1j04: Difference between revisions

Latest revision as of 07:13, 25 October 2023

Structural mechanism of enzyme mistargeting in hereditary kidney stone disease in vitro

Structural highlights

1j04 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	AOA, GOL, LLP
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AGT1_HUMAN Primary hyperoxaluria type 1. The disease is caused by variants affecting the gene represented in this entry.

Function

AGT1_HUMAN Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification (PubMed:10960483, PubMed:12777626, PubMed:24055001, PubMed:23229545, PubMed:26149463). Also catalyzes the transamination between L-serine and pyruvate and contributes to gluconeogenesis from the L-serine metabolism (PubMed:10347152).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

In a subset of patients with the hereditary kidney-stone disease primary hyperoxaluria type 1 (PH1), the liver-specific enzyme alanine:glyoxylate aminotransferase (AGT) is mistargeted from peroxisomes to mitochondria. This is a consequence of the combined presence of the common P11L polymorphism and a disease-specific G170R mutation. In this paper, the crystal structure of mutant human AGT containing the G170R replacement determined at a resolution of 2.6 A is reported. The crystal structure of AGT consists of an intimate dimer in which an extended N-terminal segment of 21 amino acids from one subunit wraps as an elongated irregular coil around the outside of the crystallographic symmetry-related subunit. In addition to the N-terminal segment, the monomer structure contains a large domain of 261 amino acids and a small C-terminal domain of 110 amino acids. Comparison of the mutant AGT structure and that of wild-type normal AGT shows that the two structures are almost identical, with a backbone-atom r.m.s. deviation of 0.34 A. However, evidence of significant local structural changes in the vicinity of the G170R mutation might be linked to the apparent decrease in protein stability.

Structural implications of a G170R mutation of alanine:glyoxylate aminotransferase that is associated with peroxisome-to-mitochondrion mistargeting.,Djordjevic S, Zhang X, Bartlam M, Ye S, Rao Z, Danpure CJ Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Mar 1;66(Pt, 3):233-6. Epub 2010 Feb 23. PMID:20208150^[7]

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

References

↑ Xue HH, Sakaguchi T, Fujie M, Ogawa H, Ichiyama A. Flux of the L-serine metabolism in rabbit, human, and dog livers. Substantial contributions of both mitochondrial and peroxisomal serine:pyruvate/alanine:glyoxylate aminotransferase. J Biol Chem. 1999 Jun 4;274(23):16028-33. doi: 10.1074/jbc.274.23.16028. PMID:10347152 doi:https://dx.doi.org/10.1074/jbc.274.23.16028
↑ Lumb MJ, Danpure CJ. Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem. 2000 Nov 17;275(46):36415-22. PMID:10960483 doi:10.1074/jbc.M006693200
↑ Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7277-82. Epub 2003 May 30. PMID:12777626 doi:10.1073/pnas.1131968100
↑ Fargue S, Lewin J, Rumsby G, Danpure CJ. Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele. J Biol Chem. 2013 Jan 25;288(4):2475-84. doi: 10.1074/jbc.M112.432617. Epub 2012 , Dec 10. PMID:23229545 doi:https://dx.doi.org/10.1074/jbc.M112.432617
↑ Oppici E, Roncador A, Montioli R, Bianconi S, Cellini B. Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase. Biochim Biophys Acta. 2013 Dec;1832(12):2277-88. doi:, 10.1016/j.bbadis.2013.09.002. Epub 2013 Sep 17. PMID:24055001 doi:https://dx.doi.org/10.1016/j.bbadis.2013.09.002
↑ Montioli R, Oppici E, Dindo M, Roncador A, Gotte G, Cellini B, Borri Voltattorni C. Misfolding caused by the pathogenic mutation G47R on the minor allele of alanine:glyoxylate aminotransferase and chaperoning activity of pyridoxine. Biochim Biophys Acta. 2015 Oct;1854(10 Pt A):1280-9. doi:, 10.1016/j.bbapap.2015.07.002. Epub 2015 Jul 3. PMID:26149463 doi:https://dx.doi.org/10.1016/j.bbapap.2015.07.002
↑ Djordjevic S, Zhang X, Bartlam M, Ye S, Rao Z, Danpure CJ. Structural implications of a G170R mutation of alanine:glyoxylate aminotransferase that is associated with peroxisome-to-mitochondrion mistargeting. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Mar 1;66(Pt, 3):233-6. Epub 2010 Feb 23. PMID:20208150 doi:10.1107/S1744309109054645

