5brn
From Proteopedia
(Difference between revisions)
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| - | ''' | + | ==Human HGPRT in complex with (S)-HPEPHx, an acyclic nucleoside phosphonate== |
| + | <StructureSection load='5brn' size='340' side='right' caption='[[5brn]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5brn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BRN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BRN FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4X2:(2-{[(2S)-1-HYDROXY-3-(6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)PROPAN-2-YL]OXY}ETHYL)PHOSPHONIC+ACID'>4X2</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">[[5bsk|5bsk]]</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=5brn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5brn OCA], [http://pdbe.org/5brn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5brn RCSB], [http://www.ebi.ac.uk/pdbsum/5brn 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 == | ||
| + | Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2-(phosphonoethoxy)ethyl (PEE) and (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure-activity relationship studies. In this series, (S)-3-hydroxy-2-(phosphonoethoxy)propyl (HPEP), (S)-2-(phosphonomethoxy)propanoic acid (CPME), or (S)-2-(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)-3-hydroxy-2-(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 muM and a Ki value for human HGPRT of 0.6 muM. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 muM) in a chloroquine-resistant strain was observed for the bis-amidate prodrug of HPEPG. | ||
| - | + | Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6-Oxopurine Phosphoribosyltransferases.,Kaiser MM, Hockova D, Wang TH, Dracinsky M, Postova-Slavetinska L, Prochazkova E, Edstein MD, Chavchich M, Keough DT, Guddat LW, Janeba Z ChemMedChem. 2015 Oct;10(10):1707-23. doi: 10.1002/cmdc.201500322. Epub 2015 Aug , 25. PMID:26368337<ref>PMID:26368337</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 5brn" style="background-color:#fffaf0;"></div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Hypoxanthine phosphoribosyltransferase]] | ||
| + | [[Category: Guddat, L W]] | ||
[[Category: Hockova, D]] | [[Category: Hockova, D]] | ||
[[Category: Janeba, Z]] | [[Category: Janeba, Z]] | ||
| - | [[Category: | + | [[Category: Kaiser, M M]] |
| - | [[Category: Wang, T | + | [[Category: Keough, D T]] |
| + | [[Category: Wang, T H]] | ||
| + | [[Category: Acyclic nuclesoside phosphonate]] | ||
| + | [[Category: Hypoxanthine-guanine-xanthine phosphoribosyltransferase]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 03:58, 16 October 2015
Human HGPRT in complex with (S)-HPEPHx, an acyclic nucleoside phosphonate
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