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The zinc cofactor is found at the active site and is held by Glu-24, His-21, and His 116.<ref name="Coq 2008">{{cite journal|last1=Le Coq|first1=J|last2=Pavlovsky|first2=A|last3=Malik|first3=R|last4=Sanishvili|first4=R|last5=Xu|first5=C|last6=Viola|first6=RE|title=Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue.|journal=Biochemistry|date=18 March 2008|volume=47|issue=11|pages=3484-92|pmid=18293939}}</ref> The substrate is held in place by Arg-63, Asn-70, Arg-71, Tyr-164, Arg-168, and Tyr-288. <ref name= "Bitto 2007" /> Zinc lowers the pKa of a ligated water molecule and the reaction proceeds via an attack on N-acetyl-l-aspartate. This leads to a tetrahedral intermediate that is stabilized by the zinc, Arg-63, and Glu-178. <ref name= "Coq 2008" /> |
The zinc cofactor is found at the active site and is held by Glu-24, His-21, and His 116.<ref name="Coq 2008">{{cite journal|last1=Le Coq|first1=J|last2=Pavlovsky|first2=A|last3=Malik|first3=R|last4=Sanishvili|first4=R|last5=Xu|first5=C|last6=Viola|first6=RE|title=Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue.|journal=Biochemistry|date=18 March 2008|volume=47|issue=11|pages=3484-92|pmid=18293939}}</ref> The substrate is held in place by Arg-63, Asn-70, Arg-71, Tyr-164, Arg-168, and Tyr-288. <ref name= "Bitto 2007" /> Zinc lowers the pKa of a ligated water molecule and the reaction proceeds via an attack on N-acetyl-l-aspartate. This leads to a tetrahedral intermediate that is stabilized by the zinc, Arg-63, and Glu-178. <ref name= "Coq 2008" /> |
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[[File:ASPA domains.png|thumb| |
[[File:ASPA domains.png|thumb|none|upright=1.5|Monomer of aspartoacylase with the N-domain in green, C-domain in yellow, and zinc cofactor in red., Generated from 2I3C.<ref name="Bitto 2007"/>]][[File:ASPA bound to an intermediate analogue.png|thumb|none|upright=1.5|Active site of aspartoacylase with a bound N-phosphonamidate-L-aspartate. This is a tetrahedral intermediate analogue with phosphorus replacing the attacked carbon. Generated from 2O4H.<ref name="Coq 2008" />]] |
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[[File:ASPA bound to an intermediate analogue.png|thumb|none|upright=1.5|Active site of aspartoacylase with a bound N-phosphonamidate-L-aspartate. This is a tetrahedral intermediate analogue with phosphorus replacing the attacked carbon. Generated from 2O4H.<ref name="Coq 2008" />]] |
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==Mechanism== |
==Mechanism== |
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Revision as of 00:48, 29 February 2016
| Aspartoacylase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
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| Identifiers | |||||||||
| EC no. | 3.5.1.15 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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Aspartoacylase (EC 3.5.1.15, aminoacylase II, N-acetylaspartate amidohydrolase, acetyl-aspartic deaminase, acylase II) is a hydrolase enzyme with system name N-acyl-L-aspartate amidohydrolase.,[2][3] which breaks down N-acetylaspartate. A deficiency is associated with Canavan disease.This enzyme catalyses the following chemical reaction
Structure
Aspartoacylase is a dimer of two identical monomers of 313 amino acids. There are two distinct domains in each subunit: the N-terminal domain from residues 1-212 and the C-terminal domain from residues 213-313. The N-terminal domain of aspartoacylase is similar to that of zinc-dependent hydrolases such as carboxypeptidases A. However, carboxypeptidases do not have something similar to the C-domain. In carboxypeptidase A, the active site is accessible to large substrates like the bulky C-terminal residue of polypetides, whereas the C-domain sterically hinders access to the active site in aspartoacylase. Instead, the N-domain and C-domain of aspartoacylase form a deep narrow channel that leads to the active site. [1]
The zinc cofactor is found at the active site and is held by Glu-24, His-21, and His 116.[4] The substrate is held in place by Arg-63, Asn-70, Arg-71, Tyr-164, Arg-168, and Tyr-288. [1] Zinc lowers the pKa of a ligated water molecule and the reaction proceeds via an attack on N-acetyl-l-aspartate. This leads to a tetrahedral intermediate that is stabilized by the zinc, Arg-63, and Glu-178. [4]
Mechanism
Biological Function
Aspartoacylase is used to metabolize N-acetyl-L-aspartate by catalyzing its deacylation. Aspartoacylase prevents the build up of N-acetyl-L-aspartate in the brain. N-acetyl-L-aspartate is one of the most abundant amino acids found in the brain with concentrations of up to 10mM and makes up about 1% of the brain's dry weight. [5] It is believed that controlling N-acetyl-L-aspartate levels is essential for developing and maintaining white matter.[1] It is not known why so much N-acetyl-L-aspartate is produced in the brain nor what its primary function is.[6] However, one hypothesis is that it is potentially used as a reservoir that can be tapped into for acetate for acetyl coA synthesis or aspartate for glutamate synthesis. [5] [6] [7] This way, N-acetyl-L-aspartate can be used to transport these precursor molecules and aspartoacylase is used to release them. For example, N-acetyl-L-aspartate produced in neurons can be transported into oligodendrocytes and the acetate released can be used for myelin synthesis.[8]
Disease Relevance
References
- ^ a b c d e Bitto, E; Bingman, CA; Wesenberg, GE; McCoy, JG; Phillips GN, Jr (9 January 2007). "Structure of aspartoacylase, the brain enzyme impaired in Canavan disease". Proceedings of the National Academy of Sciences of the United States of America. 104 (2): 456–61. PMID 17194761.
- ^ Birnbaum, S.M. (1955). "Aminoacylase. Amino acid aminoacylases I and II from hog kidney". Methods Enzymol. 2: 115–119. doi:10.1016/S0076-6879(55)02176-9.
- ^ Birnbaum, S.M., Levintow, L., Kingsley, R.B. and Greenstein, J.P. (1952). "Specificity of amino acid acylases". J. Biol. Chem. 194: 455–470. PMID 14927637.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c Le Coq, J; Pavlovsky, A; Malik, R; Sanishvili, R; Xu, C; Viola, RE (18 March 2008). "Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue". Biochemistry. 47 (11): 3484–92. PMID 18293939.
- ^ a b Clark, JF; Doepke, A; Filosa, JA; Wardle, RL; Lu, A; Meeker, TJ; Pyne-Geithman, GJ (2006). "N-acetylaspartate as a reservoir for glutamate". Medical hypotheses. 67 (3): 506–12. PMID 16730130.
- ^ a b Moffett, JR; Arun, P; Ariyannur, PS; Namboodiri, AM (26 December 2013). "N-Acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation". Frontiers in neuroenergetics. 5: 11. PMID 24421768.
- ^ Hershfield, JR; Madhavarao, CN; Moffett, JR; Benjamins, JA; Garbern, JY; Namboodiri, A (October 2006). "Aspartoacylase is a regulated nuclear-cytoplasmic enzyme". FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 20 (12): 2139–41. PMID 16935940.
- ^ Wijayasinghe, YS; Pavlovsky, AG; Viola, RE (5 August 2014). "Aspartoacylase catalytic deficiency as the cause of Canavan disease: a structural perspective". Biochemistry. 53 (30): 4970–8. PMID 25003821.
External links
- aspartoacylase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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