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| | ==Plasmodium falciparum purine nucleoside phosphorylase in complex with mefloquine== | | ==Plasmodium falciparum purine nucleoside phosphorylase in complex with mefloquine== |
| - | <StructureSection load='5zni' size='340' side='right' caption='[[5zni]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='5zni' size='340' side='right'caption='[[5zni]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5zni]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZNI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZNI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5zni]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZNI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZNI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=YMZ:MEFLOQUINE'>YMZ</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Purine-nucleoside_phosphorylase Purine-nucleoside phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.1 2.4.2.1] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=YMZ:MEFLOQUINE'>YMZ</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5zni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zni OCA], [http://pdbe.org/5zni PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zni RCSB], [http://www.ebi.ac.uk/pdbsum/5zni PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zni ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5zni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zni OCA], [https://pdbe.org/5zni PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zni RCSB], [https://www.ebi.ac.uk/pdbsum/5zni PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zni ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PNPH_PLAFA PNPH_PLAFA] As part of the purine salvage pathway, catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate (PubMed:11707439, PubMed:30602534). Preferentially acts on inosine and guanosine, and to a lesser extent on 2'-deoxyinosine and 2'-deoxyguanosine (PubMed:11707439). Also catalyzes the phosphorylation of S-methyl-5'-thioinosine (MTI) to hypoxanthine; MTI is produced by adenosine deaminase (ADA)-mediated breakdown of S-methyl-5'-thioadenosine (MTA), a major by-product of polyamine biosynthesis (By similarity). Generates hypoxanthine from both the purine salvage pathway and from polyamine metabolism which is required for nucleic acids synthesis (By similarity). Has no activity towards adenosine (PubMed:11707439).[UniProtKB:Q8I3X4]<ref>PMID:11707439</ref> <ref>PMID:30602534</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5zni" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5zni" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Purine nucleoside phosphorylase 3D structures|Purine nucleoside phosphorylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Purine-nucleoside phosphorylase]] | + | [[Category: Large Structures]] |
| - | [[Category: Chen, D]] | + | [[Category: Plasmodium falciparum]] |
| - | [[Category: Dziekan, J M]] | + | [[Category: Chen D]] |
| - | [[Category: Nordlund, P]] | + | [[Category: Dziekan JM]] |
| - | [[Category: Nucleoside phosphorylase]] | + | [[Category: Nordlund P]] |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
PNPH_PLAFA As part of the purine salvage pathway, catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate (PubMed:11707439, PubMed:30602534). Preferentially acts on inosine and guanosine, and to a lesser extent on 2'-deoxyinosine and 2'-deoxyguanosine (PubMed:11707439). Also catalyzes the phosphorylation of S-methyl-5'-thioinosine (MTI) to hypoxanthine; MTI is produced by adenosine deaminase (ADA)-mediated breakdown of S-methyl-5'-thioadenosine (MTA), a major by-product of polyamine biosynthesis (By similarity). Generates hypoxanthine from both the purine salvage pathway and from polyamine metabolism which is required for nucleic acids synthesis (By similarity). Has no activity towards adenosine (PubMed:11707439).[UniProtKB:Q8I3X4][1] [2]
Publication Abstract from PubMed
Mechanisms of action (MoAs) have been elusive for most antimalarial drugs in clinical use. Decreasing responsiveness to antimalarial treatments stresses the need for a better resolved understanding of their MoAs and associated resistance mechanisms. In the present work, we implemented the cellular thermal shift assay coupled with mass spectrometry (MS-CETSA) for drug target identification in Plasmodium falciparum, the main causative agent of human malaria. We validated the efficacy of this approach for pyrimethamine, a folic acid antagonist, and E64d, a broad-spectrum cysteine proteinase inhibitor. Subsequently, we applied MS-CETSA to quinine and mefloquine, two important antimalarial drugs with poorly characterized MoAs. Combining studies in the P. falciparum parasite lysate and intact infected red blood cells, we found P. falciparum purine nucleoside phosphorylase (PfPNP) as a common binding target for these two quinoline drugs. Biophysical and structural studies with a recombinant protein further established that both compounds bind within the enzyme's active site. Quinine binds to PfPNP at low nanomolar affinity, suggesting a substantial contribution to its therapeutic effect. Overall, we demonstrated that implementation of MS-CETSA for P. falciparum constitutes a promising strategy to elucidate the MoAs of existing and candidate antimalarial drugs.
Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay.,Dziekan JM, Yu H, Chen D, Dai L, Wirjanata G, Larsson A, Prabhu N, Sobota RM, Bozdech Z, Nordlund P Sci Transl Med. 2019 Jan 2;11(473). pii: 11/473/eaau3174. doi:, 10.1126/scitranslmed.aau3174. PMID:30602534[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kicska GA, Tyler PC, Evans GB, Furneaux RH, Kim K, Schramm VL. Transition state analogue inhibitors of purine nucleoside phosphorylase from Plasmodium falciparum. J Biol Chem. 2002 Feb 1;277(5):3219-25. PMID:11707439 doi:10.1074/jbc.M105905200
- ↑ Dziekan JM, Yu H, Chen D, Dai L, Wirjanata G, Larsson A, Prabhu N, Sobota RM, Bozdech Z, Nordlund P. Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay. Sci Transl Med. 2019 Jan 2;11(473). pii: 11/473/eaau3174. doi:, 10.1126/scitranslmed.aau3174. PMID:30602534 doi:http://dx.doi.org/10.1126/scitranslmed.aau3174
- ↑ Dziekan JM, Yu H, Chen D, Dai L, Wirjanata G, Larsson A, Prabhu N, Sobota RM, Bozdech Z, Nordlund P. Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay. Sci Transl Med. 2019 Jan 2;11(473). pii: 11/473/eaau3174. doi:, 10.1126/scitranslmed.aau3174. PMID:30602534 doi:http://dx.doi.org/10.1126/scitranslmed.aau3174
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