DRTS_LEIMA
ID DRTS_LEIMA Reviewed; 520 AA.
AC P07382; Q4QIZ1;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1988, sequence version 1.
DT 03-AUG-2022, entry version 144.
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;
GN ORFNames=LmjF06.0860, LmjF_06_0860;
OS Leishmania major.
OC Eukaryota; Discoba; Euglenozoa; Kinetoplastea; Metakinetoplastina;
OC Trypanosomatida; Trypanosomatidae; Leishmaniinae; Leishmania.
OX NCBI_TaxID=5664;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3458220; DOI=10.1073/pnas.83.8.2584;
RA Beverley S.M., Ellenberger T.E., Cordingley J.S.;
RT "Primary structure of the gene encoding the bifunctional dihydrofolate
RT reductase-thymidylate synthase of Leishmania major.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:2584-2588(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3461439; DOI=10.1073/pnas.83.15.5387;
RA Grumont R., Washtien W.L., Caput D., Santi D.V.;
RT "Bifunctional thymidylate synthase-dihydrofolate reductase from Leishmania
RT tropica: sequence homology with the corresponding monofunctional
RT proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:5387-5391(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=LT25Z;
RA Kapler G.M., Zhang K., Beverley S.;
RL Submitted (FEB-1990) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=MHOM/IL/81/Friedlin;
RX PubMed=16020728; DOI=10.1126/science.1112680;
RA Ivens A.C., Peacock C.S., Worthey E.A., Murphy L., Aggarwal G.,
RA Berriman M., Sisk E., Rajandream M.A., Adlem E., Aert R., Anupama A.,
RA Apostolou Z., Attipoe P., Bason N., Bauser C., Beck A., Beverley S.M.,
RA Bianchettin G., Borzym K., Bothe G., Bruschi C.V., Collins M., Cadag E.,
RA Ciarloni L., Clayton C., Coulson R.M.R., Cronin A., Cruz A.K., Davies R.M.,
RA De Gaudenzi J., Dobson D.E., Duesterhoeft A., Fazelina G., Fosker N.,
RA Frasch A.C., Fraser A., Fuchs M., Gabel C., Goble A., Goffeau A.,
RA Harris D., Hertz-Fowler C., Hilbert H., Horn D., Huang Y., Klages S.,
RA Knights A., Kube M., Larke N., Litvin L., Lord A., Louie T., Marra M.,
RA Masuy D., Matthews K., Michaeli S., Mottram J.C., Mueller-Auer S.,
RA Munden H., Nelson S., Norbertczak H., Oliver K., O'neil S., Pentony M.,
RA Pohl T.M., Price C., Purnelle B., Quail M.A., Rabbinowitsch E.,
RA Reinhardt R., Rieger M., Rinta J., Robben J., Robertson L., Ruiz J.C.,
RA Rutter S., Saunders D., Schaefer M., Schein J., Schwartz D.C., Seeger K.,
RA Seyler A., Sharp S., Shin H., Sivam D., Squares R., Squares S., Tosato V.,
RA Vogt C., Volckaert G., Wambutt R., Warren T., Wedler H., Woodward J.,
RA Zhou S., Zimmermann W., Smith D.F., Blackwell J.M., Stuart K.D.,
RA Barrell B.G., Myler P.J.;
RT "The genome of the kinetoplastid parasite, Leishmania major.";
RL Science 309:436-442(2005).
RN [5]
RP PROTEIN SEQUENCE OF 334-361.
RX PubMed=3903747; DOI=10.1073/pnas.82.21.7188;
RA Garvey E.P., Santi D.V.;
RT "Limited proteolysis of the bifunctional thymidylate synthase-dihydrofolate
RT reductase from Leishmania tropica.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:7188-7192(1985).
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 -!- 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; M12734; AAA29232.1; -; Genomic_DNA.
DR EMBL; M14330; AAA29272.1; -; Genomic_DNA.
DR EMBL; X51733; CAA36019.1; -; Genomic_DNA.
DR EMBL; FR796402; CAJ02132.1; -; Genomic_DNA.
DR PIR; A23403; RDLNTS.
DR RefSeq; XP_001680857.1; XM_001680805.1.
DR AlphaFoldDB; P07382; -.
DR SMR; P07382; -.
DR STRING; 5664.LmjF.06.0860; -.
DR BindingDB; P07382; -.
DR ChEMBL; CHEMBL4614; -.
DR DrugCentral; P07382; -.
DR EnsemblProtists; CAJ02132; CAJ02132; LMJF_06_0860.
DR GeneID; 5649109; -.
DR KEGG; lma:LMJF_06_0860; -.
DR VEuPathDB; TriTrypDB:LmjF.06.0860; -.
DR VEuPathDB; TriTrypDB:LMJSD75_060015000; -.
DR eggNOG; KOG0673; Eukaryota.
DR eggNOG; KOG1324; Eukaryota.
DR InParanoid; P07382; -.
DR OMA; HHKIEMK; -.
DR SABIO-RK; P07382; -.
DR UniPathway; UPA00077; UER00158.
DR PRO; PR:P07382; -.
DR Proteomes; UP000000542; Chromosome 6.
DR GO; GO:0005737; C:cytoplasm; ISO:GeneDB.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0004146; F:dihydrofolate reductase activity; IEA:UniProtKB-EC.
DR GO; GO:0004799; F:thymidylate synthase activity; IBA:GO_Central.
DR GO; GO:0006231; P:dTMP biosynthetic process; IBA:GO_Central.
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 Direct protein sequencing; Methyltransferase; Multifunctional enzyme; NADP;
KW Nucleotide biosynthesis; One-carbon metabolism; Oxidoreductase;
KW Reference proteome; Transferase.
FT CHAIN 1..520
FT /note="Bifunctional dihydrofolate reductase-thymidylate
FT synthase"
FT /id="PRO_0000186345"
FT DOMAIN 26..229
FT /note="DHFR"
FT REGION 234..520
FT /note="Thymidylate synthase"
FT ACT_SITE 400
FT /evidence="ECO:0000250"
FT BINDING 30
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 32
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 38..44
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 52
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 81..83
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 102..105
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 157..164
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 162
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 180
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 254
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /evidence="ECO:0000250"
FT BINDING 401
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /evidence="ECO:0000250"
FT BINDING 421..425
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /evidence="ECO:0000250"
FT BINDING 433
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /evidence="ECO:0000250"
FT BINDING 463..465
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /evidence="ECO:0000250"
FT CONFLICT 28
FT /note="S -> C (in Ref. 2; AAA29272)"
FT /evidence="ECO:0000305"
FT CONFLICT 49
FT /note="V -> S (in Ref. 2; AAA29272)"
FT /evidence="ECO:0000305"
FT CONFLICT 72..76
FT /note="KKRNA -> EEAQR (in Ref. 2; AAA29272)"
FT /evidence="ECO:0000305"
FT CONFLICT 125..127
FT /note="QDV -> RML (in Ref. 2; AAA29272)"
FT /evidence="ECO:0000305"
FT CONFLICT 307
FT /note="A -> T (in Ref. 2; AAA29272)"
FT /evidence="ECO:0000305"
FT CONFLICT 397
FT /note="L -> V (in Ref. 2; AAA29272)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 520 AA; 58689 MW; 7D221F2CF2BE43D4 CRC64;
MSRAAARFKI PMPETKADFA FPSLRAFSIV VALDMQHGIG DGESIPWRVP EDMTFFKNQT
TLLRNKKPPT EKKRNAVVMG RKTWESVPVK FRPLKGRLNI VLSSKATVEE LLAPLPEGQR
AAAAQDVVVV NGGLAEALRL LARPLYCSSI ETAYCVGGAQ VYADAMLSPC IEKLQEVYLT
RIYATAPACT RFFPFPPENA ATAWDLASSQ GRRKSEAEGL EFEICKYVPR NHEERQYLEL
IDRIMKTGIV KEDRTGVGTI SLFGAQMRFS LRDNRLPLLT TKRVFWRGVC EELLWFLRGE
TSAQLLADKD IHIWDGNGSR EFLDSRGLTE NKEMDLGPVY GFQWRHFGAD YKGFEANYDG
EGVDQIKLIV ETIKTNPNDR RLLVTAWNPC ALQKMALPPC HLLAQFYVNT DTSELSCMLY
QRSCDMGLGV PFNIASYALL TILIAKATGL RPGELVHTLG DAHVYRNHVD ALKAQLERVP
HAFPTLIFKE ERQYLEDYEL TDMEVIDYVP HPAIKMEMAV
