4kn6 - Revision history

OCA at 12:14, 1 March 2024

2024-03-01T12:14:02Z

←Older revision		Revision as of 12:14, 1 March 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4kn6]] is a 1 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=4KN6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KN6 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4kn6]] is a 1 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=4KN6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KN6 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RP:6-FLUORO-3-OXO-4-(5-O-PHOSPHONO-BETA-D-RIBOFURANOSYL)-3,4-DIHYDROPYRAZINE-2-CARBOXAMIDE'>1RP</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]] 2.728Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RP:6-FLUORO-3-OXO-4-(5-O-PHOSPHONO-BETA-D-RIBOFURANOSYL)-3,4-DIHYDROPYRAZINE-2-CARBOXAMIDE'>1RP</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=4kn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kn6 OCA], [https://pdbe.org/4kn6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kn6 RCSB], [https://www.ebi.ac.uk/pdbsum/4kn6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kn6 ProSAT]</span></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=4kn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kn6 OCA], [https://pdbe.org/4kn6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kn6 RCSB], [https://www.ebi.ac.uk/pdbsum/4kn6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kn6 ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== Function ==		== Function ==
	[https://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.		[https://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 ==
-	6-Fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) is a novel antiviral compound with broad activity against influenza virus and diverse RNA viruses. Its active metabolite, T-705-ribose-5'-triphosphate (T-705-RTP), is recognized by influenza virus RNA polymerase as a substrate competing with GTP, giving inhibition of viral RNA synthesis and lethal virus mutagenesis. Which enzymes perform the activation of T-705 is unknown. We here demonstrate that human hypoxanthine guanine phosphoribosyltransferase (HGPRT) converts T-705 into its ribose-5'-monophosphate (RMP) prior to formation of T-705-RTP. The anti-influenza virus activity of T-705 and T-1105 (3-hydroxy-2-pyrazinamide; the analogue lacking the 6-fluoro atom) was lost in HGPRT-deficient MDCK cells. This HGPRT dependency was confirmed in human HEK293T cells undergoing HGPRT-specific gene knockdown followed by influenza virus ribonucleoprotein reconstitution. Knockdown for adenine phosphoribosyltransferase (APRT) or nicotinamide phosphoribosyltransferase did not change the antiviral activity of T-705 and T-1105. Enzymatic assays showed that T-705 and T-1105 are poor substrates for human HGPRT having K mapp values of 6.4 and 4.1 mM, respectively. Formation of the RMP metabolites by APRT was negligible, and so was the formation of the ribosylated metabolites by human purine nucleoside phosphorylase. Phosphoribosylation and antiviral activity of the 2-pyrazinecarboxamide derivatives was shown to require the presence of the 3-hydroxyl but not the 6-fluoro substituent. The crystal structure of T-705-RMP in complex with human HGPRT showed how this compound binds in the active site. Since conversion of T-705 by HGPRT appears to be inefficient, T-705-RMP prodrugs may be designed to increase the antiviral potency of this new antiviral agent.
-
-	Role of Human Hypoxanthine Guanine Phosphoribosyltransferase in Activation of the Antiviral Agent T-705 (favipiravir).,Naesens L, Guddat LW, Keough DT, van Kuilenburg AB, Meijer J, Vande Voorde J, Balzarini J Mol Pharmacol. 2013 Aug 1. PMID:23907213<ref>PMID:23907213</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4kn6" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 09:01, 7 December 2022

2022-12-07T09:01:43Z

←Older revision		Revision as of 09:01, 7 December 2022
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	==Crystal structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate==		==Crystal structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate==
-	<StructureSection load='4kn6' size='340' side='right' caption='[[4kn6]], [[Resolution\|resolution]] 2.73Å' scene=''>	+	<StructureSection load='4kn6' size='340' side='right'caption='[[4kn6]], [[Resolution\|resolution]] 2.73Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4kn6]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KN6 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4KN6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4kn6]] is a 1 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=4KN6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KN6 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1RP:6-FLUORO-3-OXO-4-(5-O-PHOSPHONO-BETA-D-RIBOFURANOSYL)-3,4-DIHYDROPYRAZINE-2-CARBOXAMIDE'>1RP</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RP:6-FLUORO-3-OXO-4-(5-O-PHOSPHONO-BETA-D-RIBOFURANOSYL)-3,4-DIHYDROPYRAZINE-2-CARBOXAMIDE'>1RP</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HPRT1, HPRT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4kn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kn6 OCA], [https://pdbe.org/4kn6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kn6 RCSB], [https://www.ebi.ac.uk/pdbsum/4kn6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kn6 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/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=4kn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kn6 OCA], [~~http~~://pdbe.org/4kn6 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4kn6 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4kn6 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4kn6 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== 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> [:]	+	[https://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN] Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:[https://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:[https://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 ==		== 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.	+	[https://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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 22:

