ID   DRTS1_ARATH             Reviewed;         519 AA.
AC   Q05762; Q9SIW4;
DT   01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT   27-MAY-2002, sequence version 2.
DT   27-MAR-2024, entry version 171.
DE   RecName: Full=Bifunctional dihydrofolate reductase-thymidylate synthase 1;
DE            Short=DHFR-TS 1;
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   Name=THY-1; OrderedLocusNames=At2g16370; ORFNames=F16F14.13;
OS   Arabidopsis thaliana (Mouse-ear cress).
OC   Eukaryota; Viridiplantae; Streptophyta; Embryophyta; Tracheophyta;
OC   Spermatophyta; Magnoliopsida; eudicotyledons; Gunneridae; Pentapetalae;
OC   rosids; malvids; Brassicales; Brassicaceae; Camelineae; Arabidopsis.
OX   NCBI_TaxID=3702;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=cv. Landsberg erecta;
RX   PubMed=8374616; DOI=10.1046/j.1365-313x.1993.03050657.x;
RA   Lazar G., Zhang H., Goodman H.M.;
RT   "The origin of the bifunctional dihydrofolate reductase-thymidylate
RT   synthase isogenes of Arabidopsis thaliana.";
RL   Plant J. 3:657-668(1993).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=cv. Columbia;
RX   PubMed=10617197; DOI=10.1038/45471;
RA   Lin X., Kaul S., Rounsley S.D., Shea T.P., Benito M.-I., Town C.D.,
RA   Fujii C.Y., Mason T.M., Bowman C.L., Barnstead M.E., Feldblyum T.V.,
RA   Buell C.R., Ketchum K.A., Lee J.J., Ronning C.M., Koo H.L., Moffat K.S.,
RA   Cronin L.A., Shen M., Pai G., Van Aken S., Umayam L., Tallon L.J.,
RA   Gill J.E., Adams M.D., Carrera A.J., Creasy T.H., Goodman H.M.,
RA   Somerville C.R., Copenhaver G.P., Preuss D., Nierman W.C., White O.,
RA   Eisen J.A., Salzberg S.L., Fraser C.M., Venter J.C.;
RT   "Sequence and analysis of chromosome 2 of the plant Arabidopsis thaliana.";
RL   Nature 402:761-768(1999).
RN   [3]
RP   GENOME REANNOTATION.
RC   STRAIN=cv. Columbia;
RX   PubMed=27862469; DOI=10.1111/tpj.13415;
RA   Cheng C.Y., Krishnakumar V., Chan A.P., Thibaud-Nissen F., Schobel S.,
RA   Town C.D.;
RT   "Araport11: a complete reannotation of the Arabidopsis thaliana reference
RT   genome.";
RL   Plant J. 89:789-804(2017).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=cv. Columbia;
RX   PubMed=14593172; DOI=10.1126/science.1088305;
RA   Yamada K., Lim J., Dale J.M., Chen H., Shinn P., Palm C.J., Southwick A.M.,
RA   Wu H.C., Kim C.J., Nguyen M., Pham P.K., Cheuk R.F., Karlin-Newmann G.,
RA   Liu S.X., Lam B., Sakano H., Wu T., Yu G., Miranda M., Quach H.L.,
RA   Tripp M., Chang C.H., Lee J.M., Toriumi M.J., Chan M.M., Tang C.C.,
RA   Onodera C.S., Deng J.M., Akiyama K., Ansari Y., Arakawa T., Banh J.,
RA   Banno F., Bowser L., Brooks S.Y., Carninci P., Chao Q., Choy N., Enju A.,
RA   Goldsmith A.D., Gurjal M., Hansen N.F., Hayashizaki Y., Johnson-Hopson C.,
RA   Hsuan V.W., Iida K., Karnes M., Khan S., Koesema E., Ishida J., Jiang P.X.,
RA   Jones T., Kawai J., Kamiya A., Meyers C., Nakajima M., Narusaka M.,
RA   Seki M., Sakurai T., Satou M., Tamse R., Vaysberg M., Wallender E.K.,
RA   Wong C., Yamamura Y., Yuan S., Shinozaki K., Davis R.W., Theologis A.,
RA   Ecker J.R.;
RT   "Empirical analysis of transcriptional activity in the Arabidopsis
RT   genome.";
RL   Science 302:842-846(2003).
RN   [5]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA   Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA   Giglione C.;
RT   "Comparative large-scale characterisation of plant vs. mammal proteins
RT   reveals similar and idiosyncratic N-alpha acetylation features.";
RL   Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
CC   -!- FUNCTION: Bifunctional enzyme. Involved in de novo dTMP biosynthesis.
CC       Key enzyme in folate metabolism. Can play two different roles depending
CC       on the source of dihydrofolate: de novo synthesis of tetrahydrofolate
CC       or recycling of the dihydrofolate released as one of the end products
CC       of the TS catalyzed reaction. 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: Heterodimer or homodimer. {ECO:0000250}.
CC   -!- INTERACTION:
CC       Q05762; Q9LV27: LST8-1; NbExp=6; IntAct=EBI-4455031, EBI-4453099;
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; L08593; AAA32788.1; -; mRNA.
DR   EMBL; AC007047; AAD22302.1; -; Genomic_DNA.
DR   EMBL; CP002685; AEC06489.1; -; Genomic_DNA.
DR   EMBL; CP002685; ANM62435.1; -; Genomic_DNA.
DR   EMBL; AY063968; AAL36324.1; -; mRNA.
DR   EMBL; AY114032; AAM45080.1; -; mRNA.
DR   PIR; E84539; E84539.
DR   RefSeq; NP_001324593.1; NM_001335473.1.
DR   RefSeq; NP_179230.1; NM_127191.4.
DR   PDB; 8DAE; X-ray; 2.00 A; A=2-519.
DR   PDBsum; 8DAE; -.
DR   AlphaFoldDB; Q05762; -.
DR   SMR; Q05762; -.
DR   BioGRID; 1492; 3.
DR   IntAct; Q05762; 2.
DR   STRING; 3702.Q05762; -.
DR   iPTMnet; Q05762; -.
DR   MetOSite; Q05762; -.
DR   PaxDb; 3702-AT2G16370-1; -.
DR   ProteomicsDB; 224371; -.
DR   EnsemblPlants; AT2G16370.1; AT2G16370.1; AT2G16370.
DR   EnsemblPlants; AT2G16370.3; AT2G16370.3; AT2G16370.
DR   GeneID; 816134; -.
DR   Gramene; AT2G16370.1; AT2G16370.1; AT2G16370.
DR   Gramene; AT2G16370.3; AT2G16370.3; AT2G16370.
DR   KEGG; ath:AT2G16370; -.
DR   Araport; AT2G16370; -.
DR   TAIR; AT2G16370; DHFR-TS-1.
DR   eggNOG; KOG0673; Eukaryota.
DR   eggNOG; KOG1324; Eukaryota.
DR   HOGENOM; CLU_021669_2_2_1; -.
DR   InParanoid; Q05762; -.
DR   OrthoDB; 1118873at2759; -.
DR   PhylomeDB; Q05762; -.
DR   BioCyc; ARA:AT2G16370-MONOMER; -.
DR   UniPathway; UPA00077; UER00158.
DR   PRO; PR:Q05762; -.
DR   Proteomes; UP000006548; Chromosome 2.
DR   ExpressionAtlas; Q05762; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:TAIR.
DR   GO; GO:0004146; F:dihydrofolate reductase activity; IDA:TAIR.
DR   GO; GO:0004799; F:thymidylate synthase activity; ISS:TAIR.
DR   GO; GO:0009257; P:10-formyltetrahydrofolate biosynthetic process; ISS:TAIR.
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.
DR   Genevisible; Q05762; AT.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Methyltransferase; Multifunctional enzyme; NADP;
KW   Nucleotide biosynthesis; One-carbon metabolism; Oxidoreductase;
KW   Reference proteome; Transferase.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:22223895"
FT   CHAIN           2..519
FT                   /note="Bifunctional dihydrofolate reductase-thymidylate
FT                   synthase 1"
FT                   /id="PRO_0000186355"
FT   DOMAIN          21..198
FT                   /note="DHFR"
FT   REGION          201..234
FT                   /note="Hinge"
FT   REGION          235..519
FT                   /note="Thymidylate synthase"
FT   ACT_SITE        401
FT                   /evidence="ECO:0000250"
FT   BINDING         25
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         27
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   BINDING         33..39
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   BINDING         47
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         71..73
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   BINDING         92..95
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   BINDING         134
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         135..142
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250"
FT   BINDING         155
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         256
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250"
FT   BINDING         402
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250"
FT   BINDING         420..424
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250"
FT   BINDING         432
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250"
FT   BINDING         462..464
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0007744|PubMed:22223895"
FT   CONFLICT        120
FT                   /note="A -> R (in Ref. 1; AAA32788)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        478
FT                   /note="L -> P (in Ref. 1; AAA32788)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        485
FT                   /note="M -> L (in Ref. 1; AAA32788)"
FT                   /evidence="ECO:0000305"
FT   STRAND          22..29
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          33..39
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           45..56
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          59..62
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          64..70
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           71..76
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          87..92
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          104..110
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           112..119
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           124..127
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          128..133
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           137..143
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          149..158
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          164..166
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   TURN            172..174
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          175..180
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          184..186
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          189..198
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           228..231
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           236..249
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          251..254
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          260..272
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          274..276
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          281..283
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           287..299
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           305..308
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   TURN            309..311
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           316..318
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           321..326
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           341..347
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           366..376
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          384..386
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           390..395
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          401..410
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          413..424
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   TURN            425..427
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           428..446
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          450..464
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           465..467
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           468..474
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          484..487
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           494..496
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   HELIX           499..501
FT                   /evidence="ECO:0007829|PDB:8DAE"
FT   STRAND          502..506
FT                   /evidence="ECO:0007829|PDB:8DAE"
SQ   SEQUENCE   519 AA;  58143 MW;  B5EB36A3A936580F CRC64;
     MATTTLNDSV TTTLASEPQR TYQVVVAATK EMGIGKDGKL PWNLPTDLKF FKDITLTTSD
     SSKKNAVVMG RKTWESIPIK YRPLSGRLNV VLTRSGGFDI ANTENVVTCS SVDSALDLLA
     APPYCLSIER VFVIGGGDIL REALNRPSCD AIHLTEIDTS VDCDTFIPAI DTSVYQPWSS
     SFPVTENGLR FCFTTFVRVK SSADESSDES NGSQSLQFDG KKFLFLPKMV FDQHEEFLYL
     NMVEDIISNG NVKNDRTGTG TLSKFGCQMK FNLRRSFPLL TTKRVFWRGV VEELLWFISG
     STNAKVLQEK GIHIWDGNAS REYLDGIGLT EREEGDLGPV YGFQWRHFGA KYTDMHADYT
     GQGFDQLVDV IDKIKNNPDD RRIIMSAWNP SDLKLMALPP CHMFAQFYVA EGELSCQMYQ
     RSADMGLGVP FNIASYSLLT CMLAHVCDLV PGDFIHVLGD AHVYKTHVRP LQEQLLNLPK
     PFPVMKINPE KKQIDSFVAS DFDLTGYDPH KKIEMKMAV
//