ID DRTS_PLAFK Reviewed; 608 AA.
AC P13922; Q27734;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1990, sequence version 2.
DT 13-SEP-2023, entry version 135.
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 falciparum (isolate K1 / Thailand).
OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida;
OC Plasmodiidae; Plasmodium; Plasmodium (Laverania).
OX NCBI_TaxID=5839;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Isolate FCR3, and K1;
RX PubMed=2663650; DOI=10.1016/0378-1119(89)90006-1;
RA Snewin V.A., England S.M., Sims P.F.G., Hyde J.E.;
RT "Characterisation of the dihydrofolate reductase-thymidylate synthetase
RT gene from human malaria parasites highly resistant to pyrimethamine.";
RL Gene 76:41-52(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2677719; DOI=10.1016/0166-6851(89)90173-4;
RA Zolg J.W., Plitt J.R., Chen G.-X., Palmer S.;
RT "Point mutations in the dihydrofolate reductase-thymidylate synthase gene
RT as the molecular basis for pyrimethamine resistance in Plasmodium
RT falciparum.";
RL Mol. Biochem. Parasitol. 36:253-262(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Isolate Palo-Alto;
RX PubMed=3057499; DOI=10.1073/pnas.85.23.9109;
RA Cowman A.F., Morry M.J., Biggs B.A., Cross G.A.M., Foote S.J.;
RT "Amino acid changes linked to pyrimethamine resistance in the dihydrofolate
RT reductase-thymidylate synthase gene of Plasmodium falciparum.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:9109-9113(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Isolate FCR3;
RX PubMed=2825189; DOI=10.1073/pnas.84.23.8360;
RA Bzik D.J., Li W.B., Horii T., Inselburg J.;
RT "Molecular cloning and sequence analysis of the Plasmodium falciparum
RT dihydrofolate reductase-thymidylate synthase gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:8360-8364(1987).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF WILD TYPE AND DRUG-RESISTANT
RP VARIANTS IN COMPLEXES WITH NADP; UMP AND THE SYNTHETIC INHIBITORS WR99210
RP AND PYRIMETHAMINE, CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=12704428; DOI=10.1038/nsb921;
RA Yuvaniyama J., Chitnumsub P., Kamchonwongpaisan S., Vanichtanankul J.,
RA Sirawaraporn W., Taylor P., Walkinshaw M.D., Yuthavong Y.;
RT "Insights into antifolate resistance from malarial DHFR-TS structures.";
RL Nat. Struct. Biol. 10:357-365(2003).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.58 ANGSTROMS) OF WILD TYPE AND DRUG-RESISTANT
RP VARIANTS IN COMPLEXES WITH NADP AND INHIBITORS RJF 001302; RJF 00670 AND
RP RJF 00719, AND CATALYTIC ACTIVITY.
RX PubMed=19146480; DOI=10.1021/cb8002804;
RA Dasgupta T., Chitnumsub P., Kamchonwongpaisan S., Maneeruttanarungroj C.,
RA Nichols S.E., Lyons T.M., Tirado-Rives J., Jorgensen W.L., Yuthavong Y.,
RA Anderson K.S.;
RT "Exploiting structural analysis, in silico screening, and serendipity to
RT identify novel inhibitors of drug-resistant falciparum malaria.";
RL ACS Chem. Biol. 4:29-40(2009).
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 -!- 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:0000269|PubMed:12704428}.
CC -!- MISCELLANEOUS: K1 is from a pyrimethamine-resistant strain; FCR3 is a
CC pyrimethamine-sensitive strain.
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}.
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DR EMBL; M22159; AAA29580.1; -; Genomic_DNA.
DR EMBL; J04643; AAA29586.1; -; Genomic_DNA.
DR EMBL; J03772; AAB59212.1; -; Genomic_DNA.
DR EMBL; J03028; AAA29585.1; -; Genomic_DNA.
DR PIR; A39975; RDZQK1.
DR PDB; 1J3I; X-ray; 2.33 A; A/B=1-280, C/D=281-608.
DR PDB; 1J3J; X-ray; 2.30 A; A/B=1-280, C/D=281-608.
DR PDB; 1J3K; X-ray; 2.10 A; A/B=1-280, C/D=281-608.
DR PDB; 3DG8; X-ray; 2.58 A; A/B=1-280, C/D=281-608.
DR PDB; 3DGA; X-ray; 2.70 A; A/B=1-280, C/D=281-608.
DR PDB; 7CTW; X-ray; 2.51 A; A/B=1-608.
DR PDB; 7F3Y; X-ray; 2.25 A; A/B=1-608.
DR PDB; 7F3Z; X-ray; 2.60 A; A/B=1-608.
DR PDBsum; 1J3I; -.
DR PDBsum; 1J3J; -.
DR PDBsum; 1J3K; -.
DR PDBsum; 3DG8; -.
DR PDBsum; 3DGA; -.
DR PDBsum; 7CTW; -.
DR PDBsum; 7F3Y; -.
DR PDBsum; 7F3Z; -.
DR AlphaFoldDB; P13922; -.
DR SMR; P13922; -.
DR BindingDB; P13922; -.
