5bsk

From Proteopedia

(Difference between revisions)

Revision as of 06:22, 30 September 2015

Human HGPRT in complex with (S)-HPEPG, an acyclic nucleoside phosphonate

Structural highlights

5bsk is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	5brn
Activity:	Hypoxanthine phosphoribosyltransferase, with EC number 2.4.2.8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[HPRT_HUMAN] Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:300322]. LNS is characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self-mutilation.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] Defects in HPRT1 are the cause of gout HPRT-related (GOUT-HPRT) [MIM:300323]; also known as HPRT-related gout or Kelley-Seegmiller syndrome. Gout is characterized by partial enzyme activity and hyperuricemia.^[11] ^[12] ^[13] ^[14] ^[15] ^[16] [:]

Function

[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.

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^[17]

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

References

↑ Wilson JM, Kelley WN. Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in a patient with the Lesch-Nyhan syndrome. J Clin Invest. 1983 May;71(5):1331-5. PMID:6853716
↑ Davidson BL, Pashmforoush M, Kelley WN, Palella TD. Genetic basis of hypoxanthine guanine phosphoribosyltransferase deficiency in a patient with the Lesch-Nyhan syndrome (HPRTFlint). Gene. 1988 Mar 31;63(2):331-6. PMID:3384338
↑ Davidson BL, Palella TD, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase: a single nucleotide substitution in cDNA clones isolated from a patient with Lesch-Nyhan syndrome (HPRTMidland). Gene. 1988 Aug 15;68(1):85-91. PMID:3265398
↑ Fujimori S, Davidson BL, Kelley WN, Palella TD. Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome. J Clin Invest. 1989 Jan;83(1):11-3. PMID:2910902 doi:http://dx.doi.org/10.1172/JCI113846
↑ Gibbs RA, Nguyen PN, Edwards A, Civitello AB, Caskey CT. Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. Genomics. 1990 Jun;7(2):235-44. PMID:2347587
↑ Skopek TR, Recio L, Simpson D, Dallaire L, Melancon SB, Ogier H, O'Neill JP, Falta MT, Nicklas JA, Albertini RJ. Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures. Hum Genet. 1990 Jun;85(1):111-6. PMID:2358296
↑ Gordon RB, Sculley DG, Dawson PA, Beacham IR, Emmerson BT. Identification of a single nucleotide substitution in the coding sequence of in vitro amplified cDNA from a patient with partial HPRT deficiency (HPRTBRISBANE). J Inherit Metab Dis. 1990;13(5):692-700. PMID:2246854
↑ Tarle SA, Davidson BL, Wu VC, Zidar FJ, Seegmiller JE, Kelley WN, Palella TD. Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects. Genomics. 1991 Jun;10(2):499-501. PMID:2071157
↑ Burgemeister R, Rotzer E, Gutensohn W, Gehrke M, Schiel W. Identification of a new missense mutation in exon 2 of the human hypoxanthine phosphoribosyltransferase gene (HPRTIsar): a further example of clinical heterogeneity in HPRT deficiencies. Hum Mutat. 1995;5(4):341-4. PMID:7627191 doi:http://dx.doi.org/10.1002/humu.1380050413
↑ Liu G, Aral B, Zabot MT, Kamoun P, Ceballos-Picot I. The molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in French families; report of two novel mutations. Hum Mutat. 1998;Suppl 1:S88-90. PMID:9452051
↑ Wilson JM, Kobayashi R, Fox IH, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem. 1983 May 25;258(10):6458-60. PMID:6853490
↑ Wilson JM, Tarr GE, Kelley WN. Human hypoxanthine (guanine) phosphoribosyltransferase: an amino acid substitution in a mutant form of the enzyme isolated from a patient with gout. Proc Natl Acad Sci U S A. 1983 Feb;80(3):870-3. PMID:6572373
↑ Wilson JM, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase. Structural alteration in a dysfunctional enzyme variant (HPRTMunich) isolated from a patient with gout. J Biol Chem. 1984 Jan 10;259(1):27-30. PMID:6706936
↑ Cariello NF, Scott JK, Kat AG, Thilly WG, Keohavong P. Resolution of a missense mutant in human genomic DNA by denaturing gradient gel electrophoresis and direct sequencing using in vitro DNA amplification: HPRT Munich. Am J Hum Genet. 1988 May;42(5):726-34. PMID:3358423
↑ Davidson BL, Chin SJ, Wilson JM, Kelley WN, Palella TD. Hypoxanthine-guanine phosphoribosyltransferase. Genetic evidence for identical mutations in two partially deficient subjects. J Clin Invest. 1988 Dec;82(6):2164-7. PMID:3198771 doi:http://dx.doi.org/10.1172/JCI113839
↑ Davidson BL, Pashmforoush M, Kelley WN, Palella TD. Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular defect in a patient with gout (HPRTAshville). J Biol Chem. 1989 Jan 5;264(1):520-5. PMID:2909537
↑ Kaiser MM, Hockova D, Wang TH, Dracinsky M, Postova-Slavetinska L, Prochazkova E, Edstein MD, Chavchich M, Keough DT, Guddat LW, Janeba Z. Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6-Oxopurine Phosphoribosyltransferases. ChemMedChem. 2015 Oct;10(10):1707-23. doi: 10.1002/cmdc.201500322. Epub 2015 Aug , 25. PMID:26368337 doi:http://dx.doi.org/10.1002/cmdc.201500322

