ID DRTS_PLAVI Reviewed; 623 AA. AC O02604; O15873; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 30-MAY-2000, sequence version 2. DT 13-SEP-2023, entry version 121. 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 vivax. OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida; OC Plasmodiidae; Plasmodium; Plasmodium (Plasmodium). OX NCBI_TaxID=5855; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC STRAIN=Isolate Ari/Pakistan, Isolate BUR-151, and Isolate BUR-98; RX PubMed=9573357; DOI=10.1016/s0378-1119(98)00118-8; RA Eldin de Pecoulas P., Basco L.K., Tahar R., Ouatas T., Mazabraud A.; RT "Analysis of the Plasmodium vivax dihydrofolate reductase-thymidylate RT synthase gene sequence."; RL Gene 211:177-185(1998). RN [2] RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1-238 OF WILD TYPE AND MUTANT RP ARG-58/ASN-117 IN COMPLEXES WITH THE SYNTHETIC INHIBITORS PYR; PYR20 AND RP WITH NADP, SUBUNIT, CHARACTERIZATION OF PYRIMETHAMINE-RESISTANT VARIANT RP ASN-117, AND CATALYTIC ACTIVITY. RX PubMed=16135570; DOI=10.1073/pnas.0501747102; RA Kongsaeree P., Khongsuk P., Leartsakulpanich U., Chitnumsub P., RA Tarnchompoo B., Walkinshaw M.D., Yuthavong Y.; RT "Crystal structure of dihydrofolate reductase from Plasmodium vivax: RT pyrimethamine displacement linked with mutation-induced resistance."; RL Proc. Natl. Acad. Sci. U.S.A. 102:13046-13051(2005). 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. 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 Evidence={ECO:0000269|PubMed:16135570}; 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; Evidence={ECO:0000269|PubMed:16135570}; 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:16135570}. CC -!- DOMAIN: The repeat region is missing in the pyrimethamine-resistant CC isolates BUR-98 and BUR-151. 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; X98123; CAA66805.1; -; Genomic_DNA. DR PIR; JC6568; JC6568. DR PDB; 2BL9; X-ray; 1.90 A; A=1-238. DR PDB; 2BLA; X-ray; 2.50 A; A=1-238. DR PDB; 2BLB; X-ray; 3.00 A; A=1-238. DR PDB; 2BLC; X-ray; 2.25 A; A=1-238. DR PDBsum; 2BL9; -. DR PDBsum; 2BLA; -. DR PDBsum; 2BLB; -. DR PDBsum; 2BLC; -. DR AlphaFoldDB; O02604; -. DR SMR; O02604; -. DR BindingDB; O02604; -. DR DrugCentral; O02604; -. DR VEuPathDB; PlasmoDB:PVP01_0526600; -. DR VEuPathDB; PlasmoDB:PVW1_050031800; -. DR VEuPathDB; PlasmoDB:PVX_089950; -. DR BRENDA; 1.5.1.3; 4894. DR UniPathway; UPA00077; UER00158. DR EvolutionaryTrace; O02604; -. 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; 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 1: Evidence at protein level; KW 3D-structure; Methyltransferase; Multifunctional enzyme; NADP; KW Nucleotide biosynthesis; One-carbon metabolism; Oxidoreductase; Repeat; KW Transferase. FT CHAIN 1..623 FT /note="Bifunctional dihydrofolate reductase-thymidylate FT synthase" FT /id="PRO_0000186351" FT DOMAIN 9..237 FT /note="DHFR" FT REPEAT 88..91 FT /note="1" FT REPEAT 94..97 FT /note="2" FT REPEAT 100..103 FT /note="3" FT REGION 88..103 FT /note="3 X 4 AA repeats of G-G-D-N" FT REGION 263..309 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 337..623 FT /note="Thymidylate synthase" FT ACT_SITE 505 FT /evidence="ECO:0000250" FT BINDING 13..14 FT /ligand="substrate" FT BINDING 15 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT BINDING 38..44 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT BINDING 53 FT /ligand="substrate" FT BINDING 115..117 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT BINDING 137..139 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT BINDING 153 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT BINDING 173 FT /ligand="substrate" FT BINDING 174..181 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT BINDING 179 FT /ligand="substrate" FT BINDING 194 FT /ligand="substrate" FT BINDING 360 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT BINDING 506 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT BINDING 524..528 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT BINDING 536 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT BINDING 566..568 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /evidence="ECO:0000250" FT VARIANT 58 FT /note="S -> R (in the pyrimethamine-resistant isolates FT BUR-98 and BUR-151; interferes with inhibitor binding)" FT VARIANT 117 FT /note="S -> N (in the pyrimethamine-resistant isolates FT BUR-98 and BUR-151)" FT /evidence="ECO:0000269|PubMed:16135570" FT HELIX 4..7 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 10..19 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 23..26 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 38..41 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 46..48 FT /evidence="ECO:0007829|PDB:2BL9" FT HELIX 51..62 FT /evidence="ECO:0007829|PDB:2BL9" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:2BL9" FT HELIX 69..83 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 109..114 FT /evidence="ECO:0007829|PDB:2BL9" FT HELIX 115..119 FT /evidence="ECO:0007829|PDB:2BL9" FT HELIX 123..125 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 131..136 FT /evidence="ECO:0007829|PDB:2BL9" FT TURN 142..144 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 150..153 FT /evidence="ECO:0007829|PDB:2BL9" FT HELIX 155..163 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 170..174 FT /evidence="ECO:0007829|PDB:2BL9" FT HELIX 176..184 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 189..200 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 203..205 FT /evidence="ECO:0007829|PDB:2BL9" FT HELIX 211..213 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 214..219 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 223..225 FT /evidence="ECO:0007829|PDB:2BL9" FT STRAND 228..237 FT /evidence="ECO:0007829|PDB:2BL9" SQ SEQUENCE 623 AA; 71057 MW; 3E6E958F04FB5828 CRC64; MEDLSDVFDI YAICACCKVA PTSEGTKNEP FSPRTFRGLG NKGTLPWKCN SVDMKYFSSV TTYVDESKYE KLKWKRERYL RMEASQGGGD NTSGGDNTHG GDNADKLQNV VVMGRSSWES IPKQYKPLPN RINVVLSKTL TKEDVKEKVF IIDSIDDLLL LLKKLKYYKC FIIGGAQVYR ECLSRNLIKQ IYFTRINGAY PCDVFFPEFD ESQFRVTSVS EVYNSKGTTL DFLVYSKVGG GVDGGASNGS TATALRRTAM RSTAMRRNVA PRTAAPPMGP HSRANGERAP PRARARRTTP RQRKTTSCTS ALTTKWGRKT RSTCKILKFT TASRLMQHPE YQYLGIIYDI IMNGNKQGDR TGVGVMSNFG YMMKFNLSEY FPLLTTKKLF LRGIIEELLW FIRGETNGNT LLNKNVRIWE ANGTREFLDN RKLFHREVND LGPIYGFQWR HFGAEYTNMH DNYEDKGVDQ LKNVIHLIKN EPTSRRIILC AWNVKDLDQM ALPPCHILCQ FYVFDGKLSC IMYQRSCDLG LGVPFNIASY SIFTHMIAQV CNLQPAQFIH ILGNAHVYNN HVDSLKVQLN RIPYPFPTLK LNPEVKNIED FTISDFTIEN YVHHDKITME MAA //