DRTS_TRYCR
ID DRTS_TRYCR Reviewed; 521 AA.
AC Q27793;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 2.
DT 03-AUG-2022, entry version 108.
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 Trypanosoma cruzi.
OC Eukaryota; Discoba; Euglenozoa; Kinetoplastea; Metakinetoplastina;
OC Trypanosomatida; Trypanosomatidae; Trypanosoma; Schizotrypanum.
OX NCBI_TaxID=5693;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Y;
RX PubMed=7969266; DOI=10.1016/0166-6851(94)90076-0;
RA Reche P., Arrebola R., Olmo A., Santi D.V., Gonzalez-Pacanowska D.,
RA Ruiz-Perez L.M.;
RT "Cloning and expression of the dihydrofolate reductase-thymidylate synthase
RT gene from Trypanosoma cruzi.";
RL Mol. Biochem. Parasitol. 65:247-258(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Y;
RX PubMed=8920005; DOI=10.1016/0166-6851(95)02557-x;
RA Reche P., Arrebola R., Santi D.V., Gonzalez-Pacanowska D., Ruiz-Perez L.M.;
RT "Expression and characterization of the Trypanosoma cruzi dihydrofolate
RT reductase domain.";
RL Mol. Biochem. Parasitol. 76:175-185(1996).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) IN COMPLEXES WITH NADP; METHOTREXATE
RP AND TRIMETREXATE, AND CATALYTIC ACTIVITY.
RX PubMed=18536013; DOI=10.1002/prot.22115;
RA Schormann N., Senkovich O., Walker K., Wright D.L., Anderson A.C.,
RA Rosowsky A., Ananthan S., Shinkre B., Velu S., Chattopadhyay D.;
RT "Structure-based approach to pharmacophore identification, in silico
RT screening, and three-dimensional quantitative structure-activity
RT relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate
RT reductase function.";
RL Proteins 73:889-901(2008).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) IN COMPLEXES WITH NADP; UMP;
RP METHOTREXATE AND TRIMETREXATE, AND SUBUNIT.
RX PubMed=19564691; DOI=10.1107/s090744490901230x;
RA Senkovich O., Schormann N., Chattopadhyay D.;
RT "Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma
RT cruzi in the folate-free state and in complex with two antifolate drugs,
RT trimetrexate and methotrexate.";
RL Acta Crystallogr. D 65:704-716(2009).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) IN COMPLEXES WITH NADP; UMP AND THE
RP SYNTHETIC INHIBITORS C-448; CYC AND Q-8, AND CATALYTIC ACTIVITY.
RX PubMed=19923744; DOI=10.1107/s1744309109041979;
RA Chitnumsub P., Yuvaniyama J., Chahomchuen T., Vilaivan T., Yuthavong Y.;
RT "Crystallization and preliminary crystallographic studies of dihydrofolate
RT reductase-thymidylate synthase from Trypanosoma cruzi, the Chagas disease
RT pathogen.";
RL Acta Crystallogr. F 65:1175-1178(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:19564691}.
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; L22484; AAB49898.1; -; Genomic_DNA.
DR PDB; 2H2Q; X-ray; 2.40 A; A/B=1-521.
DR PDB; 3CL9; X-ray; 3.30 A; A=1-521.
DR PDB; 3CLB; X-ray; 3.00 A; A/B/C/D=1-521.
DR PDB; 3HBB; X-ray; 3.00 A; A/B/C/D=1-521.
DR PDB; 3INV; X-ray; 2.37 A; A/B=1-521.
DR PDB; 3IRM; X-ray; 2.10 A; A/B/C/D=1-521.
DR PDB; 3IRN; X-ray; 2.60 A; A/B/C/D=1-521.
DR PDB; 3IRO; X-ray; 2.80 A; A/B/C/D=1-521.
DR PDBsum; 2H2Q; -.
DR PDBsum; 3CL9; -.
DR PDBsum; 3CLB; -.
DR PDBsum; 3HBB; -.
DR PDBsum; 3INV; -.
DR PDBsum; 3IRM; -.
DR PDBsum; 3IRN; -.
DR PDBsum; 3IRO; -.
DR AlphaFoldDB; Q27793; -.
DR SMR; Q27793; -.
DR BindingDB; Q27793; -.
DR ChEMBL; CHEMBL1163130; -.
DR DrugCentral; Q27793; -.
DR VEuPathDB; TriTrypDB:BCY84_16439; -.
DR VEuPathDB; TriTrypDB:C3747_84g65; -.
DR VEuPathDB; TriTrypDB:C4B63_30g231; -.
DR VEuPathDB; TriTrypDB:Tc_MARK_668; -.
DR VEuPathDB; TriTrypDB:TcBrA4_0087940; -.
