DRTS_PLAVI
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 03-AUG-2022, entry version 118.
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}.
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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: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; 3.30.572.10; -; 1.
DR Gene3D; 3.40.430.10; -; 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 PANTHER; PTHR11548; PTHR11548; 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; SSF53597; 1.
DR SUPFAM; SSF55831; SSF55831; 1.
DR TIGRFAMs; TIGR03284; thym_sym; 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 BUR-
FT 98 and BUR-151; interferes with inhibitor binding)"
FT VARIANT 117
FT /note="S -> N (in the pyrimethamine-resistant isolates BUR-
FT 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
