This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

4nfr

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 10:05, 15 November 2017

Human brain aspartoacylase mutant E285A complex with intermediate analog (N-phosphonomethyl-L-aspartate)

Structural highlights

4nfr is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	2o4h, 2o53
Gene:	ACY2, ASP, ASPA (HUMAN)
Activity:	Aspartoacylase, with EC number 3.5.1.15
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.

Publication Abstract from PubMed

Canavan disease (CD) is a fatal, childhood neurological disorder caused by mutations in the ASPA gene, leading to catalytic deficiencies in the aspartoacylase (ASPA) enzyme and impaired N-acetyl-l-aspartic acid metabolism in the brain. To study the possible structural defects triggered by these mutations, four ASPA missense mutations associated with different disease severities have been structurally characterized. These mutant enzymes each have overall structures similar to that of the native ASPA enzyme, but with varying degrees of alterations that offer explanations for the respective loss of catalytic activity. The K213E mutant, a nonconservative mutant associated with a mild disease phenotype, has minimal structural differences compared to the native enzyme. In contrast, the loss of van der Waals contacts in the F295S mutant and the loss of hydrophobic and hydrogen bonding interactions in the Y231C mutant lead to a local collapse of the hydrophobic core structure in the carboxyl-terminal domain, contributing to a decrease in protein stability. The structure of the E285A mutant, the most common clinical mutant, reveals that the loss of hydrogen bonding interactions with the carboxylate side chain of Glu285 disturbs the active site architecture, leading to altered substrate binding and lower catalytic activity. Our improved understanding of the nature of these structural defects provides a basis for the development of treatment therapies for CD.

Aspartoacylase Catalytic Deficiency as the Cause of Canavan Disease: A Structural Perspective.,Wijayasinghe YS, Pavlovsky AG, Viola RE Biochemistry. 2014 Jul 16. PMID:25003821^[13]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Wijayasinghe YS, Pavlovsky AG, Viola RE. Aspartoacylase Catalytic Deficiency as the Cause of Canavan Disease: A Structural Perspective. Biochemistry. 2014 Jul 16. PMID:25003821 doi:http://dx.doi.org/10.1021/bi500719k

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/4nfr"

@@ Line 3: / Line 3: @@
 <StructureSection load='4nfr' size='340' side='right' caption='[[4nfr]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4nfr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NFR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4nfr]] is a 2 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=4NFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NFR FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AS9:N-[HYDROXY(METHYL)PHOSPHORYL]-L-ASPARTIC+ACID'>AS9</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2o4h|2o4h]], [[2o53|2o53]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACY2, ASP, ASPA ([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/Aspartoacylase Aspartoacylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.15 3.5.1.15] </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=4nfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nfr OCA], [http://pdbe.org/4nfr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nfr RCSB], [http://www.ebi.ac.uk/pdbsum/4nfr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4nfr ProSAT]</span></td></tr>
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 4nfr" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Aspartoacylase|Aspartoacylase]]
 == References ==
 <references/>
@@ Line 30: / Line 28: @@
 </StructureSection>
 [[Category: Aspartoacylase]]
+[[Category: Human]]
 [[Category: Pavlovsky, A G]]
 [[Category: Viola, R E]]

4nfr

From Proteopedia

Revision as of 10:05, 15 November 2017

Human brain aspartoacylase mutant E285A complex with intermediate analog (N-phosphonomethyl-L-aspartate)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox