P45381 (ACY2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Aspartoacylase
EC=3.5.1.15

Alternative name(s):
Aminoacylase-2
Short name=ACY-2

Gene names

Name:	ASPA
Synonyms:	ACY2, ASP

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	313 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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.
Catalytic activity	N-acyl-L-aspartate + H2O = a carboxylate + L-aspartate. Ref.4
Cofactor	Binds 1 zinc ion per subunit. Ref.5 Ref.6
Subunit structure	Homodimer Probable. Ref.5 Ref.6
Subcellular location	Cytoplasm. Nucleus By similarity.
Tissue specificity	Brain white matter, skeletal muscle, kidney, adrenal glands, lung and liver.
Involvement in disease	Canavan disease (CAND) [MIM:271900]: 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.3 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16
Sequence similarities	Belongs to the AspA/AstE family. Aspartoacylase subfamily.

Ontologies

Keywords
Cellular component	Cytoplasm Nucleus
Disease	Disease mutation Leukodystrophy
Ligand	Metal-binding Zinc
Molecular function	Hydrolase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	aspartate catabolic process Traceable author statement Ref.1. Source: ProtInc central nervous system myelination Inferred from electronic annotation. Source: Compara positive regulation of oligodendrocyte differentiation Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from direct assay. Source: HPA nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	aminoacylase activity Traceable author statement Ref.1. Source: ProtInc aspartoacylase activity Inferred from electronic annotation. Source: EC hydrolase activity, acting on ester bonds Inferred from electronic annotation. Source: InterPro metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 313

313

Aspartoacylase

PRO_0000216871

Regions

Region

70 – 71

2

Substrate binding

Region

164 – 168

5

Substrate binding

Sites

Active site

178

1

Ref.4

Metal binding

21

1

Zinc

Metal binding

24

1

Zinc

Metal binding

116

1

Zinc

Binding site

63

1

Substrate

Binding site

178

1

Substrate

Binding site

288

1

Substrate

Natural variations

Natural variant

16

1

I → T in CAND; <0.5% residual enzyme activity. Ref.10 Ref.13

VAR_039079

Natural variant

21

1

H → P in CAND. Ref.14

VAR_016778

Natural variant

24

1

E → G in CAND. Ref.15

VAR_016782

Natural variant

27

1

G → R in CAND; 3% residual enzyme activity. Ref.10 Ref.13

VAR_039080

Natural variant

57

1

A → T in CAND. Ref.14

VAR_016779

Natural variant

68

1

D → A in CAND. Ref.15

VAR_016783

Natural variant

114

1

D → E in CAND; <0.5% residual enzyme activity. Ref.10

VAR_039081

Natural variant

114

1

D → Y in CAND. Ref.16

VAR_016784

Natural variant

123

1

G → E in CAND; about 25% residual enzyme activity. Ref.10

VAR_039082

Natural variant

143

1

I → T in CAND; in a Japanese patient. Ref.11

VAR_004995

Natural variant

152

1

C → R in CAND; loss of activity. Ref.9

VAR_004996

Natural variant

152

1

C → W in CAND. Ref.15

VAR_016785

Natural variant

152

1

C → Y in CAND; <0.5% residual enzyme activity. Ref.10

VAR_039083

Natural variant

168

1

R → C in CAND; undetectable enzyme activity. Ref.10

VAR_039084

Natural variant

168

1

R → H in CAND. Ref.14

VAR_016780

Natural variant

176 – 177

2

Missing in CAND.

VAR_004997

Natural variant

181

1

P → T in CAND. Ref.14

VAR_016781

Natural variant

183

1

P → H in CAND. Ref.13

VAR_039085

Natural variant

186

1

V → F in CAND. Ref.13

VAR_039086

Natural variant

195

1

M → R in CAND. Ref.13

VAR_039087

Natural variant

231

1

Y → C in CAND. Ref.12

VAR_016786

Natural variant

244

1

H → R in CAND. Ref.15

VAR_016787

Natural variant

249

1

D → V in CAND. Ref.15 Ref.16

VAR_016788

Natural variant

274

1

G → R in CAND. Ref.8 Ref.13

VAR_004998

Natural variant

280

1

P → L in CAND. Ref.13

VAR_039088

Natural variant

280

1

P → S in CAND. Ref.13

VAR_039089

Natural variant

285

1

E → A in CAND; predominant mutation in Ashkenazi Jewish population; 99% loss of activity. Ref.1 Ref.3 Ref.7 Ref.10
Corresponds to variant rs28940279 [ dbSNP | Ensembl ].

VAR_004999

Natural variant

287

1

A → T in CAND. Ref.13

VAR_039090

Natural variant

295

1

F → S in CAND. Ref.8 Ref.13

VAR_005000

Natural variant

305

1

A → E in CAND; loss of activity; pan-European origin; most prevalent among non-Jewish CAND patients; probably the most ancient mutation. Ref.7 Ref.8 Ref.10 Ref.13
Corresponds to variant rs28940574 [ dbSNP | Ensembl ].

VAR_005001

Natural variant

310

1

C → G. Ref.10

VAR_039091

Experimental info

Mutagenesis

71

1

R → K: Reduces activity by 99%. Ref.5

Mutagenesis

164

1

Y → F: Reduces activity by 99%. Ref.5

Mutagenesis

168

1

R → K: Reduces activity by 99%. Ref.5

Mutagenesis

178

1

E → A: Reduces activity by 99%. Ref.4 Ref.5

Mutagenesis

178

1

E → D: Abolishes enzymatic activity. Ref.4 Ref.5

Mutagenesis

178

1

E → Q: Abolishes enzymatic activity. Ref.4 Ref.5

Mutagenesis

285

1

E → D: 5-fold decrease in activity. Ref.3

Mutagenesis

288

1

Y → F: Reduces activity by 99%. Ref.5

Secondary structure

1

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313

Helix Strand Turn

Details...

