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P13922

- DRTS_PLAFK

UniProt

P13922 - DRTS_PLAFK

Protein

Bifunctional dihydrofolate reductase-thymidylate synthase

Gene
N/A
Organism
Plasmodium falciparum (isolate K1 / Thailand)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 102 (01 Oct 2014)
      Sequence version 2 (01 Aug 1990)
      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 sitei16 – 161NADP; via amide nitrogen and carbonyl oxygen
    Binding sitei31 – 311Substrate; via carbonyl oxygenBy similarity
    Binding sitei54 – 541Substrate
    Binding sitei108 – 1081Substrate
    Binding sitei144 – 1441NADP; via carbonyl oxygen
    Binding sitei164 – 1641Substrate; via carbonyl oxygen
    Binding sitei170 – 1701Substrate
    Binding sitei185 – 1851SubstrateBy similarity
    Binding sitei345 – 3451dUMP
    Active sitei490 – 4901By similarity
    Binding sitei491 – 4911dUMP
    Binding sitei521 – 5211dUMP

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi39 – 457NADP
    Nucleotide bindingi106 – 1083NADP
    Nucleotide bindingi128 – 1303NADP
    Nucleotide bindingi165 – 1728NADP
    Nucleotide bindingi509 – 5135dUMP
    Nucleotide bindingi551 – 5533dUMP

    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

    SABIO-RKP13922.
    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)
    OrganismiPlasmodium falciparum (isolate K1 / Thailand)
    Taxonomic identifieri5839 [NCBI]
    Taxonomic lineageiEukaryotaAlveolataApicomplexaAconoidasidaHaemosporidaPlasmodiumPlasmodium (Laverania)

    Pathology & Biotechi

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 608608Bifunctional dihydrofolate reductase-thymidylate synthasePRO_0000186349Add
    BLAST

    Interactioni

    Subunit structurei

    Homodimer.1 Publication

    Structurei

    Secondary structure

    1
    608
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi5 – 84
    Beta strandi11 – 2010
    Turni23 – 253
    Helixi27 – 293
    Helixi34 – 363
    Beta strandi37 – 426
    Beta strandi47 – 493
    Helixi52 – 6312
    Helixi67 – 8115
    Beta strandi101 – 1055
    Helixi106 – 1116
    Helixi114 – 1163
    Beta strandi122 – 1276
    Helixi133 – 1353
    Beta strandi141 – 1455
    Helixi146 – 15510
    Beta strandi161 – 1633
    Helixi167 – 1759
    Beta strandi180 – 19112
    Beta strandi194 – 1963
    Turni202 – 2043
    Beta strandi205 – 2106
    Beta strandi214 – 2163
    Beta strandi219 – 22810
    Helixi285 – 2939
    Turni294 – 2963
    Helixi304 – 3074
    Helixi309 – 3124
    Helixi313 – 3175
    Beta strandi319 – 3213
    Helixi325 – 33814
    Beta strandi340 – 3423
    Turni346 – 3483
    Beta strandi350 – 36112
    Turni362 – 3643
    Beta strandi370 – 3723
    Helixi377 – 38711
    Helixi393 – 3975
    Turni398 – 4003
    Turni403 – 4053
    Helixi406 – 4083
    Helixi410 – 4156
    Helixi430 – 4367
    Helixi455 – 46511
    Beta strandi473 – 4753
    Helixi479 – 4846
    Beta strandi485 – 4873
    Beta strandi490 – 49910
    Beta strandi502 – 51312
    Turni514 – 5163
    Helixi517 – 53519
    Beta strandi539 – 55315
    Helixi554 – 5563
    Helixi557 – 5637
    Beta strandi573 – 5764
    Helixi583 – 5853
    Helixi588 – 5903
    Beta strandi591 – 5944

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1J3IX-ray2.33A/B1-280[»]
    C/D281-608[»]
    1J3JX-ray2.30A/B1-280[»]
    C/D281-608[»]
    1J3KX-ray2.10A/B1-280[»]
    C/D281-608[»]
    3DG8X-ray2.58A/B1-280[»]
    C/D281-608[»]
    3DGAX-ray2.70A/B1-280[»]
    C/D281-608[»]
    ProteinModelPortaliP13922.
    SMRiP13922. Positions 2-231, 283-608.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP13922.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini10 – 228219DHFRAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni14 – 152Substrate binding
    Regioni322 – 608287Thymidylate 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.

