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[[Image:2o53.jpg|left|200px]]


{{Structure
==Crystal structure of apo-Aspartoacylase from human brain==
|PDB= 2o53 |SIZE=350|CAPTION= <scene name='initialview01'>2o53</scene>, resolution 2.70&Aring;
<StructureSection load='2o53' size='340' side='right'caption='[[2o53]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> and <scene name='pdbligand=PO4:PHOSPHATE ION'>PO4</scene>
<table><tr><td colspan='2'>[[2o53]] is a 2 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=2O53 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2O53 FirstGlance]. <br>
|ACTIVITY= [http://en.wikipedia.org/wiki/Aspartoacylase Aspartoacylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.15 3.5.1.15]  
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
|GENE= ASPA, ACY2, ASP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=2o53 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2o53 OCA], [https://pdbe.org/2o53 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2o53 RCSB], [https://www.ebi.ac.uk/pdbsum/2o53 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2o53 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ACY2_HUMAN ACY2_HUMAN] Defects in ASPA are the cause of Canavan disease (CAND) [MIM:[https://omim.org/entry/271900 271900]; also known as spongy degeneration of the brain. CAND is a rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demeylination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average.<ref>PMID:8252036</ref> <ref>PMID:12706335</ref> <ref>PMID:8023850</ref> <ref>PMID:7668285</ref> <ref>PMID:7599639</ref> <ref>PMID:8659549</ref> <ref>PMID:9452117</ref> <ref>PMID:10564886</ref> <ref>PMID:10407784</ref> <ref>PMID:10909858</ref> <ref>PMID:12638939</ref> <ref>PMID:12205125</ref>
== Function ==
[https://www.uniprot.org/uniprot/ACY2_HUMAN ACY2_HUMAN] Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it act as a scavenger of NAA from body fluids.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/o5/2o53_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2o53 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Canavan disease is a fatal neurological disorder caused by the malfunctioning of a single metabolic enzyme, aspartoacylase, that catalyzes the deacetylation of N-acetyl- l-aspartate to produce l-aspartate and acetate. The structure of human brain aspartoacylase has been determined in complex with a stable tetrahedral intermediate analogue, N-phosphonomethyl- l-aspartate. This potent inhibitor forms multiple interactions between each of its heteroatoms and the substrate binding groups arrayed within the active site. The binding of the catalytic intermediate analogue induces the conformational ordering of several substrate binding groups, thereby setting up the active site for catalysis. The highly ordered binding of this inhibitor has allowed assignments to be made for substrate binding groups and provides strong support for a carboxypeptidase-type mechanism for the hydrolysis of the amide bond of the substrate, N-acetyl- l-aspartate.


'''Crystal structure of apo-Aspartoacylase from human brain'''
Examination of the Mechanism of Human Brain Aspartoacylase through the Binding of an Intermediate Analogue(,).,Le Coq J, Pavlovsky A, Malik R, Sanishvili R, Xu C, Viola RE Biochemistry. 2008 Mar 18;47(11):3484-92. Epub 2008 Feb 23. PMID:18293939<ref>PMID:18293939</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2o53" style="background-color:#fffaf0;"></div>


==Disease==
==See Also==
Known diseases associated with this structure: Canavan disease OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608034 608034]]
*[[Aminoacylase 3D structures|Aminoacylase 3D structures]]
 
*[[Aspartoacylase 3D structures|Aspartoacylase 3D structures]]
==About this Structure==
== References ==
2O53 is a [[Single protein]] structure of 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=2O53 OCA].
<references/>
[[Category: Aspartoacylase]]
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Coq, J Le.]]
[[Category: Le Coq J]]
[[Category: Pavlovsky, A.]]
[[Category: Pavlovsky A]]
[[Category: Sanishvili, R.]]
[[Category: Sanishvili R]]
[[Category: Viola, R E.]]
[[Category: Viola RE]]
[[Category: PO4]]
[[Category: ZN]]
[[Category: acy2]]
[[Category: aminoacylase-2]]
[[Category: aspa]]
[[Category: aspartoacylase family]]
[[Category: canavan disease]]
[[Category: n-acetyl-l-aspartate]]
[[Category: n-phosphonomethyl-l-aspartate]]
[[Category: zinc-dependent hydrolase]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:55:13 2008''

Latest revision as of 13:30, 30 August 2023

Crystal structure of apo-Aspartoacylase from human brainCrystal structure of apo-Aspartoacylase from human brain

Structural highlights

2o53 is a 2 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 2.7Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ACY2_HUMAN Defects in ASPA are the cause of Canavan disease (CAND) [MIM:271900; also known as spongy degeneration of the brain. CAND is a rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demeylination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

Function

ACY2_HUMAN Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it act as a scavenger of NAA from body fluids.