Beta strand

13 – 18

6

Helix

25 – 34

10

Helix

39 – 41

3

Beta strand

46 – 53

8

Helix

55 – 60

6

Beta strand

65 – 67

3

Helix

69 – 71

3

Helix

75 – 78

4

Helix

88 – 100

13

Beta strand

105 – 108

4

Beta strand

110 – 117

8

Beta strand

119 – 121

3

Beta strand

123 – 129

7

Helix

134 – 147

14

Beta strand

152 – 156

5

Beta strand

160 – 162

3

Helix

167 – 170

4

Beta strand

171 – 180

10

Helix

189 – 210

22

Beta strand

218 – 229

12

Beta strand

235 – 237

3

Beta strand

241 – 243

3

Turn

245 – 249

5

Beta strand

259 – 263

5

Beta strand

269 – 271

3

Beta strand

274 – 276

3

Beta strand

278 – 282

5

Helix

286 – 288

3

Turn

289 – 292

4

Beta strand

294 – 305

12

Sequences

	Sequence		Length	Mass (Da)
	P45381 [UniParc]. Last modified November 1, 1995. Version 1. Checksum: 33C0B9B07839E7F5	FASTA	313	35,735
	10 20 30 40 50 60 MTSCHIAEEH IQKVAIFGGT HGNELTGVFL VKHWLENGAE IQRTGLEVKP FITNPRAVKK 70 80 90 100 110 120 CTRYIDCDLN RIFDLENLGK KMSEDLPYEV RRAQEINHLF GPKDSEDSYD IIFDLHNTTS 130 140 150 160 170 180 NMGCTLILED SRNNFLIQMF HYIKTSLAPL PCYVYLIEHP SLKYATTRSI AKYPVGIEVG 190 200 210 220 230 240 PQPQGVLRAD ILDQMRKMIK HALDFIHHFN EGKEFPPCAI EVYKIIEKVD YPRDENGEIA 250 260 270 280 290 300 AIIHPNLQDQ DWKPLHPGDP MFLTLDGKTI PLGGDCTVYP VFVNEAAYYE KKEAFAKTTK 310 LTLNAKSIRC CLH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease." Kaul R., Gao G.P., Balamurugan K., Matalon R. Nat. Genet. 5:118-123(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT CAND ALA-285. Tissue: Kidney.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[3]	"Purification and preliminary characterization of brain aspartoacylase." Moore R.A., Le Coq J., Faehnle C.R., Viola R.E. Arch. Biochem. Biophys. 413:1-8(2003) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION, CHARACTERIZATION OF VARIANT CAND ALA-285, MUTAGENESIS OF GLU-285. Tissue: Brain.
[4]	"Identification of the zinc binding ligands and the catalytic residue in human aspartoacylase, an enzyme involved in Canavan disease." Herga S., Berrin J.G., Perrier J., Puigserver A., Giardina T. FEBS Lett. 580:5899-5904(2006) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, ZINC-BINDING SITES, ACTIVE SITE, MUTAGENESIS OF GLU-178.
[5]	"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 R.E. Biochemistry 47:3484-3492(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) IN COMPLEXES WITH ZINC IONS; PHOSPHATE AND N-PHOSPHONOMETHYL-L-ASPARTATE, COFACTOR, SUBUNIT, MUTAGENESIS OF ARG-71; TYR-164; ARG-168; GLU-178 AND TYR-288.
[6]	"Structure of aspartoacylase, the brain enzyme impaired in Canavan disease." Bitto E., Bingman C.A., Wesenberg G.E., McCoy J.G., Phillips G.N. Jr. Proc. Natl. Acad. Sci. U.S.A. 104:456-461(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH ZINC IONS, SUBUNIT, COFACTOR.
[7]	"Canavan disease: mutations among Jewish and non-Jewish patients." Kaul R., Gao G.P., Aloya M., Balamurugan K., Petrosky A., Michals K., Matalon R. Am. J. Hum. Genet. 55:34-41(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CAND ALA-285 AND GLU-305.
[8]	"The molecular basis of canavan (aspartoacylase deficiency) disease in European non-Jewish patients." Shaag A., Anikster Y., Christensen E., Glustein J.Z., Fois A., Michelakakis H., Nigro F., Pronicka E., Ribes A., Zabot M.-T., Elpeleg O.N. Am. J. Hum. Genet. 57:572-580(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CAND 176-GLY-ILE-177 DEL; ARG-274; SER-295 AND GLU-305.
[9]	"Novel (Cys152 > Arg) missense mutation in an Arab patient with Canavan disease." Kaul R., Gao G.P., Michals K., Whelan D.T., Levin S., Matalon R. Hum. Mutat. 5:269-271(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CAND ARG-152.
[10]	"Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease." Kaul R., Gao G.P., Matalon R., Aloya M., Su Q., Jin M., Johnson A.B., Schutgens R.B.H., Clarke J.T.R. Am. J. Hum. Genet. 59:95-102(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CAND THR-16; ARG-27; GLU-114; GLU-123; TYR-152; CYS-168; ALA-285 AND GLU-305, VARIANT GLY-310, CHARACTERIZATION OF VARIANTS CAND THR-16; ARG-27; GLU-114; GLU-123; TYR-152 AND CYS-168.
[11]	"Missense mutation (I143T) in a Japanese patient with Canavan disease." Kobayashi K., Tsujino S., Ezoe T., Hamaguchi H., Nihei K., Sakuragawa N. Hum. Mutat. Suppl. 1:S308-S309(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CAND THR-143.
[12]	"Novel missense mutation (Y231C) in a Turkish patient with Canavan disease." Rady P.L., Vargas T., Tyring S.K., Matalon R., Langenbeck U. Am. J. Med. Genet. 87:273-275(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CAND CYS-231.
[13]	"The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients." Elpeleg O.N., Shaag A. J. Inherit. Metab. Dis. 22:531-534(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CAND THR-16; ARG-27; HIS-183; PHE-186; ARG-195; ARG-274; SER-280; LEU-280; THR-287; SER-295 AND GLU-305.
[14]	"Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population." Sistermans E.A., de Coo R.F., van Beerendonk H.M., Poll-The B.T., Kleijer W.J., van Oost B.A. Eur. J. Hum. Genet. 8:557-560(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CAND PRO-21; THR-57; HIS-168 AND THR-181.
[15]	"Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease." Zeng B.J., Wang Z.H., Ribeiro L.A., Leone P., De Gasperi R., Kim S.J., Raghavan S., Ong E., Pastores G.M., Kolodny E.H. J. Inherit. Metab. Dis. 25:557-570(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CAND GLY-24; ALA-68; TRP-152; ARG-244 AND VAL-249.
[16]	"Two novel aspartoacylase gene (ASPA) missense mutations specific to Norwegian and Swedish patients with Canavan disease." Olsen T.R., Tranebjaerg L., Kvittingen E.A., Hagenfeldt L., Moller C., Nilssen O. J. Med. Genet. 39:E55-E55(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CAND TYR-114 AND VAL-249.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

