Information on EC 3.5.1.15 - aspartoacylase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
3.5.1.15
-
RECOMMENDED NAME
GeneOntology No.
aspartoacylase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
N-acyl-L-aspartate + H2O = a carboxylate + L-aspartate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of amide bond
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Alanine, aspartate and glutamate metabolism
-
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Histidine metabolism
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Metabolic pathways
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SYSTEMATIC NAME
IUBMB Comments
N-acyl-L-aspartate amidohydrolase
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CAS REGISTRY NUMBER
COMMENTARY hide
9031-86-1
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bovine
-
-
Manually annotated by BRENDA team
goldfish
-
-
Manually annotated by BRENDA team
guinea pig, strain Hartley
-
-
Manually annotated by BRENDA team
pigeon
-
-
Manually annotated by BRENDA team
cat
-
-
Manually annotated by BRENDA team
Macaca iris
java monkey
-
-
Manually annotated by BRENDA team
rhesus monkey
-
-
Manually annotated by BRENDA team
hamster
-
-
Manually annotated by BRENDA team
no activity in Cavia porcellus
rabbit
-
-
Manually annotated by BRENDA team
strain Wistar
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
enzyme substrate N-acetylaspartate is the second-most abundant metabolite in the brain, being produced by neurons and used by oligodendrocytes to coordinate their differentiation, energy production, and lipid synthesis
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
acetyl-DL-alanine + H2O
acetate + DL-alanine
show the reaction diagram
-
-
-
-
?
acetyl-DL-aspartic acid + H2O
acetate + DL-aspartate
show the reaction diagram
-
-
-
-
?
acetyl-DL-methionine + H2O
acetate + methionine
show the reaction diagram
acetyl-L-glutamate + H2O
acetate + glutamate
show the reaction diagram
-
-
-
-
?
acetyl-L-leucine + H2O
acetate + leucine
show the reaction diagram
-
-
-
-
?
chloroacetyl-DL-alanine + H2O
chloroacetate + DL-alanine
show the reaction diagram
chloroacetyl-DL-aspartic acid + H2O
chloroacetate + DL-aspartate
show the reaction diagram
-
-
-
-
?
chloroacetyl-DL-glutamic acid + H2O
chloroacetate + DL-glutamate
show the reaction diagram
-
-
-
-
?
chloroacetyl-DL-leucine + H2O
chloroacetate + DL-leucine
show the reaction diagram
-
-
-
-
?
chloroacetyl-DL-norleucine + H2O
chloroacetate + DL-norleucine
show the reaction diagram
-
-
-
-
?
chloroacetyl-DL-serine + H2O
chloroacetate + DL-serine
show the reaction diagram
-
-
-
-
?
chloroacetyl-L-asparagine + H2O
chloroacetate + L-asparagine
show the reaction diagram
-
poor substrate
-
-
?
chloroacetyl-L-aspartate + H2O
chloroacetate + L-aspartate
show the reaction diagram
chloroacetyl-L-glutamic acid + H2O
chloroacetate + L-glutamate
show the reaction diagram
-
-
-
-
?
chloroacetyl-L-leucine + H2O
chloroacetate + L-leucine
show the reaction diagram
-
-
-
-
?
glycyl-L-asparagine + H2O
glycine + L-asparagine
show the reaction diagram
-
-
-
-
?
glycyl-L-aspartic acid + H2O
glycine + L-aspartate
show the reaction diagram
-
-
-
-
?
glycyl-L-glutamic acid + H2O
glycine + L-glutamate
show the reaction diagram
-
-
-
-
?
N-acetyl-L-aspartate + H2O
aspartate + acetate
show the reaction diagram
N-acetyl-L-aspartate + H2O
L-aspartate + acetate
show the reaction diagram
N-acetyl-L-aspartate + H2O
L-aspartate + acetic acid
show the reaction diagram
-
-
-
-
?