DR ChEMBL; CHEMBL1939; -.
DR DrugBank; DB01131; Proguanil.
DR DrugBank; DB00205; Pyrimethamine.
DR DrugBank; DB01299; Sulfadoxine.
DR DrugCentral; P13922; -.
DR MoonProt; P13922; -.
DR BRENDA; 1.5.1.3; 4889.
DR BRENDA; 2.1.1.45; 4889.
DR SABIO-RK; P13922; -.
DR UniPathway; UPA00077; UER00158.
DR EvolutionaryTrace; P13922; -.
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 1: Evidence at protein level;
KW 3D-structure; Methyltransferase; Multifunctional enzyme; NADP;
KW Nucleotide biosynthesis; One-carbon metabolism; Oxidoreductase;
KW Transferase.
FT CHAIN 1..608
FT /note="Bifunctional dihydrofolate reductase-thymidylate
FT synthase"
FT /id="PRO_0000186349"
FT DOMAIN 10..228
FT /note="DHFR"
FT REGION 322..608
FT /note="Thymidylate synthase"
FT ACT_SITE 490
FT /evidence="ECO:0000250"
FT BINDING 14..15
FT /ligand="substrate"
FT BINDING 16
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 31
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 39..45
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 54
FT /ligand="substrate"
FT BINDING 106..108
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 108
FT /ligand="substrate"
FT BINDING 128..130
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 144
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 164
FT /ligand="substrate"
FT BINDING 165..172
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 170
FT /ligand="substrate"
FT BINDING 185
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 345
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT BINDING 491
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT BINDING 509..513
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT BINDING 521
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT BINDING 551..553
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT VARIANT 16
FT /note="A -> V (in strain: Isolate Palo-Alto)"
FT VARIANT 51
FT /note="N -> I"
FT VARIANT 59
FT /note="R -> C (in strain: Isolate FCR-3, Isolate Gambia and
FT Isolate Palo-Alto)"
FT VARIANT 108
FT /note="N -> T (in strain: Isolate FCR-3, Isolate Gambia and
FT Isolate Palo-Alto)"
FT HELIX 5..8
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 11..20
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 23..25
FT /evidence="ECO:0007829|PDB:3DGA"
FT HELIX 27..29
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 34..36
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 37..42
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 47..49
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 52..63
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 67..81
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 101..105
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 106..111
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 114..116
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 122..127
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 133..135
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 141..145
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 146..155
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 161..163
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 167..175
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 180..191
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 194..196
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 202..204
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 205..210
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 214..216
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 219..228
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 285..293
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 294..296
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 302..306
FT /evidence="ECO:0007829|PDB:7F3Y"
FT HELIX 309..312
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 313..317
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 319..321
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 325..338
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 340..342
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 346..348
FT /evidence="ECO:0007829|PDB:1J3J"
FT STRAND 350..361
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 362..364
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 370..372
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 377..387
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 393..397
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 398..400
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 403..405
FT /evidence="ECO:0007829|PDB:1J3J"
FT HELIX 406..408
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 410..415
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 430..436
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 455..465
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 473..475
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 479..484
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 485..487
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 490..499
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 502..513
FT /evidence="ECO:0007829|PDB:1J3K"
FT TURN 514..516
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 517..535
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 539..553
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 554..556
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 557..563
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 573..576
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 583..585
FT /evidence="ECO:0007829|PDB:1J3K"
FT HELIX 588..590
FT /evidence="ECO:0007829|PDB:1J3K"
FT STRAND 591..594
FT /evidence="ECO:0007829|PDB:1J3K"
SQ SEQUENCE 608 AA; 71817 MW; 7727EEB4A3946996 CRC64;
MMEQVCDVFD IYAICACCKV ESKNEGKKNE VFNNYTFRGL GNKGVLPWKC NSLDMKYFRA
VTTYVNESKY EKLKYKRCKY LNKETVDNVN DMPNSKKLQN VVVMGRTNWE SIPKKFKPLS
NRINVILSRT LKKEDFDEDV YIINKVEDLI VLLGKLNYYK CFIIGGSVVY QEFLEKKLIK
KIYFTRINST YECDVFFPEI NENEYQIISV SDVYTSNNTT LDFIIYKKTN NKMLNEQNCI
KGEEKNNDMP LKNDDKDTCH MKKLTEFYKN VDKYKINYEN DDDDEEEDDF VYFNFNKEKE
EKNKNSIHPN DFQIYNSLKY KYHPEYQYLN IIYDIMMNGN KQSDRTGVGV LSKFGYIMKF
DLSQYFPLLT TKKLFLRGII EELLWFIRGE TNGNTLLNKN VRIWEANGTR EFLDNRKLFH
REVNDLGPIY GFQWRHFGAE YTNMYDNYEN KGVDQLKNII NLIKNDPTSR RILLCAWNVK
DLDQMALPPC HILCQFYVFD GKLSCIMYQR SCDLGLGVPF NIASYSIFTH MIAQVCNLQP
AQFIHVLGNA HVYNNHIDSL KIQLNRIPYP FPTLKLNPDI KNIEDFTISD FTIQNYVHHE
KISMDMAA
//