	==See Also==		==See Also==
-	*[[Phosphoribosyltransferase\|Phosphoribosyltransferase]]	+	*[[Phosphoribosyltransferase 3D structures\|Phosphoribosyltransferase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Hypoxanthine phosphoribosyltransferase~~]]	+	[[Category: Large Structures]]
-	[[Category: Balzarini, J]]	+	[[Category: Balzarini J]]
-	[[Category: Guddat, L]]	+	[[Category: Guddat L]]
-	[[Category: Keough, D]]	+	[[Category: Keough D]]
-	~~[[Category: Kuilenburg, A B.P van~~]]	+	[[Category: Meijer J]]
-	[[Category: Meijer, J]]	+	[[Category: Naesens L]]
-	[[Category: Naesens, L]]	+	[[Category: Vande Voorde J]]
-	[[Category: Voorde, J ~~Vande~~]]	+	[[Category: Van Kuilenburg ABP]]
-	[[Category: ~~6-oxopurine phosphoribosyltransferase]]~~	+
-	~~[[Category: Favipiravir]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 10:48, 4 August 2016

2016-08-04T10:48:42Z

←Older revision		Revision as of 10:48, 4 August 2016
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		+
	==Crystal structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate==		==Crystal structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate==
	<StructureSection load='4kn6' size='340' side='right' caption='[[4kn6]], [[Resolution\|resolution]] 2.73Å' scene=''>		<StructureSection load='4kn6' size='340' side='right' caption='[[4kn6]], [[Resolution\|resolution]] 2.73Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4kn6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KN6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KN6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4kn6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KN6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KN6 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1RP:6-FLUORO-3-OXO-4-(5-O-PHOSPHONO-BETA-D-RIBOFURANOSYL)-3,4-DIHYDROPYRAZINE-2-CARBOXAMIDE'>1RP</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1RP:6-FLUORO-3-OXO-4-(5-O-PHOSPHONO-BETA-D-RIBOFURANOSYL)-3,4-DIHYDROPYRAZINE-2-CARBOXAMIDE'>1RP</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HPRT1, HPRT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HPRT1, HPRT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='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=4kn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kn6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4kn6 RCSB], [http://www.ebi.ac.uk/pdbsum/4kn6 PDBsum]</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=4kn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kn6 OCA], [http://pdbe.org/4kn6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4kn6 RCSB], [http://www.ebi.ac.uk/pdbsum/4kn6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4kn6 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4kn6" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Hypoxanthine phosphoribosyltransferase]]		[[Category: Hypoxanthine phosphoribosyltransferase]]
	[[Category: Balzarini, J]]		[[Category: Balzarini, J]]

OCA at 15:02, 21 December 2014

2014-12-21T15:02:32Z

←Older revision		Revision as of 15:02, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4kn6\| PDB=4kn6 \| SCENE= }}~~	+	==Crystal structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate==
-	===Crystal structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate===	+	<StructureSection load='4kn6' size='340' side='right' caption='[[4kn6]], [[Resolution\|resolution]] 2.73Å' scene=''>
-	~~{{ABSTRACT_PUBMED_23907213}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4kn6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KN6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KN6 FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1RP:6-FLUORO-3-OXO-4-(5-O-PHOSPHONO-BETA-D-RIBOFURANOSYL)-3,4-DIHYDROPYRAZINE-2-CARBOXAMIDE'>1RP</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HPRT1, HPRT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4kn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kn6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4kn6 RCSB], [http://www.ebi.ac.uk/pdbsum/4kn6 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> [:]		[[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 ==
		+	6-Fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) is a novel antiviral compound with broad activity against influenza virus and diverse RNA viruses. Its active metabolite, T-705-ribose-5'-triphosphate (T-705-RTP), is recognized by influenza virus RNA polymerase as a substrate competing with GTP, giving inhibition of viral RNA synthesis and lethal virus mutagenesis. Which enzymes perform the activation of T-705 is unknown. We here demonstrate that human hypoxanthine guanine phosphoribosyltransferase (HGPRT) converts T-705 into its ribose-5'-monophosphate (RMP) prior to formation of T-705-RTP. The anti-influenza virus activity of T-705 and T-1105 (3-hydroxy-2-pyrazinamide; the analogue lacking the 6-fluoro atom) was lost in HGPRT-deficient MDCK cells. This HGPRT dependency was confirmed in human HEK293T cells undergoing HGPRT-specific gene knockdown followed by influenza virus ribonucleoprotein reconstitution. Knockdown for adenine phosphoribosyltransferase (APRT) or nicotinamide phosphoribosyltransferase did not change the antiviral activity of T-705 and T-1105. Enzymatic assays showed that T-705 and T-1105 are poor substrates for human HGPRT having K mapp values of 6.4 and 4.1 mM, respectively. Formation of the RMP metabolites by APRT was negligible, and so was the formation of the ribosylated metabolites by human purine nucleoside phosphorylase. Phosphoribosylation and antiviral activity of the 2-pyrazinecarboxamide derivatives was shown to require the presence of the 3-hydroxyl but not the 6-fluoro substituent. The crystal structure of T-705-RMP in complex with human HGPRT showed how this compound binds in the active site. Since conversion of T-705 by HGPRT appears to be inefficient, T-705-RMP prodrugs may be designed to increase the antiviral potency of this new antiviral agent.

