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Q27793

- DRTS_TRYCR

UniProt

Q27793 - DRTS_TRYCR

Protein

Bifunctional dihydrofolate reductase-thymidylate synthase

Gene
N/A
Organism
Trypanosoma cruzi
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 77 (01 Oct 2014)
      Sequence version 2 (01 May 1997)
      Previous versions | rss
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    Functioni

    Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.

    Catalytic activityi

    5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH.
    5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP.

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei26 – 261Substrate; via carbonyl oxygen
    Binding sitei28 – 281NADP; via amide nitrogen and carbonyl oxygen
    Binding sitei48 – 481Substrate
    Binding sitei154 – 1541Substrate; via carbonyl oxygen
    Binding sitei160 – 1601Substrate
    Binding sitei178 – 1781Substrate
    Binding sitei257 – 2571dUMP
    Active sitei403 – 4031By similarity
    Binding sitei404 – 4041dUMP
    Binding sitei434 – 4341dUMP

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi34 – 407NADP
    Nucleotide bindingi78 – 803NADP
    Nucleotide bindingi99 – 1024NADP
    Nucleotide bindingi155 – 1628NADP
    Nucleotide bindingi422 – 4265dUMP
    Nucleotide bindingi464 – 4663dUMP

    GO - Molecular functioni

    1. dihydrofolate reductase activity Source: UniProtKB-EC
    2. thymidylate synthase activity Source: UniProtKB-EC

    GO - Biological processi

    1. dTMP biosynthetic process Source: InterPro
    2. glycine biosynthetic process Source: InterPro
    3. one-carbon metabolic process Source: UniProtKB-KW
    4. tetrahydrofolate biosynthetic process Source: UniProtKB-UniPathway

    Keywords - Molecular functioni

    Methyltransferase, Oxidoreductase, Transferase

    Keywords - Biological processi

    Nucleotide biosynthesis, One-carbon metabolism

    Keywords - Ligandi

    NADP

    Enzyme and pathway databases

    UniPathwayiUPA00077; UER00158.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Bifunctional dihydrofolate reductase-thymidylate synthase
    Short name:
    DHFR-TS
    Including the following 2 domains:
    Dihydrofolate reductase (EC:1.5.1.3)
    Thymidylate synthase (EC:2.1.1.45)
    OrganismiTrypanosoma cruzi
    Taxonomic identifieri5693 [NCBI]
    Taxonomic lineageiEukaryotaEuglenozoaKinetoplastidaTrypanosomatidaeTrypanosomaSchizotrypanum

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 521521Bifunctional dihydrofolate reductase-thymidylate synthasePRO_0000186354Add
    BLAST

    Interactioni

    Subunit structurei

    Homodimer.1 Publication

    Structurei

    Secondary structure

    1
    521
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi2 – 43
    Turni10 – 134
    Helixi14 – 163
    Beta strandi23 – 308
    Beta strandi33 – 397
    Helixi46 – 5712
    Beta strandi60 – 634
    Beta strandi70 – 778
    Helixi78 – 825
    Helixi86 – 883
    Beta strandi94 – 996
    Helixi105 – 1106
    Beta strandi112 – 1143
    Helixi115 – 1217
    Helixi122 – 1243
    Beta strandi125 – 1306
    Helixi132 – 1398
    Turni142 – 1476
    Beta strandi148 – 1536
    Helixi157 – 1637
    Helixi168 – 1714
    Beta strandi172 – 1809
    Beta strandi188 – 1903
    Helixi199 – 2013
    Beta strandi206 – 2116
    Beta strandi218 – 2214
    Beta strandi224 – 2329
    Helixi235 – 25016
    Beta strandi252 – 2554
    Beta strandi261 – 27313
    Helixi275 – 2773
    Beta strandi283 – 2853
    Helixi289 – 30012
    Helixi307 – 3104
    Turni311 – 3133
    Turni319 – 3213
    Helixi323 – 3286
    Helixi343 – 3497
    Beta strandi357 – 3593
    Helixi368 – 37811
    Beta strandi386 – 3883
    Turni392 – 3943
    Helixi395 – 3973
    Beta strandi398 – 4003
    Beta strandi403 – 41210
    Beta strandi415 – 42612
    Turni427 – 4293
    Helixi430 – 44819
    Beta strandi452 – 46615
    Helixi467 – 4693
    Helixi470 – 4767
    Beta strandi486 – 4905
    Helixi496 – 4983
    Helixi501 – 5033
    Beta strandi504 – 5085