N-acetyl-L-aspartic acid + H2O
acetate + aspartic acid
show the reaction diagram
N-acetylalanine + H2O
acetate + alanine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetylarginine + H2O
acetate + arginine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetylasparagine + H2O
acetate + aspartate + NH3
show the reaction diagram
N-acetylaspartate + H2O
acetate + L-aspartate
show the reaction diagram
N-acetylaspartate + H2O
aspartate + acetate
show the reaction diagram
N-acetylaspartate + H2O
L-aspartate + acetate
show the reaction diagram
-
aspartocylase deficiency results in elevated levels of substrate, brain edema and dysmyelination
-
-
?
N-acetylaspartic acid + H2O
aspartate + acetate
show the reaction diagram
N-acetylaspartic acid + H2O
L-asparatate + acetate
show the reaction diagram
N-acetylcysteine + H2O
acetate + cysteine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetylglutamate + H2O
acetate + glutamate
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetylglutamine + H2O
acetate + glutamine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetylleucine + H2O
acetate + leucine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetyllysine + H2O
acetate + lysine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetylmethionine + H2O
acetate + methionine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetylphenylalanine + H2O
acetate + phenylalanine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetylproline + H2O
acetate + proline
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acetyltyrosine + H2O
acetate + tyrosine
show the reaction diagram
poor substrate, 0.1% of the activity towards N-acetyl-aspartate
-
-
?
N-acyl L-aspartic acid + H2O
acetate + L-aspartate
show the reaction diagram
N-carbobenzoxy-L-aspartate + H2O
?
show the reaction diagram
-
-
-
-
?
N-formyl aspartic acid + H2O
formate + aspartate
show the reaction diagram
-
-
-
-
?
N-tert-butoxycarbonyl-L-aspartic acid alpha-benzyl ester + H2O
?
show the reaction diagram
-
-
-
-
?
N-tert-butoxycarbonyl-L-aspartic acid beta-benzyl ester + H2O
?
show the reaction diagram
-
-
-
-
?
N-trifluoroacetyl-L-aspartate + H2O
L-aspartate + trifluoroacetate
show the reaction diagram
-
-
-
-
?
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
N-acetyl-L-aspartate + H2O
aspartate + acetate
show the reaction diagram
N-acetyl-L-aspartate + H2O
L-aspartate + acetate
show the reaction diagram
N-acetyl-L-aspartic acid + H2O
acetate + aspartic acid
show the reaction diagram
N-acetylaspartate + H2O
acetate + L-aspartate
show the reaction diagram
N-acetylaspartate + H2O
aspartate + acetate
show the reaction diagram
N-acetylaspartate + H2O
L-aspartate + acetate
show the reaction diagram
-
aspartocylase deficiency results in elevated levels of substrate, brain edema and dysmyelination
-
-
?
N-acetylaspartic acid + H2O
aspartate + acetate
show the reaction diagram
N-acetylaspartic acid + H2O
L-asparatate + acetate
show the reaction diagram
additional information
?
-
-
the enzyme functions in concert with the plasma membrane transporter NaDC3, that specifically transports N-acetylaspartic acid into the cell
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+
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stimulates activity 20-40%
Mg2+
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stimulates activity 20-40%
Mn2+
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stimulates activity 20-40%, above 0.1 mM inhibition
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
aspartic acid
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0.002 M, 20-25% inhibition
diisopropyl fluorophosphate
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glutamic acid
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0.002 M, 20-25% inhibition
Glycyl-L-aspartate
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methylphosphonamidate
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N-acetylaspartic acid
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substrate inhibition at concentration above 0.2 mM
N-carbobenzoxy-D-aspartic acid
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N-ethylmaleimide
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N-phosphonomethyl-L-aspartate
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N-tert-butoxycarbonyl-D-aspartic acid-beta-benzyl ester
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p-hydroxymercuribenzoate
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
chloroacetylamino acids
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dithiothreitol
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enhances activity
NP-40
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enhances activity
Triton X-100
Tween-20
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enhances activity
additional information
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upregulation of aspartoacylase activity in the duodenum of obesity induced diabetes mouse
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.1
N-acetyl-L-aspartic acid
0.163 - 5
N-acetylaspartate
0.12 - 0.36
N-acetylaspartic acid
0.2
N-acyl L-aspartic acid
0.3 - 0.5
