Aspartoacylase
From Proteopedia
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| - | <StructureSection load=" | + | <StructureSection load="2o4h" size="350" color="" Scene='49/498146/Cv/1' caption="Human aspartocyclase dimer complex with aspartate analogue and Zn+2 (grey) [[2o4h]]" > |
| - | + | SEE ALSO [[Aminoacylase]] | |
==Function== | ==Function== | ||
| - | '''Aspartoacylase''' catalyzes the [http://en.wikipedia.org/wiki/Deacetylation 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 [http://en.wikipedia.org/wiki/White_matter white matter].<ref name="UniProt">http://www.uniprot.org/uniprot/Q9R1T5</ref> | + | '''Aspartoacylase''' catalyzes the [http://en.wikipedia.org/wiki/Deacetylation 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 [http://en.wikipedia.org/wiki/White_matter white matter].<ref name="UniProt">http://www.uniprot.org/uniprot/Q9R1T5</ref> '''Succinylglutamate desuccinylase/aspartoacylase''' catalyzes the last step in arginine catabolism and cleavage of acylaspartate into fatty acid and aspartate. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8- and 1.8-A resolution, respectively. The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10-13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded beta-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N- and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypeptides in the active site. The structures revealed that residues 158-164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase.<ref name="Abstract"> PMID: 17194761</ref>. | We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8- and 1.8-A resolution, respectively. The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10-13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded beta-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N- and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypeptides in the active site. The structures revealed that residues 158-164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase.<ref name="Abstract"> PMID: 17194761</ref>. | ||
| - | 2GU2 is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GU2 OCA]. | + | 2GU2 is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GU2 OCA]. |
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| + | <scene name='49/498146/Cv/4'>Catalytic site</scene> of human aspartocyclase with <scene name='49/498146/Cv/5'>aspartate analogue and Zn+2</scene> ([[2o4h]]).<ref>PMID:18293939</ref> | ||
| + | ==3D structures of aspartoacylase== | ||
| + | [[Aspartoacylase 3D structures]] | ||
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| + | </StructureSection> | ||
==GO Annotation== | ==GO Annotation== | ||
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|}<ref name="QuickGO">http://www.ebi.ac.uk/QuickGO/GProtein?ac=Q9R1T5</ref> | |}<ref name="QuickGO">http://www.ebi.ac.uk/QuickGO/GProtein?ac=Q9R1T5</ref> | ||
| - | </StructureSection> | ||
| - | ==3D structures of aspartoacylase== | ||
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| - | Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | ||
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| - | [[2gu2]], [[2q4z]] – AAC – rat<br /> | ||
| - | [[2i3c]], [[2q51]], [[2o53]] – hAAC – human<br /> | ||
| - | [[2o4h]] – hAAC + intermediate analog<br /> | ||
| - | [[4mri]], [[4mxu]], [[4nfr]], [[4tnu]] - hAAC (mutant) + intermediate analog<br /> | ||
| - | [[3nfz]] – mAAC-2 (mutant) + acetyl-tyrosine – mouse<br /> | ||
| - | [[3nh4]] – mAAC-2<br /> | ||
| - | [[3nh5]] - mAAC-2 (mutant)<br /> | ||
| - | [[3nh8]] - mAAC-2 (mutant) + acetyl-dichlorovinyl-cysteine | ||
Current revision
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GO Annotation
| Database | ID | Symbol | Qualifier | GO Identifier | GO Term Name | Aspect | Evidence | Reference | With | Taxon | Date | Assigned By | Product Form ID |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Process | |||||||||||||
| UniProtKB | Q9R1T5 | Aspa | GO:0008152 | metabolic process | P | IEA | InterPro2GO | InterPro:IPR007036 | 10116 | 20101127 | InterPro | ||
| UniProtKB | Q9R1T5 | Aspa | GO:0022010 | central nervous system myelination | P | IEP | PMID:12524181 | 10116 | 20070129 | RGD | |||
| UniProtKB | Q9R1T5 | Aspa | GO:0048714 | positive regulation of oligodendrocyte differentiation | P | IMP | PMID:16634055 | 10116 | 20070129 | RGD | |||
| Function | |||||||||||||
| UniProtKB | Q9R1T5 | Aspa | GO:0016787 | hydrolase activity | F | IEA | Swiss-Prot Keywords2GO | SP_KW:KW-0378 | 10116 | 20101127 | UniProtKB | ||
| UniProtKB | Q9R1T5 | Aspa | GO:0016788 | hydrolase activity, acting on ester bonds | F | IEA | InterPro2GO | InterPro:IPR007036 | 10116 | 20101127 | InterPro | ||
| UniProtKB | Q9R1T5 | Aspa | GO:0019807 | aspartoacylase activity | F | IEA | EC2GO | EC:3.5.1.15 | 10116 | 20100703 | UniProtKB | ||
| UniProtKB | Q9R1T5 | Aspa | GO:0019807 | aspartoacylase activity | F | TAS | PMID:12524181 | 10116 | 20050217 | RGD | |||
| UniProtKB | Q9R1T5 | Aspa | GO:0046872 | metal ion binding | F | IEA | Swiss-Prot Keywords2GO | SP_KW:KW-0479 | 10116 | 20101127 | UniProtKB | ||
| Component | |||||||||||||
| UniProtKB | Q9R1T5 | Aspa | GO:0005634 | nucleus | C | IDA | PMID:16935940 | 10116 | 20070129 | RGD | |||
| UniProtKB | Q9R1T5 | Aspa | GO:0005634 | nucleus | C | IEA | Swiss-Prot Keywords2GO | SP_KW:KW-0539 | 10116 | 20101127 | UnitProtKB | ||
| UniProtKB | Q9R1T5 | Aspa | GO:0005634 | nucleus | C | IEA | Subcellular Location2GO | SP_SL:SL-0191 | 10116 | 20101127 | UniProtKB | ||
| UniProtKB | Q9R1T5 | Aspa | GO:0005737 | cytoplasm | C | IDA | PMID:16935940 | 10116 | 20070129 | RGD | |||
| UniProtKB | Q9R1T5 | Aspa | GO:0005737 | cytoplasm | C | IEA | Swiss-Prot Keywords2GO | SP_KW:KW-0963 | 10116 | 20101127 | UniProtKB | ||
| UniProtKB | Q9R1T5 | Aspa | GO:0005737 | cytoplasm | C | IEA | Subcellular Location2GO | SP_SL:SL-0086 | 10116 | 20101127 | UniProtKB | ||
References
- ↑ http://www.uniprot.org/uniprot/Q9R1T5
- ↑ Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN Jr. Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):456-61. Epub 2006 Dec 28. PMID:17194761
- ↑ 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
- ↑ http://www.ebi.ac.uk/QuickGO/GProtein?ac=Q9R1T5
Additional Literature and Resources
- Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN Jr. Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):456-61. Epub 2006 Dec 28. PMID:17194761
- See: Canavan disease for Additional information on this disease.
- Created with the participation of Robert Abbott.
Categories: Topic Page | Aspartoacylase | Rattus norvegicus | Bingman, C A. | Bitto, E. | CESG, Center for Eukaryotic Structural Genomics. | Jr., G N.Phillips. | Wesenberg, G E. | Acy-2 | Acy2 rat | Aminoacylase-2 | Aspartoacylase family | Center for eukaryotic structural genomic | Cesg | Protein structure initiative | Psi | Structural genomic
