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P13922

- DRTS_PLAFK

UniProt

P13922 - DRTS_PLAFK

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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

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
Complete GO annotation...

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

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
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

        10         20         30         40         50
MMEQVCDVFD IYAICACCKV ESKNEGKKNE VFNNYTFRGL GNKGVLPWKC
60 70 80 90 100
NSLDMKYFRA VTTYVNESKY EKLKYKRCKY LNKETVDNVN DMPNSKKLQN
110 120 130 140 150
VVVMGRTNWE SIPKKFKPLS NRINVILSRT LKKEDFDEDV YIINKVEDLI
160 170 180 190 200
VLLGKLNYYK CFIIGGSVVY QEFLEKKLIK KIYFTRINST YECDVFFPEI
210 220 230 240 250
NENEYQIISV SDVYTSNNTT LDFIIYKKTN NKMLNEQNCI KGEEKNNDMP
260 270 280 290 300
LKNDDKDTCH MKKLTEFYKN VDKYKINYEN DDDDEEEDDF VYFNFNKEKE
310 320 330 340 350
EKNKNSIHPN DFQIYNSLKY KYHPEYQYLN IIYDIMMNGN KQSDRTGVGV
360 370 380 390 400
LSKFGYIMKF DLSQYFPLLT TKKLFLRGII EELLWFIRGE TNGNTLLNKN
410 420 430 440 450
VRIWEANGTR EFLDNRKLFH REVNDLGPIY GFQWRHFGAE YTNMYDNYEN
460 470 480 490 500
KGVDQLKNII NLIKNDPTSR RILLCAWNVK DLDQMALPPC HILCQFYVFD
510 520 530 540 550
GKLSCIMYQR SCDLGLGVPF NIASYSIFTH MIAQVCNLQP AQFIHVLGNA
560 570 580 590 600
HVYNNHIDSL KIQLNRIPYP FPTLKLNPDI KNIEDFTISD FTIQNYVHHE

KISMDMAA
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:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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:
PDBei
RCSB PDBi
PDBji
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.
DB01299. Sulfadoxine.

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: November 26, 2014
This is version 104 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