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2H2QX-ray2.40A/B1-521[»]
    3CL9X-ray3.30A1-521[»]
    3CLBX-ray3.00A/B/C/D1-521[»]
    3HBBX-ray3.00A/B/C/D1-521[»]
    3INVX-ray2.37A/B1-521[»]
    3IRMX-ray2.10A/B/C/D1-521[»]
    3IRNX-ray2.60A/B/C/D1-521[»]
    3IROX-ray2.80A/B/C/D1-521[»]
    ProteinModelPortaliQ27793.
    SMRiQ27793. Positions 2-515.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ27793.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini22 – 232211DHFRAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni237 – 521285Thymidylate synthaseAdd
    BLAST

    Sequence similaritiesi

    In the N-terminal section; belongs to the dihydrofolate reductase family.Curated
    In the C-terminal section; belongs to the thymidylate synthase family.Curated

    Family and domain databases

    Gene3Di3.30.572.10. 1 hit.
    3.40.430.10. 1 hit.
    HAMAPiMF_00008. Thymidy_synth_bact.
    InterProiIPR024072. DHFR-like_dom.
    IPR012262. DHFR-TS.
    IPR017925. DHFR_CS.
    IPR001796. DHFR_dom.
    IPR023451. Thymidate_synth/dCMP_Mease.
    IPR000398. Thymidylate_synthase.
    IPR020940. Thymidylate_synthase_AS.
    [Graphical view]
    PfamiPF00186. DHFR_1. 1 hit.
    PF00303. Thymidylat_synt. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000389. DHFR-TS. 1 hit.
    PRINTSiPR00108. THYMDSNTHASE.
    SUPFAMiSSF53597. SSF53597. 1 hit.
    SSF55831. SSF55831. 1 hit.
    TIGRFAMsiTIGR03284. thym_sym. 1 hit.
    PROSITEiPS00075. DHFR_1. 1 hit.
    PS51330. DHFR_2. 1 hit.
    PS00091. THYMIDYLATE_SYNTHASE. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q27793-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSLFKIRMPE TVAEGTRLAL RAFSLVVAVD EHGGIGDGRS IPWNVPEDMK    50
    FFRDLTTKLR GKNVKPSPAK RNAVVMGRKT WDSIPPKFRP LPGRLNVVLS 100
    STLTTQHLLD GLPDEEKRNL HADSIVAVNG GLEQALRLLA SPNYTPSIET 150
    VYCIGGGSVY AEALRPPCVH LLQAIYRTTI RASESSCSVF FRVPESGTEA 200
    AAGIEWQRET ISEELTSANG NETKYYFEKL IPRNREEEQY LSLVDRIIRE 250
    GNVKHDRTGV GTLSIFGAQM RFSLRNNRLP LLTTKRVFWR GVCEELLWFL 300
    RGETYAKKLS DKGVHIWDDN GSRAFLDSRG LTEYEEMDLG PVYGFQWRHF 350
    GAAYTHHDAN YDGQGVDQIK AIVETLKTNP DDRRMLFTAW NPSALPRMAL 400
    PPCHLLAQFY VSNGELSCML YQRSCDMGLG VPFNIASYAL LTILIAKATG 450
    LRPGELVHTL GDAHVYSNHV EPCNEQLKRV PRAFPYLVFR REREFLEDYE 500
    EGDMEVIDYA PYPPISMKMA V 521
    Length:521
    Mass (Da):58,853
    Last modified:May 1, 1997 - v2
    Checksum:iDCB9F8782855810C
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L22484 Genomic DNA. Translation: AAB49898.1.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L22484 Genomic DNA. Translation: AAB49898.1 .