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Xue HH, Sakaguchi T, Fujie M, Ogawa H, Ichiyama A. Flux of the L-serine metabolism in rabbit, human, and dog livers. Substantial contributions of both mitochondrial and peroxisomal serine:pyruvate/alanine:glyoxylate aminotransferase. J Biol Chem. 1999 Jun 4;274(23):16028-33. doi: 10.1074/jbc.274.23.16028. PMID:10347152 doi:https://dx.doi.org/10.1074/jbc.274.23.16028

[2] Lumb MJ, Danpure CJ. Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem. 2000 Nov 17;275(46):36415-22. PMID:10960483 doi:10.1074/jbc.M006693200

[3] Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7277-82. Epub 2003 May 30. PMID:12777626 doi:10.1073/pnas.1131968100

[4] Fargue S, Lewin J, Rumsby G, Danpure CJ. Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele. J Biol Chem. 2013 Jan 25;288(4):2475-84. doi: 10.1074/jbc.M112.432617. Epub 2012 , Dec 10. PMID:23229545 doi:https://dx.doi.org/10.1074/jbc.M112.432617

[5] Oppici E, Roncador A, Montioli R, Bianconi S, Cellini B. Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase. Biochim Biophys Acta. 2013 Dec;1832(12):2277-88. doi:, 10.1016/j.bbadis.2013.09.002. Epub 2013 Sep 17. PMID:24055001 doi:https://dx.doi.org/10.1016/j.bbadis.2013.09.002

[6] Montioli R, Oppici E, Dindo M, Roncador A, Gotte G, Cellini B, Borri Voltattorni C. Misfolding caused by the pathogenic mutation G47R on the minor allele of alanine:glyoxylate aminotransferase and chaperoning activity of pyridoxine. Biochim Biophys Acta. 2015 Oct;1854(10 Pt A):1280-9. doi:, 10.1016/j.bbapap.2015.07.002. Epub 2015 Jul 3. PMID:26149463 doi:https://dx.doi.org/10.1016/j.bbapap.2015.07.002

[7] Djordjevic S, Zhang X, Bartlam M, Ye S, Rao Z, Danpure CJ. Structural implications of a G170R mutation of alanine:glyoxylate aminotransferase that is associated with peroxisome-to-mitochondrion mistargeting. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Mar 1;66(Pt, 3):233-6. Epub 2010 Feb 23. PMID:20208150 doi:10.1107/S1744309109054645

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@@ Line 3: / Line 3: @@
 <StructureSection load='1j04' size='340' side='right'caption='[[1j04]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1j04]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1J04 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1J04 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1j04]] 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=1J04 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1J04 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AOA:(AMINOOXY)ACETIC+ACID'>AOA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.6&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AOA:(AMINOOXY)ACETIC+ACID'>AOA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1h0c|1h0c]]</div></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=1j04 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1j04 OCA], [https://pdbe.org/1j04 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1j04 RCSB], [https://www.ebi.ac.uk/pdbsum/1j04 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1j04 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/SPYA_HUMAN SPYA_HUMAN]] Defects in AGXT are the cause of hyperoxaluria primary type 1 (HP1) [MIM:[https://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>
+[https://www.uniprot.org/uniprot/AGT1_HUMAN AGT1_HUMAN] Primary hyperoxaluria type 1. The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/AGT1_HUMAN AGT1_HUMAN] Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification (PubMed:10960483, PubMed:12777626, PubMed:24055001, PubMed:23229545, PubMed:26149463). Also catalyzes the transamination between L-serine and pyruvate and contributes to gluconeogenesis from the L-serine metabolism (PubMed:10347152).<ref>PMID:10347152</ref> <ref>PMID:10960483</ref> <ref>PMID:12777626</ref> <ref>PMID:23229545</ref> <ref>PMID:24055001</ref> <ref>PMID:26149463</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 37: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Bartlam, M]]
+[[Category: Bartlam M]]
-[[Category: Danpure, C J]]
+[[Category: Danpure CJ]]
-[[Category: Djordjevic, S]]
+[[Category: Djordjevic S]]
-[[Category: Rao, Z]]
+[[Category: Rao Z]]
-[[Category: Ye, S]]
+[[Category: Ye S]]
-[[Category: Zhang, X]]
+[[Category: Zhang X]]
-[[Category: Aminotransferase]]
-[[Category: Pyridoxal phosphate]]
-[[Category: Transferase]]

1j04: Difference between revisions

Latest revision as of 07:13, 25 October 2023

Structural mechanism of enzyme mistargeting in hereditary kidney stone disease in vitro

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

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