4i8a

From Proteopedia

(Difference between revisions)

Revision as of 12:13, 21 December 2014

Alanine-glyoxylate aminotransferase variant S187F

Structural highlights

4i8a is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Related:	1h0c, 1jo4
Gene:	AGXT, AGT1, SPAT (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[SPYA_HUMAN] Defects in AGXT are the cause of hyperoxaluria primary type 1 (HP1) [MIM: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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15] ^[16] ^[17] ^[18]

Function

Publication Abstract from PubMed

Biochemical Properties of the S187F Mutant AGT The substitution of Ser187, a residue located far from the active site of human liver peroxisomal alanine:glyoxylate aminotransferase (AGT), by Phe gives rise to a variant associated with primary hyperoxaluria type I (PH1). Unexpectedly, previous studies revealed that the recombinant form of S187F exhibits a remarkable loss of catalytic activity, an increased pyridoxal 5'-phosphate (PLP) binding affinity and a different coenzyme binding mode compared with normal AGT. To shed light on the structural elements responsible for these defects, we solved the crystal structure of the variant to a resolution of 2.9 A. Although the overall conformation of the variant is similar to that of normal AGT, we noticed: (i) a displacement of the PLP-binding Lys209 and Val185, located on the re and si side of PLP, respectively, and (ii) slight conformational changes of other active site residues, in particular Trp108, the base stacking residue with the pyridine cofactor moiety. This active site perturbation results in a mispositioning of the AGT-pyridoxamine 5'-phosphate (PMP) complex and of the external aldimine, as predicted by molecular modelling studies. Taken together, both predicted and observed movements caused by the S187F mutation are consistent with the following functional properties of the variant: (i) a 300-500-fold decrease in both the rate constant of L-alanine half-transamination and the kcat of the overall transamination, (ii) a different PMP binding mode and affinity, and (iii) a different microenvironment of the external aldimine. Proposals for the treatment of patients bearing S187F mutation are discussed on the basis of these results. (c) Proteins 2013;. (c) 2013 Wiley Periodicals, Inc.

Crystal structure of the S187F variant of human liver alanine: Glyoxylate aminotransferase associated with primary hyperoxaluria TYPE I and its functional implications.,Oppici E, Fodor K, Paiardini A, Williams C, Voltattorni CB, Willmanns M, Cellini B Proteins. 2013 Apr 15. doi: 10.1002/prot.24300. PMID:23589421^[19]

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

References

↑ Purdue PE, Takada Y, Danpure CJ. Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol. 1990 Dec;111(6 Pt 1):2341-51. PMID:1703535
↑ Nishiyama K, Funai T, Katafuchi R, Hattori F, Onoyama K, Ichiyama A. Primary hyperoxaluria type I due to a point mutation of T to C in the coding region of the serine:pyruvate aminotransferase gene. Biochem Biophys Res Commun. 1991 May 15;176(3):1093-9. PMID:2039493
↑ Purdue PE, Lumb MJ, Allsop J, Minatogawa Y, Danpure CJ. A glycine-to-glutamate substitution abolishes alanine:glyoxylate aminotransferase catalytic activity in a subset of patients with primary hyperoxaluria type 1. Genomics. 1992 May;13(1):215-8. PMID:1349575
↑ Minatogawa Y, Tone S, Allsop J, Purdue PE, Takada Y, Danpur CJ, Kido R. A serine-to-phenylalanine substitution leads to loss of alanine:glyoxylate aminotransferase catalytic activity and immunoreactivity in a patient with primary hyperoxaluria type 1. Hum Mol Genet. 1992 Nov;1(8):643-4. PMID:1301173
↑ Danpure CJ, Purdue PE, Fryer P, Griffiths S, Allsop J, Lumb MJ, Guttridge KM, Jennings PR, Scheinman JI, Mauer SM, et al.. Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation. Am J Hum Genet. 1993 Aug;53(2):417-32. PMID:8101040
↑ von Schnakenburg C, Rumsby G. Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene. J Med Genet. 1997 Jun;34(6):489-92. PMID:9192270
↑ von Schnakenburg C, Rumsby G. Identification of new mutations in primary hyperoxaluria type 1 (PH1). J Nephrol. 1998 Mar-Apr;11 Suppl 1:15-7. PMID:9604803
↑ Amoroso A, Pirulli D, Puzzer D, Ferri L, Crovella S, Ferrettini C, Marangella M, Mazzola G, Florian F. Gene symbol: AGXT. Disease: primary hyperoxaluria type I. Hum Genet. 1999 May;104(5):441. PMID:10394939
↑ Pirulli D, Puzzer D, Ferri L, Crovella S, Amoroso A, Ferrettini C, Marangella M, Mazzola G, Florian F. Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine: glyoxylate aminotransferase gene. Hum Genet. 1999 Jun;104(6):523-5. PMID:10453743
↑ Rinat C, Wanders RJ, Drukker A, Halle D, Frishberg Y. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999 Nov;10(11):2352-8. PMID:10541294
↑ Basmaison O, Rolland MO, Cochat P, Bozon D. Identification of 5 novel mutations in the AGXT gene. Hum Mutat. 2000 Jun;15(6):577. PMID:10862087 doi:<577::AID-HUMU9>3.0.CO;2-# 10.1002/1098-1004(200006)15:6<577::AID-HUMU9>3.0.CO;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
↑ Coulter-Mackie MB, Tung A, Henderson HE, Toone JR, Applegarth DA. The AGT gene in Africa: a distinctive minor allele haplotype, a polymorphism (V326I), and a novel PH1 mutation (A112D) in Black Africans. Mol Genet Metab. 2003 Jan;78(1):44-50. PMID:12559847
↑ 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
↑ van Woerden CS, Groothoff JW, Wijburg FA, Annink C, Wanders RJ, Waterham HR. Clinical implications of mutation analysis in primary hyperoxaluria type 1. Kidney Int. 2004 Aug;66(2):746-52. PMID:15253729 doi:10.1111/j.1523-1755.2004.00796.x
↑ Monico CG, Olson JB, Milliner DS. Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria. Am J Nephrol. 2005 Mar-Apr;25(2):183-8. Epub 2005 Apr 21. PMID:15849466 doi:10.1159/000085411
↑ Frishberg Y, Rinat C, Shalata A, Khatib I, Feinstein S, Becker-Cohen R, Weismann I, Wanders RJ, Rumsby G, Roels F, Mandel H. Intra-familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel. Am J Nephrol. 2005 May-Jun;25(3):269-75. Epub 2005 Jun 15. PMID:15961946 doi:10.1159/000086357
↑ Coulter-Mackie MB, Lian Q, Applegarth D, Toone J. The major allele of the alanine:glyoxylate aminotransferase gene: nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1. Mol Genet Metab. 2005 Sep-Oct;86(1-2):172-8. Epub 2005 Jun 15. PMID:15963748 doi:10.1016/j.ymgme.2005.05.005
↑ Oppici E, Fodor K, Paiardini A, Williams C, Voltattorni CB, Willmanns M, Cellini B. Crystal structure of the S187F variant of human liver alanine: Glyoxylate aminotransferase associated with primary hyperoxaluria TYPE I and its functional implications. Proteins. 2013 Apr 15. doi: 10.1002/prot.24300. PMID:23589421 doi:10.1002/prot.24300

