Plasmodium falciparum purine nucleoside phosphorylase

Target id: 3077

Nomenclature: Plasmodium falciparum purine nucleoside phosphorylase

Abbreviated Name: PfPNP

Family: Nucleoside synthesis and metabolism (Plasmodium spp.)

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Plasmodium falciparum 3D7	-	245		PNP	purine nucleoside phosphorylase

Previous and Unofficial Names
PNP \| Pf3D7_05_v3:568,594..570,527(-) \| PFE0660c

Database Links
Alphafold	Q8I3X4 (Pf3D7)
ChEMBL Target	CHEMBL4523389 (Pf3D7)
PlasmoDB	PF3D7_0513300 (Pf3D7)
UniProtKB	Q8I3X4 (Pf3D7)

Ligand		Sp.	Action	Value	Parameter	Reference
forodesine		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	-	9.2	pK_i	3
⤷	pK_i 9.2 (K_i 6x10^-10 M) [3]
quinine		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	-	6.9	pK_i	2
⤷	pK_i 6.9 (K_i 1.38x10^-7 M) [2]
mefloquine		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	-	5.2	pK_i	2
⤷	pK_i 5.2 (K_i 5.9x10^-6 M) [2]

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
forodesine										Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	Parasite growth inhibition assay	-	-	7.5	pIC₅₀	4
⤷	pIC₅₀ 7.5 (IC₅₀ 3.5x10^-8 M) Tran³⁵S incorporation [4] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)

Malaria Pharmacology Comments
Protozoan parasites, including Plasmodium spp., are unable to synthesize purines de novo and instead salvage and recycle these molecules from the host. P. falciparum purine nucleoside phosphorylase (PfPNP), an enzyme involved in the nucleotide salvage pathway is inhibited by several compounds with antimalarial activity. Immucillins are inhibitors of both mammalian PNP and PfPNP, leading to death of the malaria parasite in culture and in an animal model of the disease [1,3-4,6]. PfPNP has also been shown to be the common binding target for mefloquine and quinine, two approved antimalarial drugs from the same chemical class and with complex and poorly understood MoAs [2]. The high affinity interaction for quinine indicates that inhibition of PfPNP may be of clinical relevance.

Malaria Pharmacology Comments

Protozoan parasites, including Plasmodium spp., are unable to synthesize purines de novo and instead salvage and recycle these molecules from the host. P. falciparum purine nucleoside phosphorylase (PfPNP), an enzyme involved in the nucleotide salvage pathway is inhibited by several compounds with antimalarial activity. Immucillins are inhibitors of both mammalian PNP and PfPNP, leading to death of the malaria parasite in culture and in an animal model of the disease [1,3-4,6]. PfPNP has also been shown to be the common binding target for mefloquine and quinine, two approved antimalarial drugs from the same chemical class and with complex and poorly understood MoAs [2]. The high affinity interaction for quinine indicates that inhibition of PfPNP may be of clinical relevance.

References

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1. Cassera MB, Hazleton KZ, Merino EF, Obaldia 3rd N, Ho MC, Murkin AS, DePinto R, Gutierrez JA, Almo SC, Evans GB et al.. (2011) Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model. PLoS ONE, 6 (11): e26916. [PMID:22096507]

2. Dziekan JM, Yu H, Chen D, Dai L, Wirjanata G, Larsson A, Prabhu N, Sobota RM, Bozdech Z, Nordlund P. (2019) Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay. Sci Transl Med, 11 (473). [PMID:30602534]

3. Kicska GA, Tyler PC, Evans GB, Furneaux RH, Kim K, Schramm VL. (2002) Transition state analogue inhibitors of purine nucleoside phosphorylase from Plasmodium falciparum. J Biol Chem, 277 (5): 3219-25. [PMID:11707439]

4. Kicska GA, Tyler PC, Evans GB, Furneaux RH, Schramm VL, Kim K. (2002) Purine-less death in Plasmodium falciparum induced by immucillin-H, a transition state analogue of purine nucleoside phosphorylase. J Biol Chem, 277 (5): 3226-31. [PMID:11706018]

5. Shi W, Ting LM, Kicska GA, Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Kim K, Almo SC, Schramm VL. (2004) Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function. J Biol Chem, 279 (18): 18103-6. [PMID:14982926]

6. Ting LM, Shi W, Lewandowicz A, Singh V, Mwakingwe A, Birck MR, Ringia EA, Bench G, Madrid DC, Tyler PC et al.. (2005) Targeting a novel Plasmodium falciparum purine recycling pathway with specific immucillins. J Biol Chem, 280 (10): 9547-54. [PMID:15576366]

How to cite this page

Nucleoside synthesis and metabolism (Plasmodium spp.): Plasmodium falciparum purine nucleoside phosphorylase. Last modified on 12/10/2021. Accessed on 10/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3077.

Plasmodium falciparum purine nucleoside phosphorylase

Contents:

Plasmodium falciparum

Plasmodium falciparum

Plasmodium falciparum

Plasmodium falciparum

References

How to cite this page