Genome location: Pf3D7_04_v3:747,897..750,065(+)
Genome classification: Core
Product Description: bifunctional dihydrofolate reductase-thymidylate synthase
SignalP Peptide: N/A
# Transmembrane Domains: 0
EC Numbers: 1.5.1.3 (Dihydrofolate reductase);2.1.1.45 (Thymidylate synthase)
Curated GO (PlasmoDB):
| Type | GO Term | Name |
|---|---|---|
| Component | GO:0005737 | cytoplasm |
| Component | GO:0005829 | cytosol |
| Component | GO:0005739 | mitochondrion |
| Function | GO:0003723 | RNA binding |
| Function | GO:0004799 | thymidylate synthase activity |
| Process | GO:0006231 | dTMP biosynthetic process |
| Process | GO:1902349 | response to chloroquine |
| Process | GO:0042493 | response to drug |
| Process | GO:0009410 | response to xenobiotic stimulus |
Expression by stage (LR - Le Roch et al., and MCA - Malaria Cell Atlas):
| Stage | LR class | MCA mean | MCA prop. zeros |
|---|---|---|---|
| Sporozoite | not expressed | N/A | N/A |
| Ring | not expressed | 0.13 | 0.93 |
| Trophozoite | expressed | 0.77 | 0.58 |
| Schizont | expressed | 0.33 | 0.79 |
| Gametocyte | not expressed | 0.61 | 0.67 |
More info:
Old (Pf3D7v3) Gene ID: PF3D7_0417200
Resistome Missense Mutations: G378E, I403L, H551N
Resistome Compounds with Missense Mutations: MMV027634
Resistome # Samples with Disruptive Mutations: 3 (3 missense, 3 "interesting" missense)
Zhang Phenotype: Non - Mutable in CDS
MIS: 0.125 | MFS: -3.031 | #Insertions: 0
PlasmoGEM Phenotype: N/A
RMgmDB ABS Phenotype: Different from wild type (Pb ortholog: PBANKA_0719300)
Modification: Mutated | RMgm-4883
More info: PhenoPlasm Link
AlphaFill Uniprot ID: Q8I1R6
"Best" AlphaFill ligand hit: BU1 (1,4-butanediol, Local RMSD=0.02) with 4E5O (Global RMSD=1.02)
BRENDA EC Inhibitors:
Orthology to BindingDB Entries:
| UniProt | Protein Name | Species | Homology Source | BindingDB Ligands |
|---|---|---|---|---|
| Q8I1R6 | Bifunctional dihydrofolate reductase-thymidylate synthase | Plasmodium falciparum (isolate K1 / Thailand) | HOGENOM, OMA, OrthoDB, OrthoMCL, OrthoMCL BLAST | Pyrimethamine (Pyr)CycloguanilWR99210Pyrimethamine (Pyr)... |
| Q07422 | Bifunctional dihydrofolate reductase-thymidylate synthase | OMA, OrthoMCL BLAST | Diaminopyrimidine analogue, 3Trimethoprim (TMP)PiritreximPiritrexim analogue, 6... | |
| A7UD81 | Bifunctional dihydrofolate reductase-thymidylate synthase | OMA, OrthoMCL, OrthoMCL BLAST | CHEMBL7005CHEMBL90703CHEMBL90292CHEMBL92182... | |
| P07607 | Thymidylate synthase | Mus musculus | OrthoDB, OrthoMCL BLAST | CHEMBL157459CHEMBL160502CHEMBL157459CHEMBL420935... |
| Q920D2 | Dihydrofolate reductase | Rattus norvegicus | OrthoDB | Diaminopyrimidine analogue, 3PiritreximPiritrexim analogue, 6Piritrexim analogue, 7... |
| Q582G3 | Bifunctional dihydrofolate reductase-thymidylate synthase | OrthoDB, OrthoMCL | MethotrexateCHEMBL1232702CHEMBL2178602CHEMBL2178600... | |
| P04818 | Thymidylate synthase | Homo sapiens | OrthoDB | 1,2-naphthalein derivative, 21,8-naphthalein derivative, 121,8-naphthalein derivative, 141,8-naphthalein derivative, 15... |
| Q2TA32 | Thymidylate synthase | OrthoDB | DEOXYURIDINE MONOPHOSPHATECHEMBL3248468 | |
| P00374 | Dihydrofolate reductase | Homo sapiens | OrthoDB | GW345GW997GW578GW995... |
| P07807 | Dihydrofolate reductase | Saccharomyces cerevisiae | OrthoDB | CHEMBL53318CHEMBL417746CHEMBL445359CHEMBL300886... |
| A0A0W4ZHR8 | Dihydrofolate reductase | OrthoDB | US11111252, Compound 1US11001595, Compound 2US11111252, Compound 2US11111252, Compound 3... | |
