PA143; -. 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 OpenTargets; ENSG00000228716; -. DR Orphanet; 319651; Constitutional megaloblastic anemia with severe neurologic disease. 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 OrthoDB; 4664297at2759; -. DR PAN-GO; P00374; 6 GO annotations based on evolutionary models. DR PhylomeDB; P00374; -. DR BioCyc; MetaCyc:HS09699-MONOMER; -. 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 Agora; ENSG00000228716; -. DR BioGRID-ORCS; 1719; 611 hits in 1175 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 210 other cell types or tissues. DR ExpressionAtlas; P00374; baseline and differential. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0005634; C:nucleus; EXP:UniProtKB. DR GO; GO:0005657; C:replication fork; IDA:UniProt. 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:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; IDA:UniProt. DR GO; GO:0031103; P:axon regeneration; ISS:BHF-UCL. DR GO; GO:0046452; P:dihydrofolate metabolic process; IDA:BHF-UCL. DR GO; GO:0006260; P:DNA replication; IDA:UniProt. 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:2000121; P:regulation of removal of superoxide radicals; 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 FunFam; 3.40.430.10:FF:000002; Dihydrofolate reductase; 1. DR Gene3D; 3.40.430.10; Dihydrofolate Reductase, subunit A; 1. DR InterPro; IPR012259; DHFR. DR InterPro; IPR024072; DHFR-like_dom_sf. DR InterPro; IPR017925; DHFR_CS. DR InterPro; IPR001796; DHFR_dom. DR PANTHER; PTHR48069; DIHYDROFOLATE REDUCTASE; 1. DR PANTHER; PTHR48069:SF6; DIHYDROFOLATE REDUCTASE; 1. DR Pfam; PF00186; DHFR_1; 1. DR PRINTS; PR00070; DHFR. DR SUPFAM; SSF53597; Dihydrofolate reductase-like; 1. DR PROSITE; PS00075; DHFR_1; 1. DR PROSITE; PS51330; DHFR_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant; KW Methotrexate resistance; Mitochondrion; NADP; Nucleus; KW One-carbon metabolism; Oxidoreductase; Proteomics identification; KW Reference proteome; RNA-binding; Ubl conjugation. 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 FT E-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 FT R-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 FT 3-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 FT 2-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 FT 3-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 FT 15-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 HELIX 149..152 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 //