Plasmodium falciparum prolyl-tRNA synthetase

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Aminoacyl-tRNA synthetases
Plasmodium falciparum prolyl-tRNA synthetase

Target id: 3056

Nomenclature: Plasmodium falciparum prolyl-tRNA synthetase

Abbreviated Name: PfcPRS

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Plasmodium falciparum 3D7	-	746		PRS	proline--tRNA ligase
Gene and Protein Information Comments
The Plasmodium genome encodes two forms of prolyl-tRNA synthetase, one found in the cytoplasm (PfcPRS, described here) and one in the apicoplast (PfaPRS, encoded by PF3D7_0925300).

Previous and Unofficial Names
Pf3D7_12_v3:589,729..593,777(-) \| PfProRS \| PFL0670c \| Plasmodium falciparum proline--tRNA ligase

Previous and Unofficial Names

Pf3D7_12_v3:589,729..593,777(-) | PfProRS | PFL0670c | Plasmodium falciparum proline--tRNA ligase

Database Links
Alphafold	Q8I5R7 (Pf3D7)
ChEMBL Target	CHEMBL3301560 (Pf3D7)
PlasmoDB	PF3D7_1213800 (Pf3D7)
SynPHARM	85927 (in complex with halofuginone)
UniProtKB	Q8I5R7 (Pf3D7)

Selected 3D Structures

Image of receptor 3D structure from RCSB PDB

Description:	Crystal Structure of Prolyl-tRNA Synthetase (PRS) from Plasmodium falciparum in complex with Halofuginone and AMPPNP
PDB Id:	4YDQ
Ligand:	halofuginone
Resolution:	2.3Å
Species:	Plasmodium falciparum
References:	5

Description:	Crystal Structure of Prolyl-tRNA Synthetase (PRS) from Plasmodium falciparum
PDB Id:	4TWA
Resolution:	3.0Å
Species:	Plasmodium falciparum
References:	4

Whole Organism Assay Data Linked to This Target

Key to terms and symbols

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Ligand		Sp.	Assay description	Type	Action	Value	Parameter	Reference
halofuginone		PfDd2 Plasmodium falciparum Dd2 P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine. ✖	Parasite growth inhibition assay	-	-	9.1	pEC₅₀	3
⤷	pEC₅₀ 9.1 (EC₅₀ 8.1x10^-10 M) SYBR Green assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
halofuginone		Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	Parasite growth inhibition assay	-	-	9.1	pEC₅₀	3
⤷	pEC₅₀ 9.1 (EC₅₀ 8.6x10^-10 M) SYBR Green assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1 [PMID: 33929818]		Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	Parasite growth inhibition assay	-	-	8.0	pIC₅₀	6
⤷	pIC₅₀ 8.0 (IC₅₀ 1x10^-8 M) DAPI incorporation assay (72h) [6] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
halofuginone		Pb Plasmodium berghei P. berghei (Pb) is a malaria parasite that infects mammals other than humans with the natural mammalian host being the thicket rat (G. surdaster) from Central Africa. Pb is used in rodent model studies of malaria. ✖	Parasite liver stage assay	-	-	7.8	pIC₅₀	1
⤷	pIC₅₀ 7.8 (IC₅₀ 1.7x10^-8 M) [1] Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
compound 1 [PMID: 33929818]		PfTM90C2B Plasmodium falciparum TM90C2B P. falciparum TM90C2B (PfTM90C2B) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). A point mutation (Y268S) at the Q_o site of cytochrome b results in a 3,000-fold loss of atovaquone sensitivity. It is used as a screening tool for the development of new cytochrome b inhibitors. ✖	Parasite growth inhibition assay	-	-	7.8	pIC₅₀	6
⤷	pIC₅₀ 7.8 (IC₅₀ 1.7x10^-8 M) [³H]-hypoxanthine incorporation assay (72h) [6] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1 [PMID: 33929818]		PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	Parasite growth inhibition assay	-	-	7.7	pIC₅₀	6
⤷	pIC₅₀ 7.7 (IC₅₀ 1.8x10^-8 M) [³H]-hypoxanthine incorporation assay (72h) [6] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1 [PMID: 33929818]		Pf7G8 Plasmodium falciparum 7G8 P. falciparum strain 7G8 (Pf7G8) was subcloned from the IMTM22 strain by limiting dilution. The original IMTM22 strain was isolated from a 12 year old male near Manaus, Brazil in 1980. Pf7G8 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4). This strain is a gametocyte producer and is reported to be chloroquine-sensitive and pyrimethamine-resistant. ✖	Parasite growth inhibition assay	-	-	7.7	pIC₅₀	6
⤷	pIC₅₀ 7.7 (IC₅₀ 1.8x10^-8 M) [³H]-hypoxanthine incorporation assay (72h) [6] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1 [PMID: 33929818]		PfK1 Plasmodium falciparum K1 P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979. PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain. ✖	Parasite growth inhibition assay	-	-	7.7	pIC₅₀	6
⤷	pIC₅₀ 7.7 (IC₅₀ 2x10^-8 M) [³H]-hypoxanthine incorporation assay (72h) [6] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1 [PMID: 33929818]		PfDd2 Plasmodium falciparum Dd2 P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine. ✖	Parasite growth inhibition assay	-	-	7.6	pIC₅₀	6
⤷	pIC₅₀ 7.6 (IC₅₀ 2.4x10^-8 M) [³H]-hypoxanthine incorporation assay (72h) [6] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)

Malaria Pharmacology Comments
PfcPRS is ranked as a "High Priority" target in the Malaria Drug Accelerator (MalDA) portfolio [2].

Malaria Pharmacology Comments

PfcPRS is ranked as a "High Priority" target in the Malaria Drug Accelerator (MalDA) portfolio [2].

References

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1. Derbyshire ER, Mazitschek R, Clardy J. (2012) Characterization of Plasmodium liver stage inhibition by halofuginone. ChemMedChem, 7 (5): 844-9. [PMID:22438279]

2. Forte B, Ottilie S, Plater A, Campo B, Dechering KJ, Gamo FJ, Goldberg DE, Istvan ES, Lee M, Lukens AK et al.. (2021) Prioritization of Molecular Targets for Antimalarial Drug Discovery. ACS Infect Dis, 7 (10): 2764-2776. [PMID:34523908]

3. Herman JD, Pepper LR, Cortese JF, Estiu G, Galinsky K, Zuzarte-Luis V, Derbyshire ER, Ribacke U, Lukens AK, Santos SA et al.. (2015) The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Sci Transl Med, 7 (288): 288ra77. [PMID:25995223]

4. Jain V, Kikuchi H, Oshima Y, Sharma A, Yogavel M. (2014) Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase. J Struct Funct Genomics, 15 (4): 181-90. [PMID:25047712]

5. Jain V, Yogavel M, Oshima Y, Kikuchi H, Touquet B, Hakimi MA, Sharma A. (2015) Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis. Structure, 23 (5): 819-829. [PMID:25817387]

6. Okaniwa M, Shibata A, Ochida A, Akao Y, White KL, Shackleford DM, Duffy S, Lucantoni L, Dey S, Striepen J et al.. (2021) Repositioning and Characterization of 1-(Pyridin-4-yl)pyrrolidin-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors. ACS Infect Dis, 7 (6): 1680-1689. [PMID:33929818]

How to cite this page

Aminoacyl-tRNA synthetases: Plasmodium falciparum prolyl-tRNA synthetase. Last modified on 29/03/2022. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3056.