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/4i8a"

@@ Line 1: / Line 1: @@
-{{STRUCTURE_4i8a|  PDB=4i8a  |  SCENE=  }}
+==Alanine-glyoxylate aminotransferase variant S187F==
-===Alanine-glyoxylate aminotransferase variant S187F===
+<StructureSection load='4i8a' size='340' side='right' caption='[[4i8a]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
-{{ABSTRACT_PUBMED_23589421}}
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4i8a]] is a 4 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=4I8A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I8A FirstGlance]. <br>
-==Disease==
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=LLP:2-LYSINE(3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YLMETHANE)'>LLP</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1h0c|1h0c]], [[1jo4|1jo4]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AGXT, AGT1, SPAT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4i8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i8a OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i8a RCSB], [http://www.ebi.ac.uk/pdbsum/4i8a PDBsum]</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>
+== Function ==
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Biochemical Properties of the S187F Mutant AGT The substitution of Ser187, a residue located far from the active site of human liver peroxisomal alanine:glyoxylate aminotransferase (AGT), by Phe gives rise to a variant associated with primary hyperoxaluria type I (PH1). Unexpectedly, previous studies revealed that the recombinant form of S187F exhibits a remarkable loss of catalytic activity, an increased pyridoxal 5'-phosphate (PLP) binding affinity and a different coenzyme binding mode compared with normal AGT. To shed light on the structural elements responsible for these defects, we solved the crystal structure of the variant to a resolution of 2.9 A. Although the overall conformation of the variant is similar to that of normal AGT, we noticed: (i) a displacement of the PLP-binding Lys209 and Val185, located on the re and si side of PLP, respectively, and (ii) slight conformational changes of other active site residues, in particular Trp108, the base stacking residue with the pyridine cofactor moiety. This active site perturbation results in a mispositioning of the AGT-pyridoxamine 5'-phosphate (PMP) complex and of the external aldimine, as predicted by molecular modelling studies. Taken together, both predicted and observed movements caused by the S187F mutation are consistent with the following functional properties of the variant: (i) a 300-500-fold decrease in both the rate constant of L-alanine half-transamination and the kcat of the overall transamination, (ii) a different PMP binding mode and affinity, and (iii) a different microenvironment of the external aldimine. Proposals for the treatment of patients bearing S187F mutation are discussed on the basis of these results. (c) Proteins 2013;. (c) 2013 Wiley Periodicals, Inc.
-==About this Structure==
+Crystal structure of the S187F variant of human liver alanine: Glyoxylate aminotransferase associated with primary hyperoxaluria TYPE I and its functional implications.,Oppici E, Fodor K, Paiardini A, Williams C, Voltattorni CB, Willmanns M, Cellini B Proteins. 2013 Apr 15. doi: 10.1002/prot.24300. PMID:23589421<ref>PMID:23589421</ref>
-[[4i8a]] is a 4 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=4I8A OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<ref group="xtra">PMID:023589421</ref><references group="xtra"/><references/>
+</div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Cellini, B.]]
+[[Category: Cellini, B]]
-[[Category: Fodor, K.]]
+[[Category: Fodor, K]]
-[[Category: Oppici, E.]]
+[[Category: Oppici, E]]
-[[Category: Williams, C.]]
+[[Category: Williams, C]]
-[[Category: Wilmanns, M.]]
+[[Category: Wilmanns, M]]
 [[Category: Aminotransferase]]
 [[Category: Peroxisome]]
 [[Category: Primary hyperoxaluria type 1]]
 [[Category: Transferase]]

4i8a

From Proteopedia

Revision as of 12:13, 21 December 2014

Alanine-glyoxylate aminotransferase variant S187F

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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