| P00376 | Dihydrofolate reductase | OrthoDB | 6,8,10-Traiazaspiro[4.5]deca-6,8-diene-7,9-diamine, Ib6,8,10-Traiazaspiro[4.5]deca-6,8-diene-7,9-diamine, Ic6,8,10-Traiazaspiro[4.5]deca-6,8-diene-7,9-diamine, IdCHEMBL1800937... | |
| P0CS13 | Thymidylate synthase | Cryptococcus neoformans | OrthoDB, OrthoMCL | GA91,2-naphthalein derivative, 11,2-naphthalein derivative, 21,2-naphthalein derivative, 3... |
| P45352 | Thymidylate synthase | Rattus norvegicus | OrthoDB, OrthoMCL BLAST | PDDFCHEMBL439973CB3717Raltitrexed |
| P00375 | Dihydrofolate reductase | Mus musculus | OrthoDB | Z-isomerE/Z ratio=2:1E/Z ratio=3:1E/Z ratio=2:1... |
| P9WFR9 | Thymidylate synthase ThyA | Mycobacterium tuberculosis | OrthoMCL, OrthoMCL BLAST | CHEMBL1823492 |
| P0A884 | Thymidylate synthase | Escherichia coli | OrthoMCL, OrthoMCL BLAST | GA91,2-naphthalein derivative, 11,2-naphthalein derivative, 21,2-naphthalein derivative, 3... |
| P13922 | Bifunctional dihydrofolate reductase-thymidylate synthase | Plasmodium falciparum (isolate K1 / Thailand) | OrthoMCL BLAST | Pyrimethamine (Pyr)CycloguanilWR99210MLS001401431... |
| P0A017 | Dihydrofolate reductase | Staphylococcus aureus | OrthoMCL BLAST | IclaprimTrimethoprim (TMP)AR-709AR-709... |
| P00378 | Dihydrofolate reductase | OrthoMCL BLAST | CHEMBL31946CHEMBL31547CHEMBL2051989CHEMBL2051990... | |
| P00469 | Thymidylate synthase | Lactobacillus casei | OrthoMCL BLAST | GA91,2-naphthalein derivative, 21,2-naphthalein derivative, 31,2-naphthalein derivative, 4... |
| C7C2U7 | Dihydrofolate reductase | OrthoMCL BLAST | UCP1039UCP1164UCP1172UCP1173... | |
| Q8NWQ9 | Dihydrofolate reductase | Staphylococcus aureus (strain MW2) | OrthoMCL BLAST | CHEMBL420755CHEMBL310468CHEMBL305656CHEMBL77758... |
| Q4H3Y3 | Dihydrofolate reductase | OrthoMCL BLAST | UCP1039UCP1164UCP1172UCP1173... | |
| Q8Z9J9 | Dihydrofolate reductase | OrthoMCL BLAST | CHEMBL56101CHEMBL53516CHEMBL56468CHEMBL57034... | |
| Q27552 | Bifunctional dihydrofolate reductase-thymidylate synthase | Cryptosporidium hominis | OrthoMCL BLAST | Propargyl-linked, 2Propargyl-linked, 6Propargyl-linked, 8JMC516839 Compound 1... |
| C3SWJ7 | Thymidylate synthase | OrthoMCL BLAST | CHEMBL353191CHEMBL169726CHEMBL352620CHEMBL169727... | |
| Q834R3 | Thymidylate synthase | Enterococcus faecalis | OrthoMCL BLAST | CHEMBL1231545CHEMBL1231557CHEMBL1229651Phenolphthalein |
| P00382 | Dihydrofolate reductase type 1 | Escherichia coli | OrthoMCL BLAST | CHEMBL441503CHEMBL414610CHEMBL20812CHEMBL418741... |
| O02604 | Bifunctional dihydrofolate reductase-thymidylate synthase [1-238,S58R,S117N] | Plasmodium vivax | OrthoMCL BLAST | Pyrimethamine (Pyr)P25P375-(4-chlorophenyl)-6-(2-methylpropyl)pyrimidine-2,4-diamine... |
| P0ABQ4 | Dihydrofolate reductase | Escherichia coli | OrthoMCL BLAST | imidothiocarbamate analogue, 1imidothiocarbamate analogue, 1MLS001401431amidinothiouronium, 6... |
| J7IFZ2 | Dihydrofolate reductase | OrthoMCL BLAST | Biphenyl antifolate, 2Biphenyl antifolate, 3CHEMBL1270533CHEMBL1270439... | |
| Q27713 | Bifunctional dihydrofolate reductase-thymidylate synthase | OrthoMCL BLAST | Trimethoprim (TMP)CHEMBL339058CHEMBL325533CHEMBL149353 |
Ortholog Group (OrthoMCL): OG6_101427
Most Similar Human Ortholog: P04818
TM-align score: 0.91 | RMSD: 1.20
Seq Identity: 0.55 | Length: 291 / 608
All Human Orthologs (OrthoMCL):
| Gene ID | Description |
|---|---|
| ENSG00000176890 | thymidylate synthetase |
Protein Length: 608 | Molecular Weight (kDa): 71.737
UniProt ID(s): A0A060D1X5, A0A060D281, A0A060D5R7, A0A060D656, A0A060D6E8, A0A060DAW8, A0A060DB80, A0A060DBR7, A0A060DBW7, A7UD79, A7UD81, C3S7P8, D9N170, Q8I1R6