    P13922-1 [UniParc]FASTAAdd to Basket

    « Hide

    MMEQVCDVFD IYAICACCKV ESKNEGKKNE VFNNYTFRGL GNKGVLPWKC    50
    NSLDMKYFRA VTTYVNESKY EKLKYKRCKY LNKETVDNVN DMPNSKKLQN 100
    VVVMGRTNWE SIPKKFKPLS NRINVILSRT LKKEDFDEDV YIINKVEDLI 150
    VLLGKLNYYK CFIIGGSVVY QEFLEKKLIK KIYFTRINST YECDVFFPEI 200
    NENEYQIISV SDVYTSNNTT LDFIIYKKTN NKMLNEQNCI KGEEKNNDMP 250
    LKNDDKDTCH MKKLTEFYKN VDKYKINYEN DDDDEEEDDF VYFNFNKEKE 300
    EKNKNSIHPN DFQIYNSLKY KYHPEYQYLN IIYDIMMNGN KQSDRTGVGV 350
    LSKFGYIMKF DLSQYFPLLT TKKLFLRGII EELLWFIRGE TNGNTLLNKN 400
    VRIWEANGTR EFLDNRKLFH REVNDLGPIY GFQWRHFGAE YTNMYDNYEN 450
    KGVDQLKNII NLIKNDPTSR RILLCAWNVK DLDQMALPPC HILCQFYVFD 500
    GKLSCIMYQR SCDLGLGVPF NIASYSIFTH MIAQVCNLQP AQFIHVLGNA 550
    HVYNNHIDSL KIQLNRIPYP FPTLKLNPDI KNIEDFTISD FTIQNYVHHE 600
    KISMDMAA 608
    Length:608
    Mass (Da):71,817
    Last modified:August 1, 1990 - v2
    Checksum:i7727EEB4A3946996
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti16 – 161A → V in strain: Isolate Palo-Alto.
    Natural varianti51 – 511N → I.
    Natural varianti59 – 591R → C in strain: Isolate FCR-3, Isolate Gambia and Isolate Palo-Alto.
    Natural varianti108 – 1081N → T in strain: Isolate FCR-3, Isolate Gambia and Isolate Palo-Alto.

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M22159 Genomic DNA. Translation: AAA29580.1.
    J04643 Genomic DNA. Translation: AAA29586.1.
    J03772 Genomic DNA. Translation: AAB59212.1.
    J03028 Genomic DNA. Translation: AAA29585.1.
    PIRiA39975. RDZQK1.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M22159 Genomic DNA. Translation: AAA29580.1 .
    J04643 Genomic DNA. Translation: AAA29586.1 .
    J03772 Genomic DNA. Translation: AAB59212.1 .
    J03028 Genomic DNA. Translation: AAA29585.1 .
    PIRi A39975. RDZQK1.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1J3I X-ray 2.33 A/B 1-280 [» ]
    C/D 281-608 [» ]
    1J3J X-ray 2.30 A/B 1-280 [» ]
    C/D 281-608 [» ]
    1J3K X-ray 2.10 A/B 1-280 [» ]
    C/D 281-608 [» ]
    3DG8 X-ray 2.58 A/B 1-280 [» ]
    C/D 281-608 [» ]
    3DGA X-ray 2.70 A/B 1-280 [» ]
    C/D 281-608 [» ]
    ProteinModelPortali P13922.
    SMRi P13922. Positions 2-231, 283-608.
    ModBasei Search...
    MobiDBi Search...

    Chemistry

    ChEMBLi CHEMBL1939.
    DrugBanki DB01131. Proguanil.
    DB00205. Pyrimethamine.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Enzyme and pathway databases

    UniPathwayi UPA00077 ; UER00158 .
    SABIO-RK P13922.

    Miscellaneous databases

    EvolutionaryTracei P13922.

    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. "Characterisation of the dihydrofolate reductase-thymidylate synthetase gene from human malaria parasites highly resistant to pyrimethamine."
      Snewin V.A., England S.M., Sims P.F.G., Hyde J.E.
      Gene 76:41-52(1989) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: Isolate FCR3 and Isolate K1.
    2. "Point mutations in the dihydrofolate reductase-thymidylate synthase gene as the molecular basis for pyrimethamine resistance in Plasmodium falciparum."
      Zolg J.W., Plitt J.R., Chen G.-X., Palmer S.
      Mol. Biochem. Parasitol. 36:253-262(1989) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    3. "Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum."
      Cowman A.F., Morry M.J., Biggs B.A., Cross G.A.M., Foote S.J.
      Proc. Natl. Acad. Sci. U.S.A. 85:9109-9113(1988) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: Isolate Palo-Alto.
    4. "Molecular cloning and sequence analysis of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene."
      Bzik D.J., Li W.B., Horii T., Inselburg J.
      Proc. Natl. Acad. Sci. U.S.A. 84:8360-8364(1987) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: Isolate FCR3.
    5. Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF WILD TYPE AND DRUG-RESISTANT VARIANTS IN COMPLEXES WITH NADP; UMP AND THE SYNTHETIC INHIBITORS WR99210 AND PYRIMETHAMINE, CATALYTIC ACTIVITY, SUBUNIT.
    6. "Exploiting structural analysis, in silico screening, and serendipity to identify novel inhibitors of drug-resistant falciparum malaria."
      Dasgupta T., Chitnumsub P., Kamchonwongpaisan S., Maneeruttanarungroj C., Nichols S.E., Lyons T.M., Tirado-Rives J., Jorgensen W.L., Yuthavong Y., Anderson K.S.
      ACS Chem. Biol. 4:29-40(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.58 ANGSTROMS) OF WILD TYPE AND DRUG-RESISTANT VARIANTS IN COMPLEXES WITH NADP AND INHIBITORS RJF 001302; RJF 00670 AND RJF 00719, CATALYTIC ACTIVITY.

    Entry informationi

    Entry nameiDRTS_PLAFK
    AccessioniPrimary (citable) accession number: P13922
    Secondary accession number(s): Q27734
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: January 1, 1990
    Last sequence update: August 1, 1990
    Last modified: October 1, 2014
    This is version 102 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)

    Miscellaneousi

    Miscellaneous

    K1 is from a pyrimethamine-resistant strain; FCR3 is a pyrimethamine-sensitive strain.

    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