N-acyl-aspartic acid
recombinant enzyme, purified from bacteria
0.85 - 5.1
N-acyl-L-aspartic acid
0.15 - 0.21
N-trifluoroacetylaspartic acid
additional information
additional information
-
the enzyme shows sigmoidal behaviour and cooperative substrate bindng at low substrate concentration of 0.05-0.2 mM
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
37.5
N-acetylaspartate
Homo sapiens
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-
0.083 - 14.22
N-acetylaspartic acid
1.2 - 116
N-trifluoroacetylaspartic acid
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.3
N-phosphonomethyl-L-aspartate
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.019 - 0.02
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-
0.25
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-
0.45
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-
57
-
recombinant enzyme expressed from Escherichia coli, pH and temperature not specified in the publication
300
-
purified recombinant mutant E178D
1557
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purified recombinant wild-type enzyme
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.2
-
assay at
7.4
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assay at
7.5 - 8.5
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
immunohistochemical localization analysis, high enzyme content in oligodendrocytes along with CC1, and in white matter, including the corpus callosum and the cerebellar white matter, less abundant enzyme content in grey matter, including cerebral cortex, descending neuronal fibers, and microglial cells, no enzyme in astroyctes and forebrain, overview
Manually annotated by BRENDA team
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in situ immunostaining of the enzyme in duodenum of healthy and diabetic mice, overview
Manually annotated by BRENDA team
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ocular tissue, enzyme expression pattern
Manually annotated by BRENDA team
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-
Manually annotated by BRENDA team
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-
Manually annotated by BRENDA team
resident peritoneal
Manually annotated by BRENDA team
neurons from wild-type embryos are co-cultured with oligodendrocytes prepared from either wild-type or tremor rats
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37000
-
determined by SDS-PAGE
38000
-
1 * 38000, SDS-PAGE
58000
-
SDS-PAGE
60000
recombinant mASPA fusion protein, SDS-PAGE
70000
-
dimer
73000
-
dynamic light scattering study
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
2 * 36000, recombinant enzyme, SDS-PAGE
homodimer
monomer
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2.8 angstrom resolution
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crystallization in complex with inhibitor N-phosphonomethyl-L-aspartate, crystallization conditions: 50 mM sodium citrate (pH 6.0), 300 mM K2HPO4, and 15-19% polyethylene glycol 3350
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resolution 2.8 Angstrom
-
resolution 1.8 angstrom
-
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
57
-
rapidly denatures above
70
-
stable at
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
PEGylated forms of aspartoacylase (modified with PEG of 2 kDa, 5 kDa, 10 kDa, 20 kDa or 40 kDa) show similar activities to that of the native enzyme. The activity of PEGylated enzyme samples is monitored for 72 hours without observing a substantial loss in activity
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pure enzyme extremely unstable
-
the Escherichia coli-expressed enzyme form is quite unstable, losing a significant fraction of its catalytic activity within 24 h
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OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
the Pichia pastoris-expressed enzyme shows sensitivity to oxidation over time and will precipitate if not kept under the proper reducing conditions, addition of 1 mM DTT reverses the precipitated state of the enzyme with no significant loss of activity
-
667727
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, frozen storage of undialyzed enzyme for a few days leads to a complete disappearance of activity following a single thaw
-
-70°C, kept for up to 4 weeks without loss of activity
-
4°C, purified wild-type enzyme, expressed
-
the purified enzyme expressed in Pichia pastoris is significantly more stable than the Escherichia coli-expressed enzyme, losing less than 10% of its catalytic activity after 2 weeks when stored under conditions where the Escherichia coli-expressed enzyme becomes completely inactivated within 24 h, the Pichia pastoris-expressed enzyme shows sensitivity to oxidation over time and will precipitate if not kept under the proper reducing conditions
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
affinity chromatography
-
anion exchange chromatography followed by size exclusion chromatography
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native enzyme from brain by subcellular fractionation, and anion exchange chromatography