PDB ID(s): None
Isoelectric Point: 7.17
Protein Domain Annotations:
| Source | Family ID | Description |
|---|---|---|
| InterPro | IPR000398 | Thymidylate synthase |
| InterPro | IPR001796 | Dihydrofolate reductase domain |
| InterPro | IPR012262 | Bifunctional dihydrofolate reductase/thymidylate synthase |
| InterPro | IPR017925 | Dihydrofolate reductase conserved site |
| InterPro | IPR020940 | Thymidylate synthase, active site |
| InterPro | IPR023451 | Thymidylate synthase/dCMP hydroxymethylase domain |
| InterPro | IPR024072 | Dihydrofolate reductase-like domain superfamily |
| InterPro | IPR036926 | Thymidylate synthase/dCMP hydroxymethylase superfamily |
| PFam | PF00186 | Dihydrofolate reductase domain |
| PFam | PF00303 | Thymidylate synthase/dCMP hydroxymethylase domain |
| Superfamily | SSF53597 | Dihydrofolate reductase-like domain superfamily |
| Superfamily | SSF55831 | Thymidylate synthase/dCMP hydroxymethylase superfamily |
MalariaGEN Pf7 (worldwide samples) # unique SNV/indels:
Homozygous genotype calls only
| variant type | common | rare | doubleton | singleton |
|---|---|---|---|---|
| synonymous | 0 | 1 | 5 | 14 |
| disruptive | 5 | 5 | 4 | 28 |
| missense | 5 | 4 | 2 | 20 |
Any inclusion in genotype call
| variant type | common | rare | doubleton | singleton |
|---|---|---|---|---|
| synonymous | 0 | 20 | 15 | 20 |
| disruptive | 7 | 27 | 37 | 89 |
| missense | 5 | 16 | 26 | 57 |
PlasmoDB Total SNPs: 63
Non-coding: 32 | Synonymous: 21 | Nonsynonymous: 10 | Stop Codon: 0
| PMID | Title | Authors | DOI/Link |
|---|---|---|---|
| 2904149 | Evidence that a point mutation in dihydrofolate reductase-thymidylate synthaseconfers resistance to pyrimethamine in falciparum malaria. | Peterson DS, Walliker D, Wellems TE | 10.1073/pnas.85.23.9114 |
| 12368867 | Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13. | Hall N, Pain A, ..., Barrell BG | 10.1038/nature01095 |
| 12704428 | Insights into antifolate resistance from malarial DHFR-TS structures. | Yuvaniyama J, Chitnumsub P, ..., Yuthavong Y | 10.1038/nsb921 |
| 20577818 | Formation of catalytically active cross-species heterodimers of thymidylatesynthase from Plasmodium falciparum and Plasmodium vivax. | Chanama M, Chanama S, ..., Yuthavong Y | 10.1007/s11033-010-0199-7 |
| 23497065 | Insights into the role of the junctional region of Plasmodium falciparumdihydrofolate reductase-thymidylate synthase. | Chaianantakul N, Sirawaraporn R, Sirawaraporn W | 10.1186/1475-2875-12-91 |
| 24321120 | Mutational analysis of Plasmodium falciparum dihydrofolate reductase anddihydropteroate synthase genes in the interior division of Sabah, Malaysia. | Lau TY, Sylvi M, William T | 10.1186/1475-2875-12-445 |
| 25311473 | Genetic mutations in Plasmodium falciparum and Plasmodium vivax dihydrofolatereductase (DHFR) and dihydropteroate synthase (DHPS) in Vanuatu and SolomonIslands prior to the introduction of artemisinin combination therapy. | Gresty KJ, Gray KA, ..., Waters NC | 10.1186/1475-2875-13-402 |
| 25447287 | Molecular characterization of Plasmodium falciparum Bruno/CELF RNA bindingproteins. | Wongsombat C, Aroonsri A, ..., Shaw PJ | https://pubmed.ncbi.nlm.nih.gov/25447287/ |
| 28533179 | Polymorphisms in pfdhfr and pfdhps genes after five years of artemisinincombination therapy (ACT) implementation from urban Kolkata, India. | Chatterjee M, Ganguly S, ..., Maji AK | 10.1016/j.meegid.2017.05.013 |