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2H2Q X-ray 2.40 A/B 1-521 [» ]
    3CL9 X-ray 3.30 A 1-521 [» ]
    3CLB X-ray 3.00 A/B/C/D 1-521 [» ]
    3HBB X-ray 3.00 A/B/C/D 1-521 [» ]
    3INV X-ray 2.37 A/B 1-521 [» ]
    3IRM X-ray 2.10 A/B/C/D 1-521 [» ]
    3IRN X-ray 2.60 A/B/C/D 1-521 [» ]
    3IRO X-ray 2.80 A/B/C/D 1-521 [» ]
    ProteinModelPortali Q27793.
    SMRi Q27793. Positions 2-515.
    ModBasei Search...
    MobiDBi Search...

    Chemistry

    BindingDBi Q27793.
    ChEMBLi CHEMBL1163130.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Enzyme and pathway databases

    UniPathwayi UPA00077 ; UER00158 .

    Miscellaneous databases

    EvolutionaryTracei Q27793.

    Family and domain databases

    Gene3Di 3.30.572.10. 1 hit.
    3.40.430.10. 1 hit.
    HAMAPi MF_00008. Thymidy_synth_bact.
    InterProi IPR024072. DHFR-like_dom.
    IPR012262. DHFR-TS.
    IPR017925. DHFR_CS.
    IPR001796. DHFR_dom.
    IPR023451. Thymidate_synth/dCMP_Mease.
    IPR000398. Thymidylate_synthase.
    IPR020940. Thymidylate_synthase_AS.
    [Graphical view ]
    Pfami PF00186. DHFR_1. 1 hit.
    PF00303. Thymidylat_synt. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF000389. DHFR-TS. 1 hit.
    PRINTSi PR00108. THYMDSNTHASE.
    SUPFAMi SSF53597. SSF53597. 1 hit.
    SSF55831. SSF55831. 1 hit.
    TIGRFAMsi TIGR03284. thym_sym. 1 hit.
    PROSITEi PS00075. DHFR_1. 1 hit.
    PS51330. DHFR_2. 1 hit.
    PS00091. THYMIDYLATE_SYNTHASE. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Cloning and expression of the dihydrofolate reductase-thymidylate synthase gene from Trypanosoma cruzi."
      Reche P., Arrebola R., Olmo A., Santi D.V., Gonzalez-Pacanowska D., Ruiz-Perez L.M.
      Mol. Biochem. Parasitol. 65:247-258(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: Y.
    2. "Expression and characterization of the Trypanosoma cruzi dihydrofolate reductase domain."
      Reche P., Arrebola R., Santi D.V., Gonzalez-Pacanowska D., Ruiz-Perez L.M.
      Mol. Biochem. Parasitol. 76:175-185(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: Y.
    3. "Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function."
      Schormann N., Senkovich O., Walker K., Wright D.L., Anderson A.C., Rosowsky A., Ananthan S., Shinkre B., Velu S., Chattopadhyay D.
      Proteins 73:889-901(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) IN COMPLEXES WITH NADP; METHOTREXATE AND TRIMETREXATE, CATALYTIC ACTIVITY.
    4. "Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate."
      Senkovich O., Schormann N., Chattopadhyay D.
      Acta Crystallogr. D 65:704-716(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) IN COMPLEXES WITH NADP; UMP; METHOTREXATE AND TRIMETREXATE, SUBUNIT.
    5. "Crystallization and preliminary crystallographic studies of dihydrofolate reductase-thymidylate synthase from Trypanosoma cruzi, the Chagas disease pathogen."
      Chitnumsub P., Yuvaniyama J., Chahomchuen T., Vilaivan T., Yuthavong Y.
      Acta Crystallogr. F 65:1175-1178(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) IN COMPLEXES WITH NADP; UMP AND THE SYNTHETIC INHIBITORS C-448; CYC AND Q-8, CATALYTIC ACTIVITY.

    Entry informationi

    Entry nameiDRTS_TRYCR
    AccessioniPrimary (citable) accession number: Q27793
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 1, 1997
    Last sequence update: May 1, 1997
    Last modified: October 1, 2014
    This is version 77 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Multifunctional enzyme

    Documents

    1. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3