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3fow

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Plasmodium Purine Nucleoside Phosphorylase V66I-V73I-Y160F Mutant

Structural highlights

3fow is a 2 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PNPH_PLAF7 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:18957439, PubMed:14982926, PubMed:16131758, PubMed:19575810, PubMed:24416224, PubMed:29440412). Preferentially acts on inosine and guanosine, and to a lesser extent on 2'-deoxyguanosine and guanosine (PubMed:14982926, PubMed:16131758, PubMed:19575810). 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 (PubMed:18957439, PubMed:14982926, PubMed:24416224). Generates hypoxanthine from both the purine salvage pathway and from polyamine metabolism which is required for nucleic acids synthesis (PubMed:18957439, PubMed:14982926, PubMed:24416224). Has no activity towards adenosine (By similarity).[UniProtKB:Q8T9Z7]^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Plasmodium parasites rely upon purine salvage for survival. Plasmodium purine nucleoside phosphorylase is part of the streamlined Plasmodium purine salvage pathway that leads to the phosphorylysis of both purines and 5'-methylthiopurines, byproducts of polyamine synthesis. We have explored structural features in Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) that affect efficiency of catalysis as well as those that make it suitable for dual specificity. We used site directed mutagenesis to identify residues critical for PfPNP catalytic activity as well as critical residues within a hydrophobic pocket required for accommodation of the 5'-methylthio group. Kinetic analysis data shows that several mutants had disrupted binding of the 5'-methylthio group while retaining activity for inosine. A triple PfPNP mutant that mimics Toxoplasma gondii PNP had significant loss of 5'-methylthio activity with retention of inosine activity. Crystallographic investigation of the triple mutant PfPNP with Tyr160Phe, Val66Ile, andVal73Ile in complex with the transition state inhibitor immucillin H reveals fewer hydrogen bond interactions for the inhibitor in the hydrophobic pocket.

Structural determinants of the 5'-methylthioinosine specificity of Plasmodium purine nucleoside phosphorylase.,Donaldson TM, Ting LM, Zhan C, Shi W, Zheng R, Almo SC, Kim K PLoS One. 2014 Jan 8;9(1):e84384. doi: 10.1371/journal.pone.0084384. eCollection , 2014. PMID:24416224^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Shi W, Ting LM, Kicska GA, Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Kim K, Almo SC, Schramm VL. Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function. J Biol Chem. 2004 Apr 30;279(18):18103-6. Epub 2004 Feb 23. PMID:14982926 doi:10.1074/jbc.C400068200
↑ Schnick C, Robien MA, Brzozowski AM, Dodson EJ, Murshudov GN, Anderson L, Luft JR, Mehlin C, Hol WG, Brannigan JA, Wilkinson AJ. Structures of Plasmodium falciparum purine nucleoside phosphorylase complexed with sulfate and its natural substrate inosine. Acta Crystallogr D Biol Crystallogr. 2005 Sep;61(Pt 9):1245-54. Epub 2005, Aug 16. PMID:16131758 doi:10.1107/S0907444905020251
↑ Madrid DC, Ting LM, Waller KL, Schramm VL, Kim K. Plasmodium falciparum purine nucleoside phosphorylase is critical for viability of malaria parasites. J Biol Chem. 2008 Dec 19;283(51):35899-907. doi: 10.1074/jbc.M807218200. Epub, 2008 Oct 28. PMID:18957439 doi:http://dx.doi.org/10.1074/jbc.M807218200
↑ Chaikuad A, Brady RL. Conservation of structure and activity in Plasmodium purine nucleoside phosphorylases. BMC Struct Biol. 2009 Jul 3;9:42. PMID:19575810 doi:10.1186/1472-6807-9-42
↑ Donaldson TM, Ting LM, Zhan C, Shi W, Zheng R, Almo SC, Kim K. Structural determinants of the 5'-methylthioinosine specificity of Plasmodium purine nucleoside phosphorylase. PLoS One. 2014 Jan 8;9(1):e84384. doi: 10.1371/journal.pone.0084384. eCollection , 2014. PMID:24416224 doi:http://dx.doi.org/10.1371/journal.pone.0084384
↑ Ducati RG, Namanja-Magliano HA, Harijan RK, Fajardo JE, Fiser A, Daily JP, Schramm VL. Genetic resistance to purine nucleoside phosphorylase inhibition in Plasmodium falciparum. Proc Natl Acad Sci U S A. 2018 Feb 12. pii: 1525670115. doi:, 10.1073/pnas.1525670115. PMID:29440412 doi:http://dx.doi.org/10.1073/pnas.1525670115
↑ Donaldson TM, Ting LM, Zhan C, Shi W, Zheng R, Almo SC, Kim K. Structural determinants of the 5'-methylthioinosine specificity of Plasmodium purine nucleoside phosphorylase. PLoS One. 2014 Jan 8;9(1):e84384. doi: 10.1371/journal.pone.0084384. eCollection , 2014. PMID:24416224 doi:http://dx.doi.org/10.1371/journal.pone.0084384