1 Structural highlights
2 Disease
3 Function
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/5bsk"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+==Human HGPRT in complex with (S)-HPEPG, an acyclic nucleoside phosphonate==
+<StructureSection load='5bsk' size='340' side='right' caption='[[5bsk]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5bsk]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BSK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BSK FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4X7:(2-{[(2S)-1-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)-3-HYDROXYPROPAN-2-YL]OXY}ETHYL)PHOSPHONIC+ACID'>4X7</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">[[5brn|5brn]]</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=5bsk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bsk OCA], [http://pdbe.org/5bsk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bsk RCSB], [http://www.ebi.ac.uk/pdbsum/5bsk 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.
-The entry 5bsk is ON HOLD  until Paper Publication
+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>
-Authors: Hocka, D., Hocka, D., Wang, T.-H., Dracinsky, M., Postova-Slaveninska, L., Tichy, T., Edstein, M.D., Chavchich, M., Keough, D.T., Guddat, L.W., Janeba, Z.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Synthesis and evaluation of twelve novel acyclic phosphates as inhibitors of the Plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases and and analysis of different prodrugs on their antimalarial activity
+<div class="pdbe-citations 5bsk" style="background-color:#fffaf0;"></div>
-[[Category: Unreleased Structures]]
+== References ==
-[[Category: Postova-Slaveninska, L]]
+<references/>
-[[Category: Keough, D.T]]
+__TOC__
-[[Category: Edstein, M.D]]
+</StructureSection>
-[[Category: Dracinsky, M]]
+[[Category: Hypoxanthine phosphoribosyltransferase]]
-[[Category: Tichy, T]]
+[[Category: Guddat, L W]]
-[[Category: Hocka, D]]
+[[Category: Hockova, D]]
 [[Category: Janeba, Z]]
-[[Category: Chavchich, M]]
+[[Category: Kaiser, M M]]
-[[Category: Guddat, L.W]]
+[[Category: Keough, D T]]
-[[Category: Wang, T.-H]]
+[[Category: Wang, T H]]
+[[Category: Acyclic nucleoside phosphonate]]
+[[Category: Hypoxanthine-guanine-phosphoribosyltransferase]]
+[[Category: Inhibitor]]
+[[Category: Malaria]]
+[[Category: Transferase-transferase inhibitor complex]]

5bsk

From Proteopedia

Revision as of 06:22, 30 September 2015

Human HGPRT in complex with (S)-HPEPG, an acyclic nucleoside phosphonate

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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