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nickel Sepharose column chromatography and Source 15Q column chromatography
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One-step nickel-affinity chromatography
-
partial
recombinant enzyme by metal affinity chromatography, dialysis, and anion exchange chromatography
-
recombinant enzyme, overexpressed in bacteria
recombinant His-tagged enzyme from Pichia pastoris strain KM71H by nickel affinity chromatography, dialysis, and anion exchange chromatography
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recombinant wild-type and mutant GST-fusion enzymes from Escherichia coli strain BL21(DE3) by glutathione affinity chromatography
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Pichia pastoris
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expression in Escherichia coli
expression of the GFP-tagged enzyme in COS-7 cells in cytoplasm, nucleoplasm, and nuclei
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expression of wild-type and mutant enzymes as GST-fusion proteins in Escherichia coli strain BL21(DE3)
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gene acy2 or ASPA, recombinant expression of His-tagged enzyme in Pichia pastoris strain KM71H and in Escherichia coli. Recombinantly-expressed human aspartoacylase is not glycosylated, but is still fully functional and stable even when produced from a bacterial expression system
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gene acy2, recombinant expressionin Pichia pastoris strain KM71H
gene Aspa, expression analysis
gene for the production of aspartoacylase is located on chromosome 17
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gene identified with human cDNA, cloned into a thioredoxin fusion vector and overexpressed in bacteria
hASPA gene cloned and overexpressed in bacteria
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putative aspartoacylase identified, homologous to human ASPA
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quantitative expression analysis in brain of wild-type and tremor rats
stable expression of wild-type and mutant enzyme in Pichia pastoris, expression in Escherichia coli strain XL10 primarily in inclusion bodies, while the expression yields are lower in Pichia pastoris than in Escherichia coli, the purified enzyme is significantly more stable, the enzyme form has the same substrate specificity but is 150fold more active than the Escherichia coli-expressed enzyme
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme expression is decreased during the early stages of postnatal development
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A305E
-
Canavan disease mutation, undetectable enzyme activity
A57T
-
Canavan disease mutation, undetectable enzyme activity
C152W
-
Canavan disease mutation, undetectable enzyme activity
D249V
-
Canavan disease mutation, undetectable enzyme activity
D68A
-
Canavan disease mutation, undetectable enzyme activity
E178A
-
undetectable ASPA activity
E178Q
-
site-directed mutagenesis, inactive mutant
E214X
-
Canavan disease mutation, undetectable enzyme activity
G274R
-
Canavan disease mutation, undetectable enzyme activity
H116G
-
putative zinc ion binding sites, undetectable ASPA activity
H21G
-
putative zinc ion binding sites, undetectable ASPA activity
H21P
-
Canavan disease mutation, undetectable enzyme activity
I143T
-
Canavan disease mutation, undetectable enzyme activity
I226T
-
mutant shows no catalytic activity, mutation may be responsible in homozygosis for the phenotype corresponding to Canavan disease.
M195R
-
Canavan disease mutation, undetectable enzyme activity
P183H
-
Canavan disease mutation, undetectable enzyme activity
R71N
-
undetectable ASPA activity
Y231C
-
a naturally occuring missense mutation associated with the Canavan disease, the mutant shows loss of hydrophobic and hydrogen bonding interactions. The mutation leads to a local collapse of the hydrophobic core structure in the carboxyl-terminal domain, contributing to a decrease in protein stability
Y88X
-
the mutation is associated with Canavan disease
additional information
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
the Pichia pastoris-expressed wild-type enzyme shows sensitivity to oxidation over time and will precipitate if not kept under the proper reducing conditions, addition of 1 mM DTT reverses the precipitated state of the enzyme with no significant loss of activity
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
nutrition
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development of a general and simple procedure for the resolution of racemic amino acids
pharmacology
the enzyme is the taget for treatment of Canavan disease, enzyme replacement therapy can potentially be used to overcome these defects if a stable enzyme form that can gain access to the appropriate neural cells can be produced. PEGylated form of aspartoacylase are able to traverse the blood-brain barrier and show dramatic enhancement in brain tissue access and distribution, overview. Examination of the effect of enzyme administration on the immunological response
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