| 29348637 | Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarialaction of triclosan. | Bilsland E, van Vliet L, ..., Oliver SG | 10.1038/s41598-018-19549-x |
| 32294614 | Flexible diaminodihydrotriazine inhibitors of Plasmodium falciparum dihydrofolatereductase: Binding strengths, modes of binding and their antimalarial activities. | Kamchonwongpaisan S, Charoensetakul N, ..., Yuthavong Y | 10.1016/j.ejmech.2020.112263 |
| 32673701 | Antimalarial effect of cell penetrating peptides derived from the junctionalregion of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase. | Chaianantakul N, Sungkapong T, ..., Suwanakitti N | 10.1016/j.peptides.2020.170372 |
| 36676935 | Evaluation of Zamia floridana A. DC. Leaves and Its Isolated SecondaryMetabolites as Natural Anti-Toxoplasma and Anti-Cancer Agents Using In Vitro andIn Silico Studies | El-Seadawy HM, Abo El-Seoud KA, ..., Ragab AE | 10.3390/metabo13010010 |
| 36124481 | In silico study to predict promiscuous T cell and B cell-epitopes derived fromthe vaccine candidate antigens of Plasmodium vivax binding to MHC class-IIalleles | Khan N, Bin-Mwena MN, ..., Farooq U | 10.4103/0972-9062.335726 |
| 38239295 | Antimalarial target vulnerability of the putative Plasmodium falciparummethionine synthase | Leela N, Prommana P, ..., Shaw PJ | 10.7717/peerj.16595 |
| 36936814 | Apically-located P4-ATPase1-Lem1 complex internalizes phosphatidylserine andregulates motility-dependent invasion and egress in Toxoplasma gondii | Chen K, Huang X, ..., Gupta N | 10.1016/j.csbj.2023.02.032 |
| 36846776 | Retrospective analysis of Plasmodium vivax genomes from a pre-elimination Chinainland population in the 2010s | Liu Y, Zhang T, ..., Chen JH | 10.3389/fmicb.2023.1071689 |
| 36386564 | Molecular docking and antimalarial evaluation of novelN-(4-aminobenzoyl)-l-glutamic acid conjugated 1,3,5-triazine derivatives asPf-DHFR inhibitors | Adhikari N, Choudhury AAK, ..., Bhat HR | 10.1007/s13205-022-03400-2 |
| 36036155 | New pyrazolylpyrazoline derivatives as dual acting antimalarial-antileishamanialagents: synthesis, biological evaluation and molecular modelling simulations | Bekhit AA, Lodebo ET, ..., Ibrahim TM | 10.1080/14756366.2022.2117316 |
| 36523834 | Use of Leishmania major parasites expressing a recombinant Trypanosoma cruziantigen as live vaccines against Chagas disease | Cai CW, O'Shea A, ..., Hoft DF | 10.3389/fmicb.2022.1059115 |
| 36621136 | Identification, in-vitro anti-plasmodial assessment and docking studies of seriesof tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide molecular hybrids aspotential antimalarial agents | Pal K, Raza MK, ..., Hoda N | 10.1016/j.ejmech.2022.115055 |
| 37269671 | Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dualantileishmanial-antimalarial activity graced with antitubercular activity:Design, synthesis and biological evaluation | Ibrahim TM, Abada G, ..., Beockler FM | 10.1016/j.ejmech.2023.115534 |
| 36382189 | Plasticity and therapeutic potential of cAMP and cGMP-specific phosphodiesterasesin Toxoplasma gondii | Vo KC, Ruga L, ..., Gupta N | 10.1016/j.csbj.2022.09.022 |
| 38005256 | In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma brucei andLeishmania major Pteridine Reductase 1 and Dihydrofolate Reductase | Possart K, Herrmann FC, Jose J, Schmidt TJ | 10.3390/molecules28227526 |
| 36112587 | Single- and duplex TaqMan-quantitative PCR for determining the copy numbers ofintegrated selection markers during site-specific mutagenesis in Toxoplasmagondii by CRISPR-Cas9 | Hanggeli KPA, Hemphill A, ..., Boubaker G | 10.1371/journal.pone.0271011 |