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

Canavan disease is a fatal neurological disorder caused by the malfunctioning of a single metabolic enzyme, aspartoacylase, that catalyzes the deacetylation of N-acetyl- l-aspartate to produce l-aspartate and acetate. The structure of human brain aspartoacylase has been determined in complex with a stable tetrahedral intermediate analogue, N-phosphonomethyl- l-aspartate. This potent inhibitor forms multiple interactions between each of its heteroatoms and the substrate binding groups arrayed within the active site. The binding of the catalytic intermediate analogue induces the conformational ordering of several substrate binding groups, thereby setting up the active site for catalysis. The highly ordered binding of this inhibitor has allowed assignments to be made for substrate binding groups and provides strong support for a carboxypeptidase-type mechanism for the hydrolysis of the amide bond of the substrate, N-acetyl- l-aspartate.

Examination of the Mechanism of Human Brain Aspartoacylase through the Binding of an Intermediate Analogue(,).,Le Coq J, Pavlovsky A, Malik R, Sanishvili R, Xu C, Viola RE Biochemistry. 2008 Mar 18;47(11):3484-92. Epub 2008 Feb 23. PMID:18293939[13]

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

See Also

References

  1. ↑ Kaul R, Gao GP, Balamurugan K, Matalon R. Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet. 1993 Oct;5(2):118-23. PMID:8252036 doi:http://dx.doi.org/10.1038/ng1093-118
  2. ↑ Moore RA, Le Coq J, Faehnle CR, Viola RE. Purification and preliminary characterization of brain aspartoacylase. Arch Biochem Biophys. 2003 May 1;413(1):1-8. PMID:12706335
  3. ↑ Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, Matalon R. Canavan disease: mutations among Jewish and non-Jewish patients. Am J Hum Genet. 1994 Jul;55(1):34-41. PMID:8023850
  4. ↑ Shaag A, Anikster Y, Christensen E, Glustein JZ, Fois A, Michelakakis H, Nigro F, Pronicka E, Ribes A, Zabot MT, et al.. The molecular basis of canavan (aspartoacylase deficiency) disease in European non-Jewish patients. Am J Hum Genet. 1995 Sep;57(3):572-80. PMID:7668285
  5. ↑ Kaul R, Gao GP, Michals K, Whelan DT, Levin S, Matalon R. Novel (cys152 > arg) missense mutation in an Arab patient with Canavan disease. Hum Mutat. 1995;5(3):269-71. PMID:7599639 doi:http://dx.doi.org/10.1002/humu.1380050313
  6. ↑ Kaul R, Gao GP, Matalon R, Aloya M, Su Q, Jin M, Johnson AB, Schutgens RB, Clarke JT. Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. Am J Hum Genet. 1996 Jul;59(1):95-102. PMID:8659549
  7. ↑ Kobayashi K, Tsujino S, Ezoe T, Hamaguchi H, Nihei K, Sakuragawa N. Missense mutation (I143T) in a Japanese patient with Canavan disease. Hum Mutat. 1998;Suppl 1:S308-9. PMID:9452117
  8. ↑ Rady PL, Vargas T, Tyring SK, Matalon R, Langenbeck U. Novel missense mutation (Y231C) in a turkish patient with canavan disease. Am J Med Genet. 1999 Nov 26;87(3):273-5. PMID:10564886
  9. ↑ Elpeleg ON, Shaag A. The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients. J Inherit Metab Dis. 1999 Jun;22(4):531-4. PMID:10407784
  10. ↑ Sistermans EA, de Coo RF, van Beerendonk HM, Poll-The BT, Kleijer WJ, van Oost BA. Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population. Eur J Hum Genet. 2000 Jul;8(7):557-60. PMID:10909858 doi:10.1038/sj.ejhg.5200477
  11. ↑ Zeng BJ, Wang ZH, Ribeiro LA, Leone P, De Gasperi R, Kim SJ, Raghavan S, Ong E, Pastores GM, Kolodny EH. Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease. J Inherit Metab Dis. 2002 Nov;25(7):557-70. PMID:12638939
  12. ↑ Olsen TR, Tranebjaerg L, Kvittingen EA, Hagenfeldt L, Moller C, Nilssen O. Two novel aspartoacylase gene (ASPA) missense mutations specific to Norwegian and Swedish patients with Canavan disease. J Med Genet. 2002 Sep;39(9):e55. PMID:12205125
  13. ↑ Le Coq J, Pavlovsky A, Malik R, Sanishvili R, Xu C, Viola RE. Examination of the Mechanism of Human Brain Aspartoacylase through the Binding of an Intermediate Analogue(,). Biochemistry. 2008 Mar 18;47(11):3484-92. Epub 2008 Feb 23. PMID:18293939 doi:10.1021/bi702400x

2o53, resolution 2.70Å

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