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Protein

Bifunctional dihydrofolate reductase-thymidylate synthase

Gene
N/A
Organism
Plasmodium falciparum (isolate K1 / Thailand)
Status
Reviewed-Annotation score: 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: tetrahydrofolate biosynthesis

This protein is involved in step 1 of the subpathway that synthesizes 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate.
Proteins known to be involved in this subpathway in this organism are:
  1. Bifunctional dihydrofolate reductase-thymidylate synthase
This subpathway is part of the pathway tetrahydrofolate biosynthesis, which is itself part of Cofactor biosynthesis.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate, the pathway tetrahydrofolate biosynthesis and in Cofactor biosynthesis.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei16NADP; via amide nitrogen and carbonyl oxygen1
Binding sitei31Substrate; via carbonyl oxygenBy similarity1
Binding sitei54Substrate1
Binding sitei108Substrate1
Binding sitei144NADP; via carbonyl oxygen1
Binding sitei164Substrate; via carbonyl oxygen1
Binding sitei170Substrate1
Binding sitei185SubstrateBy similarity1
Binding sitei345dUMP1
Active sitei490By similarity1
Binding sitei491dUMP1
Binding sitei521dUMP1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi39 – 45NADP7
Nucleotide bindingi106 – 108NADP3
Nucleotide bindingi128 – 130NADP3
Nucleotide bindingi165 – 172NADP8
Nucleotide bindingi509 – 513dUMP5
Nucleotide bindingi551 – 553dUMP3

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Methyltransferase, Oxidoreductase, Transferase

Keywords - Biological processi

Nucleotide biosynthesis, One-carbon metabolism

Keywords - Ligandi

NADP

Enzyme and pathway databases

BRENDAi1.5.1.3. 4889.
2.1.1.45. 4889.
SABIO-RKP13922.
UniPathwayiUPA00077; UER00158.

Protein family/group databases

MoonProtiP13922.

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 lineageiEukaryotaAlveolataApicomplexaAconoidasidaHaemosporidaPlasmodiidaePlasmodiumPlasmodium (Laverania)

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL1939.
DrugBankiDB01131. Proguanil.
DB00205. Pyrimethamine.
DB01299. Sulfadoxine.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001863491 – 608Bifunctional dihydrofolate reductase-thymidylate synthaseAdd BLAST608

Proteomic databases

PRIDEiP13922.

Interactioni

Subunit structurei

Homodimer.1 Publication

Structurei

Secondary structure

1608
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi5 – 8Combined sources4
Beta strandi11 – 20Combined sources10
Turni23 – 25Combined sources3
Helixi27 – 29Combined sources3
Helixi34 – 36Combined sources3
Beta strandi37 – 42Combined sources6
Beta strandi47 – 49Combined sources3
Helixi52 – 63Combined sources12
Helixi67 – 81Combined sources15
Beta strandi101 – 105Combined sources5
Helixi106 – 111Combined sources6
Helixi114 – 116Combined sources3
Beta strandi122 – 127Combined sources6
Helixi133 – 135Combined sources3
Beta strandi141 – 145Combined sources5
Helixi146 – 155Combined sources10
Beta strandi161 – 163Combined sources3
Helixi167 – 175Combined sources9
Beta strandi180 – 191Combined sources12
Beta strandi194 – 196Combined sources3
Turni202 – 204Combined sources3
Beta strandi205 – 210Combined sources6
Beta strandi214 – 216Combined sources3
Beta strandi219 – 228Combined sources10
Helixi285 – 293Combined sources9
Turni294 – 296Combined sources3
Helixi304 – 307Combined sources4
Helixi309 – 312Combined sources4
Helixi313 – 317Combined sources5
Beta strandi319 – 321Combined sources3
Helixi325 – 338Combined sources14
Beta strandi340 – 342Combined sources3
Turni346 – 348Combined sources3
Beta strandi350 – 361Combined sources12
Turni362 – 364Combined sources3
Beta strandi370 – 372Combined sources3
Helixi377 – 387Combined sources11
Helixi393 – 397Combined sources5
Turni398 – 400Combined sources3
Turni403 – 405Combined sources3
Helixi406 – 408Combined sources3
Helixi410 – 415Combined sources6
Helixi430 – 436Combined sources7
Helixi455 – 465Combined sources11
Beta strandi473 – 475Combined sources3
Helixi479 – 484Combined sources6
Beta strandi485 – 487Combined sources3
Beta strandi490 – 499Combined sources10
Beta strandi502 – 513Combined sources12
Turni514 – 516Combined sources3
Helixi517 – 535Combined sources19
Beta strandi539 – 553Combined sources15
Helixi554 – 556Combined sources3
Helixi557 – 563Combined sources7
Beta strandi573 – 576Combined sources4
Helixi583 – 585Combined sources3
Helixi588 – 590Combined sources3
Beta strandi591 – 594Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP13922.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini10 – 228DHFRAdd BLAST219

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni14 – 15Substrate binding2
Regioni322 – 608Thymidylate synthaseAdd BLAST287

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

CDDicd00209. DHFR. 1 hit.
cd00351. TS_Pyrimidine_HMase. 1 hit.
Gene3Di3.30.572.10. 1 hit.
3.40.430.10. 1 hit.
HAMAPiMF_00008. Thymidy_synth_bact. 1 hit.
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)DescriptionActionsGraphical viewLength
Natural varianti16A → V in strain: Isolate Palo-Alto. 1
Natural varianti51N → I.1
Natural varianti59R → C in strain: Isolate FCR-3, Isolate Gambia and Isolate Palo-Alto. 1
Natural varianti108N → T in strain: Isolate FCR-3, Isolate Gambia and Isolate Palo-Alto. 1

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.
PIRiA39975. RDZQK1.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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.
ModBaseiSearch...
MobiDBiSearch...

Chemistry databases

ChEMBLiCHEMBL1939.
DrugBankiDB01131. Proguanil.
DB00205. Pyrimethamine.
DB01299. Sulfadoxine.

Protein family/group databases

MoonProtiP13922.

Proteomic databases

PRIDEiP13922.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Enzyme and pathway databases

UniPathwayiUPA00077; UER00158.
BRENDAi1.5.1.3. 4889.
2.1.1.45. 4889.
SABIO-RKP13922.

Miscellaneous databases

EvolutionaryTraceiP13922.

Family and domain databases

CDDicd00209. DHFR. 1 hit.
cd00351. TS_Pyrimidine_HMase. 1 hit.
Gene3Di3.30.572.10. 1 hit.
3.40.430.10. 1 hit.
HAMAPiMF_00008. Thymidy_synth_bact. 1 hit.
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]
ProtoNetiSearch...

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 30, 2016
This is version 116 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.