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3fow"

Categories: Large Structures | Plasmodium falciparum 3D7 | Donaldson T | Zhan C

@@ Line 1: / Line 1: @@
 ==Plasmodium Purine Nucleoside Phosphorylase V66I-V73I-Y160F Mutant==
-<StructureSection load='3fow' size='340' side='right' caption='[[3fow]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='3fow' size='340' side='right'caption='[[3fow]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3fow]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FOW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FOW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3fow]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FOW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FOW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IMH:1,4-DIDEOXY-4-AZA-1-(S)-(9-DEAZAHYPOXANTHIN-9-YL)-D-RIBITOL'>IMH</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.8&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nw4|1nw4]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IMH:1,4-DIDEOXY-4-AZA-1-(S)-(9-DEAZAHYPOXANTHIN-9-YL)-D-RIBITOL'>IMH</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PFE0660c, PNP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</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=3fow FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fow OCA], [https://pdbe.org/3fow PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fow RCSB], [https://www.ebi.ac.uk/pdbsum/3fow PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fow ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Uridine_phosphorylase Uridine phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.3 2.4.2.3] </span></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=3fow FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fow OCA], [http://pdbe.org/3fow PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fow RCSB], [http://www.ebi.ac.uk/pdbsum/3fow PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3fow ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/PNPH_PLAF7 PNPH_PLAF7] 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:18957439, PubMed:14982926, PubMed:16131758, PubMed:19575810, PubMed:24416224, PubMed:29440412). Preferentially acts on inosine and guanosine, and to a lesser extent on 2'-deoxyguanosine and guanosine (PubMed:14982926, PubMed:16131758, PubMed:19575810). 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 (PubMed:18957439, PubMed:14982926, PubMed:24416224). Generates hypoxanthine from both the purine salvage pathway and from polyamine metabolism which is required for nucleic acids synthesis (PubMed:18957439, PubMed:14982926, PubMed:24416224). Has no activity towards adenosine (By similarity).[UniProtKB:Q8T9Z7]<ref>PMID:14982926</ref> <ref>PMID:16131758</ref> <ref>PMID:18957439</ref> <ref>PMID:19575810</ref> <ref>PMID:24416224</ref> <ref>PMID:29440412</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 33: / Line 33: @@
 __TOC__
 </StructureSection>
-[[Category: Plaf7]]
+[[Category: Large Structures]]
-[[Category: Uridine phosphorylase]]
+[[Category: Plasmodium falciparum 3D7]]
-[[Category: Donaldson, T]]
+[[Category: Donaldson T]]
-[[Category: Zhan, C]]
+[[Category: Zhan C]]
-[[Category: Glycosyltransferase]]
-[[Category: Phosphorylase]]
-[[Category: Protein-inhibitor complex]]
-[[Category: Transferase]]

3fow

From Proteopedia

Current revision

Plasmodium Purine Nucleoside Phosphorylase V66I-V73I-Y160F Mutant

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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