4ran: Difference between revisions

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-'''Unreleased structure'''
+==Aza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their pro-drugs as antimalarial agents==
+<StructureSection load='4ran' size='340' side='right' caption='[[4ran]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4ran]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RAN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RAN FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3L6:(2-{[2-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)ETHYL](3-AMINOPROPYL)AMINO}ETHYL)PHOSPHONIC+ACID'>3L6</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rab|4rab]], [[4rac|4rac]], [[4rad|4rad]], [[4rao|4rao]], [[4raq|4raq]]</td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Hypoxanthine_phosphoribosyltransferase Hypoxanthine phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.8 2.4.2.8] </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=4ran FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ran OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ran RCSB], [http://www.ebi.ac.uk/pdbsum/4ran PDBsum]</span></td></tr>
+</table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN]] Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:[http://omim.org/entry/300322 300322]]. LNS is characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self-mutilation.<ref>PMID:6853716</ref> <ref>PMID:3384338</ref> <ref>PMID:3265398</ref> <ref>PMID:2910902</ref> <ref>PMID:2347587</ref> <ref>PMID:2358296</ref> <ref>PMID:2246854</ref> <ref>PMID:2071157</ref> <ref>PMID:7627191</ref> <ref>PMID:9452051</ref>   Defects in HPRT1 are the cause of gout HPRT-related (GOUT-HPRT) [MIM:[http://omim.org/entry/300323 300323]]; also known as HPRT-related gout or Kelley-Seegmiller syndrome. Gout is characterized by partial enzyme activity and hyperuricemia.<ref>PMID:6853490</ref> <ref>PMID:6572373</ref> <ref>PMID:6706936</ref> <ref>PMID:3358423</ref> <ref>PMID:3198771</ref> <ref>PMID:2909537</ref> [:]
+== Function ==
+[[http://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN]] Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Hypoxanthine-guanine-[xanthine] phosphoribosyltransferase (HG[X]PRT) is considered an important target for antimalarial chemotherapy as it is the only pathway for the synthesis of the purine nucleoside monophosphates required for DNA/RNA production. Thus, inhibition of this enzyme should result in cessation of replication. The aza-acyclic nucleoside phosphonates (aza-ANPs) are good inhibitors of Plasmodium falciparum HGXPRT (PfHGXPRT), with Ki values as low as 0.08 and 0.01 muM for Plasmodium vivax HGPRT (PvHGPRT). Prodrugs of these aza-ANPs exhibit antimalarial activity against Pf lines with IC50 values (0.8-6.0 muM) and have low cytotoxicity against human cells. Crystal structures of six of these compounds in complex with human HGPRT have been determined. These suggest that the different affinities of these aza-ANPs could be due to the flexibility of the loops surrounding the active site as well as the flexibility of the inhibitors, allowing them to adapt to fit into three binding pockets of the enzyme(s).
-The entry 4ran is ON HOLD  until Paper Publication
+Aza-acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group As Inhibitors of the Human, Plasmodium falciparum and vivax 6-Oxopurine Phosphoribosyltransferases and Their Prodrugs As Antimalarial Agents.,Keough DT, Hockova D, Janeba Z, Wang T, Naesens L, Edstein MD, Chavchich M, Guddat LW J Med Chem. 2014 Dec 24. PMID:25494538<ref>PMID:25494538</ref>
-Authors: Keough, D.T., Hockov, D., Janeba, Z., Wang, T.-H., Naesens, L., Edstein, M.D., Chavchich, M., Guddat, L.W.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Aza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their pro-drugs as antimalarial agents
+== References ==
-[[Category: Unreleased Structures]]
+<references/>
-[[Category: Naesens, L]]
+__TOC__
+</StructureSection>
+[[Category: Hypoxanthine phosphoribosyltransferase]]
+[[Category: Chavchich, M]]
+[[Category: Edstein, M D]]
+[[Category: Guddat, L W]]
 [[Category: Hockov, D]]
-[[Category: Edstein, M.D]]
-[[Category: Keough, D.T]]
 [[Category: Janeba, Z]]
-[[Category: Chavchich, M]]
+[[Category: Keough, D T]]
-[[Category: Guddat, L.W]]
+[[Category: Naesens, L]]
-[[Category: Wang, T.-H]]
+[[Category: Wang, T H]]
+[[Category: 6-oxopurine phosphoribosyltransferase]]
+[[Category: Cytoplasmic]]
+[[Category: Transferase-transferase inhibitor complex]]