ID DRTS_PLABA Reviewed; 587 AA. AC Q27713; Q27714; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 24-JAN-2024, entry version 110. DE RecName: Full=Bifunctional dihydrofolate reductase-thymidylate synthase; DE Short=DHFR-TS; DE Includes: DE RecName: Full=Dihydrofolate reductase; DE EC=1.5.1.3; DE Includes: DE RecName: Full=Thymidylate synthase; DE EC=2.1.1.45; OS Plasmodium berghei (strain Anka). OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida; OC Plasmodiidae; Plasmodium; Plasmodium (Vinckeia). OX NCBI_TaxID=5823; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=7891743; DOI=10.1016/0166-6851(94)00163-4; RA van Dijk M.R., McConkey G.A., Vinkenoog R., Waters A.P., Janse C.J.; RT "Mechanisms of pyrimethamine resistance in two different strains of RT Plasmodium berghei."; RL Mol. Biochem. Parasitol. 68:167-171(1994). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 12-201. RX PubMed=7969277; DOI=10.1016/0166-6851(94)90087-6; RA Cheng Q., Saul A.; RT "The dihydrofolate reductase domain of rodent malarias: point mutations and RT pyrimethamine resistance."; RL Mol. Biochem. Parasitol. 65:361-363(1994). CC -!- FUNCTION: Bifunctional enzyme. Involved in de novo dTMP biosynthesis. CC Key enzyme in folate metabolism. Catalyzes an essential reaction for de CC novo glycine and purine synthesis, DNA precursor synthesis, and for the CC conversion of dUMP to dTMP (By similarity). {ECO:0000250}. 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; CC -!- CATALYTIC ACTIVITY: CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + dUMP = 7,8- CC dihydrofolate + dTMP; Xref=Rhea:RHEA:12104, ChEBI:CHEBI:15636, CC ChEBI:CHEBI:57451, ChEBI:CHEBI:63528, ChEBI:CHEBI:246422; CC EC=2.1.1.45; CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8- CC tetrahydrofolate from 7,8-dihydrofolate: step 1/1. CC -!- SUBUNIT: Homodimer. {ECO:0000250}. CC -!- SIMILARITY: In the N-terminal section; belongs to the dihydrofolate CC reductase family. {ECO:0000305}. CC -!- SIMILARITY: In the C-terminal section; belongs to the thymidylate CC synthase family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U12275; AAB60237.1; -; Genomic_DNA. DR EMBL; L28119; AAA29581.1; -; Genomic_DNA. DR AlphaFoldDB; Q27713; -. DR SMR; Q27713; -. DR BindingDB; Q27713; -. DR ChEMBL; CHEMBL3963; -. DR DrugCentral; Q27713; -. DR eggNOG; KOG0673; Eukaryota. DR eggNOG; KOG1324; Eukaryota. DR UniPathway; UPA00077; UER00158. DR GO; GO:0004146; F:dihydrofolate reductase activity; IEA:UniProtKB-EC. DR GO; GO:0004799; F:thymidylate synthase activity; IEA:UniProtKB-EC. DR GO; GO:0006231; P:dTMP biosynthetic process; IEA:InterPro. DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW. DR GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW. DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:UniProtKB-UniPathway. DR CDD; cd00209; DHFR; 1. DR CDD; cd00351; TS_Pyrimidine_HMase; 1. DR Gene3D; 6.10.250.2210; -; 1. DR Gene3D; 3.40.430.10; Dihydrofolate Reductase, subunit A; 1. DR Gene3D; 3.30.572.10; Thymidylate synthase/dCMP hydroxymethylase domain; 1. DR HAMAP; MF_00008; Thymidy_synth_bact; 1. DR InterPro; IPR024072; DHFR-like_dom_sf. DR InterPro; IPR012262; DHFR-TS. DR InterPro; IPR017925; DHFR_CS. DR InterPro; IPR001796; DHFR_dom. DR InterPro; IPR045097; Thymidate_synth/dCMP_Mease. DR InterPro; IPR023451; Thymidate_synth/dCMP_Mease_dom. DR InterPro; IPR036926; Thymidate_synth/dCMP_Mease_sf. DR InterPro; IPR000398; Thymidylate_synthase. DR InterPro; IPR020940; Thymidylate_synthase_AS. DR NCBIfam; TIGR03284; thym_sym; 1. DR PANTHER; PTHR11548:SF2; THYMIDYLATE SYNTHASE; 1. DR PANTHER; PTHR11548; THYMIDYLATE SYNTHASE 1; 1. DR Pfam; PF00186; DHFR_1; 1. DR Pfam; PF00303; Thymidylat_synt; 1. DR PIRSF; PIRSF000389; DHFR-TS; 1. DR PRINTS; PR00108; THYMDSNTHASE. DR SUPFAM; SSF53597; Dihydrofolate reductase-like; 1. DR SUPFAM; SSF55831; Thymidylate synthase/dCMP hydroxymethylase; 1. DR PROSITE; PS00075; DHFR_1; 1. DR PROSITE; PS51330; DHFR_2; 1. DR PROSITE; PS00091; THYMIDYLATE_SYNTHASE; 1. PE 3: Inferred from homology; KW Methyltransferase; Multifunctional enzyme; NADP; Nucleotide biosynthesis; KW One-carbon metabolism; Oxidoreductase; Transferase. FT CHAIN 1..587 FT /note="Bifunctional dihydrofolate reductase-thymidylate FT synthase" FT /id="PRO_0000186347" FT DOMAIN 9..237 FT /note="DHFR" FT REGION 301..587 FT /note="Thymidylate synthase" FT ACT_SITE 469 FT /evidence="ECO:0000250" FT BINDING 36..42 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250" FT BINDING 51 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 108..110 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250" FT BINDING 129..132 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250" FT BINDING 173 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 174..181 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250" FT BINDING 179 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 194 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 324 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT BINDING 470 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT BINDING 488..492 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT BINDING 500 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT BINDING 530..532 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT VARIANT 110 FT /note="S -> N (in pyrimethamine resistance)" FT VARIANT 177 FT /note="S -> F (in pyrimethamine resistance)" SQ SEQUENCE 587 AA; 68932 MW; 6E638C2B02FEC13A CRC64; MEDLSETFDI YAICACCKVL NDDEKVRCFN NKTFKGIGNA GVLPWKCNLI DMKYFSSVTS YINENNYIRL KWKRDKYMEK HNLKNNVELN TNIISSTNNL QNIVVMGKKS WESIPKKFKP LQNRINIILS RTLKKEDIVN ENNNENNNVI IIKSVDDLFP ILKCTKYYKC FIIGGSSVYK EFLDRNLIKK IYFTRINNSY NCDVLFPEIN ENLFKITSIS DVYYSNNTTL DFIIYSKTKE INPNEEVPNN TFLGVCDEQN KAFDDEDDYT YFSFNKNKEN IKKNSEHAHN FKIYNSIKYK NHPEYQYLNI IYDIIMHGNK QDDRTGVGVL SKFGYMMKFN LNEYFPLLTT KKLFIRGIIE ELLWFIRGET NGNTLLEKNV RIWEANGTRE FLDNRKLFHR EVNDLGPIYG FQWRHFGAEY TDMHDNYKDK GVDQLKNIIN LIKNDPTCRR IILCAWNVKN LDQMALPPCH ILCQFYVFDG KLSCIMYQRS CDLGLGVPFN IASYSIFTYM IAQVCNLQAA EFIHVLGNAH VYNNHIESLK IQLNRTPYPF PTLKLNPDIK NIEDFTISDF TVQNYVHHDK INMDMAA //