DR VEuPathDB; TriTrypDB:TcCL_ESM02245; -.
DR VEuPathDB; TriTrypDB:TcCLB.420533.9; -.
DR VEuPathDB; TriTrypDB:TcCLB.509153.90; -.
DR VEuPathDB; TriTrypDB:TcCLB.510303.320; -.
DR VEuPathDB; TriTrypDB:TCDM_01885; -.
DR VEuPathDB; TriTrypDB:TcG_01595; -.
DR VEuPathDB; TriTrypDB:TCSYLVIO_001858; -.
DR VEuPathDB; TriTrypDB:TcYC6_0045790; -.
DR OMA; HHKIEMK; -.
DR BRENDA; 1.5.1.3; 6524.
DR BRENDA; 2.1.1.45; 6524.
DR SABIO-RK; Q27793; -.
DR UniPathway; UPA00077; UER00158.
DR EvolutionaryTrace; Q27793; -.
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;
KW Transferase.
FT CHAIN 1..521
FT /note="Bifunctional dihydrofolate reductase-thymidylate
FT synthase"
FT /id="PRO_0000186354"
FT DOMAIN 22..232
FT /note="DHFR"
FT REGION 237..521
FT /note="Thymidylate synthase"
FT ACT_SITE 403
FT /evidence="ECO:0000250"
FT BINDING 26
FT /ligand="substrate"
FT BINDING 28
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 34..40
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 48
FT /ligand="substrate"
FT BINDING 78..80
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 99..102
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 154
FT /ligand="substrate"
FT BINDING 155..162
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT BINDING 160
FT /ligand="substrate"
FT BINDING 178
FT /ligand="substrate"
FT BINDING 257
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT BINDING 404
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT BINDING 422..426
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT BINDING 434
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT BINDING 464..466
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT HELIX 2..4
FT /evidence="ECO:0007829|PDB:3IRM"
FT TURN 10..13
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 14..16
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 23..30
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 33..39
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 46..57
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 60..63
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 70..77
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 78..82
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 86..88
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 94..99
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 105..110
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 112..114
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 115..121
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 122..124
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 125..130
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 132..139
FT /evidence="ECO:0007829|PDB:3IRM"
FT TURN 142..147
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 148..153
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 157..163
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 168..171
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 172..180
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 188..190
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 199..201
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 206..211
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 218..221
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 224..232
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 235..250
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 252..255
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 261..273
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 275..277
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 289..300
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 307..310
FT /evidence="ECO:0007829|PDB:3IRM"
FT TURN 311..313
FT /evidence="ECO:0007829|PDB:3IRM"
FT TURN 319..321
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 323..328
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 343..349
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 357..359
FT /evidence="ECO:0007829|PDB:3CL9"
FT HELIX 368..378
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 386..388
FT /evidence="ECO:0007829|PDB:3IRM"
FT TURN 392..394
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 395..397
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 398..400
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 403..412
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 415..426
FT /evidence="ECO:0007829|PDB:3IRM"
FT TURN 427..429
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 430..448
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 452..466
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 467..469
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 470..476
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 486..490
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 496..498
FT /evidence="ECO:0007829|PDB:3IRM"
FT HELIX 501..503
FT /evidence="ECO:0007829|PDB:3IRM"
FT STRAND 504..508
FT /evidence="ECO:0007829|PDB:3IRM"
SQ SEQUENCE 521 AA; 58853 MW; DCB9F8782855810C CRC64;
MSLFKIRMPE TVAEGTRLAL RAFSLVVAVD EHGGIGDGRS IPWNVPEDMK FFRDLTTKLR
GKNVKPSPAK RNAVVMGRKT WDSIPPKFRP LPGRLNVVLS STLTTQHLLD GLPDEEKRNL
HADSIVAVNG GLEQALRLLA SPNYTPSIET VYCIGGGSVY AEALRPPCVH LLQAIYRTTI
RASESSCSVF FRVPESGTEA AAGIEWQRET ISEELTSANG NETKYYFEKL IPRNREEEQY
LSLVDRIIRE GNVKHDRTGV GTLSIFGAQM RFSLRNNRLP LLTTKRVFWR GVCEELLWFL
RGETYAKKLS DKGVHIWDDN GSRAFLDSRG LTEYEEMDLG PVYGFQWRHF GAAYTHHDAN
YDGQGVDQIK AIVETLKTNP DDRRMLFTAW NPSALPRMAL PPCHLLAQFY VSNGELSCML
YQRSCDMGLG VPFNIASYAL LTILIAKATG LRPGELVHTL GDAHVYSNHV EPCNEQLKRV
PRAFPYLVFR REREFLEDYE EGDMEVIDYA PYPPISMKMA V