S67156 mRNA. Translation: AAB29190.1.
BC029128 mRNA. Translation: AAH29128.1.

IPI

IPI00021301.

PIR

S38538.

RefSeq

NP_000040.1. NM_000049.2.
NP_001121557.1. NM_001128085.1.

UniGene

Hs.171142.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2I3C	X-ray	2.80	A/B	2-313	[»]
2O4H	X-ray	2.70	A/B	1-313	[»]
2O53	X-ray	2.70	A/B	1-313	[»]
2Q51	X-ray	2.80	A/B	2-313	[»]

ProteinModelPortal

P45381.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-1440951.

STRING

9606.ENSP00000263080.

PTM databases

PhosphoSite

P45381.

Polymorphism databases

DMDM

1168340.

Proteomic databases

PaxDb

P45381.

PRIDE

P45381.

Protocols and materials databases

DNASU

443.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263080; ENSP00000263080; ENSG00000108381.
ENST00000456349; ENSP00000409976; ENSG00000108381.

GeneID

443.

KEGG

hsa:443.

UCSC

uc002fvq.3. human.

Organism-specific databases

CTD

443.

GeneCards

GC17P003326.

HGNC

HGNC:756. ASPA.

HPA

HPA022142.
HPA022145.

MIM

271900. phenotype.
608034. gene.

neXtProt

NX_P45381.

Orphanet

141. Canavan disease.

PharmGKB

PA25055.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG2988.

HOGENOM

HOG000232489.

HOVERGEN

HBG004172.

InParanoid

P45381.

KO

K01437.

OMA

NFNEGKE.

OrthoDB

EOG473PRS.

PhylomeDB

P45381.

Enzyme and pathway databases

BioCyc

MetaCyc:HS03094-MONOMER.

Gene expression databases

ArrayExpress

P45381.

Bgee

P45381.

CleanEx

HS_ASPA.

Genevestigator

P45381.

GermOnline

ENSG00000108381. Homo sapiens.

Family and domain databases

InterPro

IPR016708. Aspartoacylase.
IPR007036. Aste_AspA.
[Graphical view]

Pfam

PF04952. AstE_AspA. 1 hit.
[Graphical view]

PIRSF

PIRSF018001. Aspartoacylase. 1 hit.

ProtoNet

Search...

Other

DrugBank

DB00128. L-Aspartic Acid.

EvolutionaryTrace

P45381.

GenomeRNAi

443.

NextBio

1855.

SOURCE

Search...

Entry information

Entry name

ACY2_HUMAN

Accession

Primary (citable) accession number: P45381

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	May 1, 2013
This is version 121 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.