Plasmodium falciparum purine nucleoside phosphorylase | Antimalarial targets | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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Plasmodium falciparum purine nucleoside phosphorylase

Target id: 3077

Nomenclature: Plasmodium falciparum purine nucleoside phosphorylase

Abbreviated Name: PfPNP

Family: Antimalarial targets

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 245 PNP purine nucleoside phosphorylase
Database Links
UniProtKB
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Plasmodium falciparum purine nucleoside phosphorylase in complex with mefloquine
PDB Id:  5ZNI
Ligand:  mefloquine
Resolution:  2.3Å
Species:  Plasmodium falciparum
References:  2
Image of receptor 3D structure from RCSB PDB
Description:  Plasmodium falciparum purine nucleoside phosphorylase in complex with quinine
PDB Id:  5ZNC
Ligand:  quinine
Resolution:  1.66Å
Species:  Plasmodium falciparum
References:  2
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Plasmodium falciparum Purine Nucleoside Phosphorylase in complex with ImmH and Sulfate
PDB Id:  1NW4
Ligand:  forodesine
Resolution:  2.2Å
Species:  Plasmodium falciparum
References:  5

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
forodesine Pf - 9.2 pKi 3
pKi 9.2 (Ki 6x10-10 M) [3]
quinine Pf - 6.9 pKi 2
pKi 6.9 (Ki 1.38x10-7 M) [2]
mefloquine Pf - 5.2 pKi 2
pKi 5.2 (Ki 5.9x10-6 M) [2]
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Value Parameter Reference
forodesine Pf 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.

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

Antimalarial targets: Plasmodium falciparum purine nucleoside phosphorylase. Last modified on 27/03/2019. Accessed on 18/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3077.