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| | ==Crystal Structure of adenosine deaminase from Plasmodial vivax in complex with MT-coformycin== | | ==Crystal Structure of adenosine deaminase from Plasmodial vivax in complex with MT-coformycin== |
| - | <StructureSection load='3ewc' size='340' side='right' caption='[[3ewc]], [[Resolution|resolution]] 2.11Å' scene=''> | + | <StructureSection load='3ewc' size='340' side='right'caption='[[3ewc]], [[Resolution|resolution]] 2.11Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ewc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Haemamoeba_vivax Haemamoeba vivax]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EWC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EWC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ewc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_vivax Plasmodium vivax]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EWC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EWC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MCF:(8R)-3-(5-S-METHYL-5-THIO-BETA-D-RIBOFURANOSYL)-3,6,7,8-TETRAHYDROIMIDAZO[4,5-D][1,3]DIAZEPIN-8-OL'>MCF</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.11Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ewd|3ewd]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MCF:(8R)-3-(5-S-METHYL-5-THIO-BETA-D-RIBOFURANOSYL)-3,6,7,8-TETRAHYDROIMIDAZO[4,5-D][1,3]DIAZEPIN-8-OL'>MCF</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PVX_111245 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5855 Haemamoeba vivax])</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=3ewc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ewc OCA], [https://pdbe.org/3ewc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ewc RCSB], [https://www.ebi.ac.uk/pdbsum/3ewc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ewc 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/Adenosine_deaminase Adenosine deaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.4 3.5.4.4] </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=3ewc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ewc OCA], [http://pdbe.org/3ewc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ewc RCSB], [http://www.ebi.ac.uk/pdbsum/3ewc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ewc ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ADA_PLAVS ADA_PLAVS] Catalyzes the hydrolytic deamination of adenosine to produce inosine (PubMed:19728741). Unlike mammalian adenosine deaminases, also catalyzes the deamination of 5'-methylthioadenosine (MTA), a by-product of polyamine biosynthesis, to produce 5'-methylthioinosine (MTI) (PubMed:19728741). Plays an essential role in the purine salvage pathway which allows the parasite to use host cell purines for the synthesis of nucleic acids (PubMed:19728741).<ref>PMID:19728741</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Adenosine deaminase|Adenosine deaminase]] | + | *[[Adenosine deaminase 3D structures|Adenosine deaminase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Adenosine deaminase]] | + | [[Category: Large Structures]] |
| - | [[Category: Haemamoeba vivax]] | + | [[Category: Plasmodium vivax]] |
| - | [[Category: Almo, S C]] | + | [[Category: Almo SC]] |
| - | [[Category: Cassera, M B]] | + | [[Category: Cassera MB]] |
| - | [[Category: Ho, M C]] | + | [[Category: Ho MC]] |
| - | [[Category: Schramm, V L]] | + | [[Category: Schramm VL]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Methylthio-coformycin]]
| + | |
| - | [[Category: Mt-coformycin]]
| + | |
| Structural highlights
Function
ADA_PLAVS Catalyzes the hydrolytic deamination of adenosine to produce inosine (PubMed:19728741). Unlike mammalian adenosine deaminases, also catalyzes the deamination of 5'-methylthioadenosine (MTA), a by-product of polyamine biosynthesis, to produce 5'-methylthioinosine (MTI) (PubMed:19728741). Plays an essential role in the purine salvage pathway which allows the parasite to use host cell purines for the synthesis of nucleic acids (PubMed:19728741).[1]
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 falciparum is a purine auxotroph requiring hypoxanthine as a key metabolic precursor. Erythrocyte adenine nucleotides are the source of the purine precursors, making adenosine deaminase (ADA) a key enzyme in the pathway of hypoxanthine formation. Methylthioadenosine (MTA) is a substrate for most malarial ADAs, but not for human ADA. The catalytic site specificity of malarial ADAs permits methylthiocoformycin (MT-coformycin) to act as a Plasmodium-specific transition state analogue with low affinity for human ADA [Tyler, P. C., Taylor, E. A., Frohlich, R. G. G., and Schramm, V. L. (2007) J. Am. Chem. Soc. 129, 6872-6879]. The structural basis for MTA and MT-coformycin specificity in malarial ADAs is the subject of speculation [Larson, E. T., et al. (2008) J. Mol. Biol. 381, 975-988]. Here, the crystal structure of ADA from Plasmodium vivax (PvADA) in a complex with MT-coformycin reveals an unprecedented binding geometry for 5'-methylthioribosyl groups in the malarial ADAs. Compared to malarial ADA complexes with adenosine or deoxycoformycin, 5'-methylthioribosyl groups are rotated 130 degrees . A hydrogen bonding network between Asp172 and the 3'-hydroxyl of MT-coformycin is essential for recognition of the 5'-methylthioribosyl group. Water occupies the 5'-hydroxyl binding site when MT-coformycin is bound. Mutagenesis of Asp172 destroys the substrate specificity for MTA and MT-coformycin. Kinetic, mutagenic, and structural analyses of PvADA and kinetic analysis of five other Plasmodium ADAs establish the unique structural basis for its specificity for MTA and MT-coformycin. Plasmodium gallinaceum ADA does not use MTA as a substrate, is not inhibited by MT-coformycin, and is missing Asp172. Treatment of P. falciparum cultures with coformycin or MT-coformycin in the presence of MTA is effective in inhibiting parasite growth.
Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases.,Ho MC, Cassera MB, Madrid DC, Ting LM, Tyler PC, Kim K, Almo SC, Schramm VL Biochemistry. 2009 Oct 13;48(40):9618-26. PMID:19728741[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ho MC, Cassera MB, Madrid DC, Ting LM, Tyler PC, Kim K, Almo SC, Schramm VL. Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases. Biochemistry. 2009 Oct 13;48(40):9618-26. PMID:19728741 doi:http://dx.doi.org/10.1021/bi9012484
- ↑ Ho MC, Cassera MB, Madrid DC, Ting LM, Tyler PC, Kim K, Almo SC, Schramm VL. Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases. Biochemistry. 2009 Oct 13;48(40):9618-26. PMID:19728741 doi:http://dx.doi.org/10.1021/bi9012484
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