View source for 6hgs


==Crystal Structure of Human APRT wild type in complex with GMP==
<StructureSection load='6hgs' size='340' side='right'caption='[[6hgs]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6hgs]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HGS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HGS FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.55&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5GP:GUANOSINE-5-MONOPHOSPHATE'>5GP</scene></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=6hgs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hgs OCA], [https://pdbe.org/6hgs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hgs RCSB], [https://www.ebi.ac.uk/pdbsum/6hgs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hgs ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/APT_HUMAN APT_HUMAN] Defects in APRT are the cause of adenine phosphoribosyltransferase deficiency (APRTD) [MIM:[https://omim.org/entry/614723 614723]; also known as 2,8-dihydroxyadenine urolithiasis. An enzymatic deficiency that can lead to urolithiasis and renal failure. Patients have 2,8-dihydroxyadenine (DHA) urinary stones.<ref>PMID:1746557</ref> <ref>PMID:7915931</ref> <ref>PMID:3680503</ref> <ref>PMID:3343350</ref> <ref>PMID:1353080</ref> <ref>PMID:11243733</ref> <ref>PMID:15571218</ref> <ref>PMID:21635362</ref> 
== Function ==
[https://www.uniprot.org/uniprot/APT_HUMAN APT_HUMAN] Catalyzes a salvage reaction resulting in the formation of AMP, that is energically less costly than de novo synthesis.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The reversible adenine phosphoribosyltransferase enzyme (APRT) is essential for purine homeostasis in prokaryotes and eukaryotes. In humans, APRT (hAPRT) is the only enzyme known to produce AMP in cells from dietary adenine. APRT can also process adenine analogs, which are involved in plant development or neuronal homeostasis. However, the molecular mechanism underlying substrate specificity of APRT and catalysis in both directions of the reaction remains poorly understood. Here we present the crystal structures of hAPRT complexed to three cellular nucleotide analogs (Hypoxanthine, IMP and GMP) that we compare to the phosphate-bound enzyme. We established that binding to hAPRT is substrate-shape-specific in the forward reaction, while it is base-specific in the reverse reaction. Furthermore, a quantum mechanics/molecular mechanics (QM/MM) analysis suggests that the forward reaction is mainly a nucleophilic substitution of type 2 (SN2) with a mix of SN1-type molecular mechanism. Based on our structural analysis, a magnesium-assisted SN2-type mechanism would be involved in the reverse reaction. These results provide a framework for understanding the molecular mechanism and substrate discrimination in both directions by APRTs. This knowledge can play an instrumental role in the design of inhibitors, such as antiparasitic agents, or adenine-based substrates.

Structural basis for substrate selectivity and nucleophilic substitution mechanisms in human adenine phosphoribosyltransferase catalyzed reaction.,Ozeir M, Huyet J, Burgevin MC, Pinson B, Chesney F, Remy JM, Siddiqi AR, Lupoli R, Pinon G, Saint-Marc C, Gibert JF, Morales R, Ceballos-Picot I, Barouki R, Daignan-Fornier B, Olivier-Bandini A, Auge F, Nioche P J Biol Chem. 2019 Jun 3. pii: RA119.009087. doi: 10.1074/jbc.RA119.009087. PMID:31160323<ref>PMID:31160323</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6hgs" style="background-color:#fffaf0;"></div>

==See Also==
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Huyet J]]
[[Category: Nioche P]]
[[Category: Ozeir M]]