-	~~==Function==~~	+	Role of Human Hypoxanthine Guanine Phosphoribosyltransferase in Activation of the Antiviral Agent T-705 (favipiravir).,Naesens L, Guddat LW, Keough DT, van Kuilenburg AB, Meijer J, Vande Voorde J, Balzarini J Mol Pharmacol. 2013 Aug 1. PMID:23907213<ref>PMID:23907213</ref>
-	~~[[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~~.	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4kn6]] is~~ a ~~1 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=4KN6 OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:023907213</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Phosphoribosyltransferase\|Phosphoribosyltransferase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Hypoxanthine phosphoribosyltransferase]]		[[Category: Hypoxanthine phosphoribosyltransferase]]
-	[[Category: Balzarini, J.]]	+	[[Category: Balzarini, J]]
-	[[Category: Guddat, L.]]	+	[[Category: Guddat, L]]
-	[[Category: Keough, D.]]	+	[[Category: Keough, D]]
-	[[Category: Kuilenburg, A B.P van.]]	+	[[Category: Kuilenburg, A B.P van]]
-	[[Category: Meijer, J.]]	+	[[Category: Meijer, J]]
-	[[Category: Naesens, L.]]	+	[[Category: Naesens, L]]
-	[[Category: Voorde, J Vande.]]	+	[[Category: Voorde, J Vande]]
	[[Category: 6-oxopurine phosphoribosyltransferase]]		[[Category: 6-oxopurine phosphoribosyltransferase]]
	[[Category: Favipiravir]]		[[Category: Favipiravir]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 07:54, 14 August 2013

2013-08-14T07:54:16Z

←Older revision		Revision as of 07:54, 14 August 2013
Line 1:		Line 1:
-	~~'''Unreleased~~ structure'''	+	{{STRUCTURE_4kn6\| PDB=4kn6 \| SCENE= }}
		+	===Crystal structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate===
		+	{{ABSTRACT_PUBMED_23907213}}

-	~~The~~ entry ~~4kn6~~ is ~~ON HOLD~~	+	==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> [:]

-	~~Authors~~: ~~Naesens, L~~.~~, Guddat, L~~., ~~Keough, D~~.~~, van Kuilenburg, A~~.~~B.P., Meijer, J., Vande Voorde, J., Balzarini, J~~.	+	==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.

-	~~Description: Crystal~~ structure ~~of human hypoxanthine~~-~~guanine~~ phosphoribosyltransferase ~~in complex with~~ 6-~~fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate~~	+	==About this Structure==
		+	[[4kn6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KN6 OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:023907213</ref><references group="xtra"/><references/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Hypoxanthine phosphoribosyltransferase]]
		+	[[Category: Balzarini, J.]]
		+	[[Category: Guddat, L.]]
		+	[[Category: Keough, D.]]
		+	[[Category: Kuilenburg, A B.P van.]]
		+	[[Category: Meijer, J.]]
		+	[[Category: Naesens, L.]]
		+	[[Category: Voorde, J Vande.]]
		+	[[Category: 6-oxopurine phosphoribosyltransferase]]
		+	[[Category: Favipiravir]]
		+	[[Category: Transferase]]

OCA: Protected "4kn6" [edit=sysop:move=sysop]

2013-05-16T07:00:43Z

Protected "4kn6" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:00, 16 May 2013

OCA: New page: '''Unreleased structure''' The entry 4kn6 is ON HOLD Authors: Naesens, L., Guddat, L., Keough, D., van Kuilenburg, A.B.P., Meijer, J., Vande Voorde, J., Balzarini, J. Description: Crys...

2013-05-16T07:00:42Z

New page: '''Unreleased structure''' The entry 4kn6 is ON HOLD Authors: Naesens, L., Guddat, L., Keough, D., van Kuilenburg, A.B.P., Meijer, J., Vande Voorde, J., Balzarini, J. Description: Crys...

New page

'''Unreleased structure'''

The entry 4kn6 is ON HOLD

Authors: Naesens, L., Guddat, L., Keough, D., van Kuilenburg, A.B.P., Meijer, J., Vande Voorde, J., Balzarini, J.

Description: Crystal structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) ribose-5'-monophosphate