OCA at 06:53, 8 April 2020

OCA — Wed, 08 Apr 2020 06:53:04 GMT

←Older revision		Revision as of 06:53, 8 April 2020
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-	'''Unreleased structure'''

-	~~The entry~~ 6rv1 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==human Alanine:Glyoxylate Aminotransferase major allele (AGT-Ma)==
		+	<StructureSection load='6rv1' size='340' side='right'caption='[[6rv1]], [[Resolution\|resolution]] 3.00Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6rv1]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RV1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RV1 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6rv0\|6rv0]]</td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6rv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rv1 OCA], [http://pdbe.org/6rv1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rv1 RCSB], [http://www.ebi.ac.uk/pdbsum/6rv1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rv1 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/SPYA_HUMAN SPYA_HUMAN]] Defects in AGXT are the cause of hyperoxaluria primary type 1 (HP1) [MIM:[http://omim.org/entry/259900 259900]]; also known as primary hyperoxaluria type I (PH1) and oxalosis I. HP1 is a rare autosomal recessive inborn error of glyoxylate metabolism characterized by increased excretion of oxalate and glycolate, and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract.<ref>PMID:1703535</ref> <ref>PMID:2039493</ref> <ref>PMID:1349575</ref> <ref>PMID:1301173</ref> <ref>PMID:8101040</ref> <ref>PMID:9192270</ref> <ref>PMID:9604803</ref> <ref>PMID:10394939</ref> <ref>PMID:10453743</ref> <ref>PMID:10541294</ref> <ref>PMID:10862087</ref> <ref>PMID:10960483</ref> <ref>PMID:12559847</ref> <ref>PMID:12777626</ref> <ref>PMID:15253729</ref> <ref>PMID:15849466</ref> <ref>PMID:15961946</ref> <ref>PMID:15963748</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Peroxisomal alanine:glyoxylate aminotransferase (AGT) is responsible for glyoxylate detoxification in human liver and utilizes pyridoxal 5'-phosphate (PLP) as coenzyme. The deficit of AGT leads to Primary Hyperoxaluria Type I (PH1), a rare disease characterized by calcium oxalate stones deposition in the urinary tract as a consequence of glyoxylate accumulation. Most missense mutations cause AGT misfolding, as in the case of the G41R, which induces aggregation and proteolytic degradation. We have investigated the interaction of wild-type AGT and the pathogenic G41R variant with d-cycloserine (DCS, commercialized as Seromycin), a natural product used as a second-line treatment of multidrug-resistant tuberculosis, and its synthetic enantiomer l-cycloserine (LCS). In contrast with evidences previously reported on other PLP-enzymes, both ligands are AGT reversible inhibitors showing inhibition constants in the micromolar range. While LCS undergoes half-transamination generating a ketimine intermediate and behaves as a classical competitive inhibitor, DCS displays a time-dependent binding mainly generating an oxime intermediate. Using a mammalian cellular model, we found that DCS, but not LCS, is able to promote the correct folding of the G41R variant, as revealed by its increased specific activity and expression as a soluble protein. This effect also translates into an increased glyoxylate detoxification ability of cells expressing the variant upon treatment with DCS. Overall, our findings establish that DCS could play a role as pharmacological chaperone, thus suggesting a new line of intervention against PH1 based on a drug repositioning approach. To a widest extent, this strategy could be applied to other disease-causing mutations leading to AGT misfolding.

-	~~Authors~~:	+	Cycloserine enantiomers are reversible inhibitors of human alanine:glyoxylate aminotransferase: implications for Primary Hyperoxaluria type 1.,Dindo M, Grottelli S, Annunziato G, Giardina G, Pieroni M, Pampalone G, Faccini A, Cutruzzola F, Laurino P, Costantino G, Cellini B Biochem J. 2019 Dec 23;476(24):3751-3768. doi: 10.1042/BCJ20190507. PMID:31794008<ref>PMID:31794008</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6rv1" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Cellini, B]]
		+	[[Category: Cutruzzola, F]]
		+	[[Category: Giardina, G]]
		+	[[Category: Mirco, D]]
		+	[[Category: Aminotransferase]]
		+	[[Category: Detoxification]]
		+	[[Category: Liver]]
		+	[[Category: Transferase]]

OCA: Protected "6rv1" [edit=sysop:move=sysop]

OCA — Wed, 12 Jun 2019 04:11:28 GMT

Protected "6rv1" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:11, 12 June 2019

OCA: New page: '''Unreleased structure''' The entry 6rv1 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

OCA — Wed, 12 Jun 2019 04:11:26 GMT

New page: '''Unreleased structure''' The entry 6rv1 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6rv1 is ON HOLD until Paper Publication

Authors:

Description:
[[Category: Unreleased Structures]]

6rv1 - Revision history

OCA at 06:53, 8 April 2020

OCA: Protected "6rv1" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6rv1 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures