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P13922 (DRTS_PLAFK) Reviewed, UniProtKB/Swiss-Prot

Last modified February 19, 2014. Version 101. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Bifunctional dihydrofolate reductase-thymidylate synthase

Short name=DHFR-TS

Including the following 2 domains:

  1. Dihydrofolate reductase
    EC=1.5.1.3
  2. Thymidylate synthase
    EC=2.1.1.45
OrganismPlasmodium falciparum (isolate K1 / Thailand)
Taxonomic identifier5839 [NCBI]
Taxonomic lineageEukaryotaAlveolataApicomplexaAconoidasidaHaemosporidaPlasmodiumPlasmodium (Laverania)

Protein attributes

Sequence length608 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. HAMAP-Rule MF_00008

Catalytic activity

5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH. Ref.5 Ref.6

5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP. Ref.5 Ref.6

Pathway

Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate: step 1/1. HAMAP-Rule MF_00008

Subunit structure

Homodimer. Ref.5

Miscellaneous

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

Sequence similarities

In the N-terminal section; belongs to the dihydrofolate reductase family.

In the C-terminal section; belongs to the thymidylate synthase family.

Contains 1 DHFR (dihydrofolate reductase) domain.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 608608Bifunctional dihydrofolate reductase-thymidylate synthase HAMAP-Rule MF_00008
PRO_0000186349

Regions

Domain10 – 228219DHFR
Nucleotide binding39 – 457NADP HAMAP-Rule MF_00008
Nucleotide binding106 – 1083NADP HAMAP-Rule MF_00008
Nucleotide binding128 – 1303NADP HAMAP-Rule MF_00008
Nucleotide binding165 – 1728NADP HAMAP-Rule MF_00008
Nucleotide binding509 – 5135dUMP HAMAP-Rule MF_00008
Nucleotide binding551 – 5533dUMP HAMAP-Rule MF_00008
Region14 – 152Substrate binding HAMAP-Rule MF_00008
Region322 – 608287Thymidylate synthase HAMAP-Rule MF_00008

Sites

Active site4901 By similarity
Binding site161NADP; via amide nitrogen and carbonyl oxygen
Binding site311Substrate; via carbonyl oxygen By similarity
Binding site541Substrate
Binding site1081Substrate
Binding site1441NADP; via carbonyl oxygen
Binding site1641Substrate; via carbonyl oxygen
Binding site1701Substrate
Binding site1851Substrate By similarity
Binding site3451dUMP
Binding site4911dUMP
Binding site5211dUMP

Natural variations

Natural variant161A → V in strain: Isolate Palo-Alto.
Natural variant511N → I.
Natural variant591R → C in strain: Isolate FCR-3, Isolate Gambia and Isolate Palo-Alto.
Natural variant1081N → T in strain: Isolate FCR-3, Isolate Gambia and Isolate Palo-Alto.

Secondary structure

...................................................................................................... 608
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P13922 [UniParc].

Last modified August 1, 1990. Version 2.
Checksum: 7727EEB4A3946996

FASTA60871,817
        10         20         30         40         50         60 
MMEQVCDVFD IYAICACCKV ESKNEGKKNE VFNNYTFRGL GNKGVLPWKC NSLDMKYFRA 

        70         80         90        100        110        120 
VTTYVNESKY EKLKYKRCKY LNKETVDNVN DMPNSKKLQN VVVMGRTNWE SIPKKFKPLS 

       130        140        150        160        170        180 
NRINVILSRT LKKEDFDEDV YIINKVEDLI VLLGKLNYYK CFIIGGSVVY QEFLEKKLIK 

       190        200        210        220        230        240 
KIYFTRINST YECDVFFPEI NENEYQIISV SDVYTSNNTT LDFIIYKKTN NKMLNEQNCI 

       250        260        270        280        290        300 
KGEEKNNDMP LKNDDKDTCH MKKLTEFYKN VDKYKINYEN DDDDEEEDDF VYFNFNKEKE 

       310        320        330        340        350        360 
EKNKNSIHPN DFQIYNSLKY KYHPEYQYLN IIYDIMMNGN KQSDRTGVGV LSKFGYIMKF 

       370        380        390        400        410        420 
DLSQYFPLLT TKKLFLRGII EELLWFIRGE TNGNTLLNKN VRIWEANGTR EFLDNRKLFH 

       430        440        450        460        470        480 
REVNDLGPIY GFQWRHFGAE YTNMYDNYEN KGVDQLKNII NLIKNDPTSR RILLCAWNVK 

       490        500        510        520        530        540 
DLDQMALPPC HILCQFYVFD GKLSCIMYQR SCDLGLGVPF NIASYSIFTH MIAQVCNLQP 

       550        560        570        580        590        600 
AQFIHVLGNA HVYNNHIDSL KIQLNRIPYP FPTLKLNPDI KNIEDFTISD FTIQNYVHHE 


KISMDMAA 

« Hide

References

[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]"Insights into antifolate resistance from malarial DHFR-TS structures."
Yuvaniyama J., Chitnumsub P., Kamchonwongpaisan S., Vanichtanankul J., Sirawaraporn W., Taylor P., Walkinshaw M.D., Yuthavong Y.
Nat. Struct. Biol. 10:357-365(2003) [PubMed] [Europe PMC] [Abstract]
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.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M22159 Genomic DNA. Translation: AAA29580.1.
J04643 Genomic DNA. Translation: AAA29586.1.
J03772 Genomic DNA. Translation: AAB59212.1.
J03028 Genomic DNA. Translation: AAA29585.1.
PIRRDZQK1. A39975.

3D structure databases

PDBe
RCSB PDB
PDBj
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[»]
ProteinModelPortalP13922.
SMRP13922. Positions 2-231, 283-608.
ModBaseSearch...
MobiDBSearch...

Chemistry

ChEMBLCHEMBL1939.
DrugBankDB01131. Proguanil.
DB00205. Pyrimethamine.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Enzyme and pathway databases

SABIO-RKP13922.
UniPathwayUPA00077; UER00158.

Family and domain databases

Gene3D3.30.572.10. 1 hit.
3.40.430.10. 1 hit.
HAMAPMF_00008. Thymidy_synth_bact.
InterProIPR024072. 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]
PfamPF00186. DHFR_1. 1 hit.
PF00303. Thymidylat_synt. 1 hit.
[Graphical view]
PIRSFPIRSF000389. DHFR-TS. 1 hit.
PRINTSPR00108. THYMDSNTHASE.
SUPFAMSSF53597. SSF53597. 1 hit.
SSF55831. SSF55831. 1 hit.
TIGRFAMsTIGR03284. thym_sym. 1 hit.
PROSITEPS00075. DHFR_1. 1 hit.
PS51330. DHFR_2. 1 hit.
PS00091. THYMIDYLATE_SYNTHASE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP13922.

Entry information

Entry nameDRTS_PLAFK
AccessionPrimary (citable) accession number: P13922
Secondary accession number(s): Q27734
Entry history
Integrated into UniProtKB/Swiss-Prot: January 1, 1990
Last sequence update: August 1, 1990
Last modified: February 19, 2014
This is version 101 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways