ID ACY2_HUMAN Reviewed; 313 AA. AC P45381; DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 1. DT 24-JAN-2024, entry version 201. DE RecName: Full=Aspartoacylase {ECO:0000303|PubMed:8252036}; DE EC=3.5.1.15 {ECO:0000269|PubMed:12706335, ECO:0000269|PubMed:24036223, ECO:0000269|PubMed:28101991, ECO:0000269|PubMed:8252036}; DE AltName: Full=Aminoacylase-2; DE Short=ACY-2; GN Name=ASPA {ECO:0000312|HGNC:HGNC:756}; GN Synonyms=ACY2, ASP {ECO:0000303|PubMed:8252036}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, TISSUE RP SPECIFICITY, AND VARIANT CAND ALA-285. RC TISSUE=Kidney; RX PubMed=8252036; DOI=10.1038/ng1093-118; RA Kaul R., Gao G.P., Balamurugan K., Matalon R.; RT "Cloning of the human aspartoacylase cDNA and a common missense mutation in RT Canavan disease."; RL Nat. Genet. 5:118-123(1993). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP CATALYTIC ACTIVITY, CHARACTERIZATION, CHARACTERIZATION OF VARIANT CAND RP ALA-285, AND MUTAGENESIS OF GLU-285. RC TISSUE=Brain; RX PubMed=12706335; DOI=10.1016/s0003-9861(03)00055-9; RA Moore R.A., Le Coq J., Faehnle C.R., Viola R.E.; RT "Purification and preliminary characterization of brain aspartoacylase."; RL Arch. Biochem. Biophys. 413:1-8(2003). RN [4] RP FUNCTION, CATALYTIC ACTIVITY, ZINC-BINDING SITES, ACTIVE SITE, AND RP MUTAGENESIS OF GLU-178. RX PubMed=17027983; DOI=10.1016/j.febslet.2006.09.056; RA Herga S., Berrin J.G., Perrier J., Puigserver A., Giardina T.; RT "Identification of the zinc binding ligands and the catalytic residue in RT human aspartoacylase, an enzyme involved in Canavan disease."; RL FEBS Lett. 580:5899-5904(2006). RN [5] {ECO:0007744|PDB:2O4H, ECO:0007744|PDB:2O53} RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) IN COMPLEXES WITH ZINC IONS; RP PHOSPHATE AND N-PHOSPHONOMETHYL-L-ASPARTATE, CATALYTIC ACTIVITY, COFACTOR, RP SUBUNIT, ACTIVE SITE, REACTION MECHANISM, AND MUTAGENESIS OF ARG-71; RP TYR-164; ARG-168; GLU-178 AND TYR-288. RX PubMed=18293939; DOI=10.1021/bi702400x; RA Le Coq J., Pavlovsky A., Malik R., Sanishvili R., Xu C., Viola R.E.; RT "Examination of the mechanism of human brain aspartoacylase through the RT binding of an intermediate analogue."; RL Biochemistry 47:3484-3492(2008). RN [6] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH ZINC IONS, SUBUNIT, RP AND COFACTOR. RX PubMed=17194761; DOI=10.1073/pnas.0607817104; RA Bitto E., Bingman C.A., Wesenberg G.E., McCoy J.G., Phillips G.N. Jr.; RT "Structure of aspartoacylase, the brain enzyme impaired in Canavan RT disease."; RL Proc. Natl. Acad. Sci. U.S.A. 104:456-461(2007). RN [7] RP VARIANTS CAND ALA-285 AND GLU-305. RX PubMed=8023850; RA Kaul R., Gao G.P., Aloya M., Balamurugan K., Petrosky A., Michals K., RA Matalon R.; RT "Canavan disease: mutations among Jewish and non-Jewish patients."; RL Am. J. Hum. Genet. 55:34-41(1994). RN [8] RP VARIANTS CAND 176-GLY-ILE-177 DEL; ARG-274; SER-295 AND GLU-305. RX PubMed=7668285; RA Shaag A., Anikster Y., Christensen E., Glustein J.Z., Fois A., RA Michelakakis H., Nigro F., Pronicka E., Ribes A., Zabot M.-T., RA Elpeleg O.N.; RT "The molecular basis of canavan (aspartoacylase deficiency) disease in RT European non-Jewish patients."; RL Am. J. Hum. Genet. 57:572-580(1995). RN [9] RP VARIANT CAND ARG-152. RX PubMed=7599639; DOI=10.1002/humu.1380050313; RA Kaul R., Gao G.P., Michals K., Whelan D.T., Levin S., Matalon R.; RT "Novel (Cys152 > Arg) missense mutation in an Arab patient with Canavan RT disease."; RL Hum. Mutat. 5:269-271(1995). RN [10] RP VARIANTS CAND THR-16; ARG-27; GLU-114; GLU-123; TYR-152; CYS-168; ALA-285 RP AND GLU-305, VARIANT GLY-310, AND CHARACTERIZATION OF VARIANTS CAND THR-16; RP ARG-27; GLU-114; GLU-123; TYR-152 AND CYS-168. RX PubMed=8659549; RA Kaul R., Gao G.P., Matalon R., Aloya M., Su Q., Jin M., Johnson A.B., RA Schutgens R.B.H., Clarke J.T.R.; RT "Identification and expression of eight novel mutations among non-Jewish RT patients with Canavan disease."; RL Am. J. Hum. Genet. 59:95-102(1996). RN [11] RP VARIANT CAND THR-143. RX PubMed=9452117; DOI=10.1002/humu.1380110196; RA Kobayashi K., Tsujino S., Ezoe T., Hamaguchi H., Nihei K., Sakuragawa N.; RT "Missense mutation (I143T) in a Japanese patient with Canavan disease."; RL Hum. Mutat. Suppl. 1:S308-S309(1998). RN [12] RP VARIANT CAND CYS-231. RX PubMed=10564886; RX DOI=10.1002/(sici)1096-8628(19991126)87:3<273::aid-ajmg17>3.0.co;2-o; RA Rady P.L., Vargas T., Tyring S.K., Matalon R., Langenbeck U.; RT "Novel missense mutation (Y231C) in a Turkish patient with Canavan RT disease."; RL Am. J. Med. Genet. 87:273-275(1999). RN [13] RP VARIANTS CAND THR-16; ARG-27; HIS-183; PHE-186; ARG-195; ARG-274; SER-280; RP LEU-280; THR-287; SER-295 AND GLU-305. RX PubMed=10407784; DOI=10.1023/a:1005512524957; RA Elpeleg O.N., Shaag A.; RT "The spectrum of mutations of the aspartoacylase gene in Canavan disease in RT non-Jewish patients."; RL J. Inherit. Metab. Dis. 22:531-534(1999). RN [14] RP VARIANTS CAND PRO-21; THR-57; HIS-168 AND THR-181. RX PubMed=10909858; DOI=10.1038/sj.ejhg.5200477; RA Sistermans E.A., de Coo R.F., van Beerendonk H.M., Poll-The B.T., RA Kleijer W.J., van Oost B.A.; RT "Mutation detection in the aspartoacylase gene in 17 patients with Canavan RT disease: four new mutations in the non-Jewish population."; RL Eur. J. Hum. Genet. 8:557-560(2000). RN [15] RP VARIANTS CAND GLY-24; ALA-68; TRP-152; ARG-244 AND VAL-249. RX PubMed=12638939; DOI=10.1023/a:1022091223498; RA Zeng B.J., Wang Z.H., Ribeiro L.A., Leone P., De Gasperi R., Kim S.J., RA Raghavan S., Ong E., Pastores G.M., Kolodny E.H.; RT "Identification and characterization of novel mutations of the RT aspartoacylase gene in non-Jewish patients with Canavan disease."; RL J. Inherit. Metab. Dis. 25:557-570(2002). RN [16] RP VARIANTS CAND TYR-114 AND VAL-249. RX PubMed=12205125; DOI=10.1136/jmg.39.9.e55; RA Olsen T.R., Tranebjaerg L., Kvittingen E.A., Hagenfeldt L., Moller C., RA Nilssen O.; RT "Two novel aspartoacylase gene (ASPA) missense mutations specific to RT Norwegian and Swedish patients with Canavan disease."; RL J. Med. Genet. 39:E55-E55(2002). RN [17] RP VARIANT CAND THR-177, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=24036223; DOI=10.1016/j.clinbiochem.2013.09.004; RA Di Pietro V., Cavallari U., Amorini A.M., Lazzarino G., Longo S., RA Poggiani C., Cavalli P., Tavazzi B.; RT "New T530C mutation in the aspartoacylase gene caused Canavan disease with RT no correlation between severity and N-acetylaspartate excretion."; RL Clin. Biochem. 46:1902-1904(2013). RN [18] RP VARIANTS CAND LYS-24; PRO-30; VAL-57; THR-63; ARG-69; VAL-101; LYS-129; RP THR-170; VAL-180; HIS-204; ARG-248 AND ASP-286, CHARACTERIZATION OF RP VARIANTS CAND LYS-24; PRO-30; VAL-57; THR-63; ARG-69; VAL-101; LYS-129; RP THR-170; VAL-180; HIS-204; ARG-248; ALA-285 AND ASP-286, CATALYTIC RP ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=28101991; DOI=10.1002/humu.23181; RA Mendes M.I., Smith D.E., Pop A., Lennertz P., Fernandez Ojeda M.R., RA Kanhai W.A., van Dooren S.J., Anikster Y., Baric I., Boelen C., RA Campistol J., de Boer L., Kariminejad A., Kayserili H., Roubertie A., RA Verbruggen K.T., Vianey-Saban C., Williams M., Salomons G.S.; RT "Clinically distinct phenotypes of Canavan disease correlate with residual RT aspartoacylase enzyme activity."; RL Hum. Mutat. 38:524-531(2017). CC -!- FUNCTION: Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to CC produce acetate and L-aspartate. NAA occurs in high concentration in CC brain and its hydrolysis NAA plays a significant part in the CC maintenance of intact white matter. In other tissues it acts as a CC scavenger of NAA from body fluids. {ECO:0000269|PubMed:17027983, CC ECO:0000269|PubMed:24036223, ECO:0000269|PubMed:8252036}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + N-acyl-L-aspartate = a carboxylate + L-aspartate; CC Xref=Rhea:RHEA:10872, ChEBI:CHEBI:15377, ChEBI:CHEBI:29067, CC ChEBI:CHEBI:29991, ChEBI:CHEBI:58497; EC=3.5.1.15; CC Evidence={ECO:0000269|PubMed:12706335, ECO:0000269|PubMed:17027983, CC ECO:0000269|PubMed:18293939, ECO:0000269|PubMed:24036223, CC ECO:0000269|PubMed:28101991, ECO:0000269|PubMed:8252036}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10873; CC Evidence={ECO:0000305|PubMed:8252036}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + N-acetyl-L-aspartate = acetate + L-aspartate; CC Xref=Rhea:RHEA:59408, ChEBI:CHEBI:15377, ChEBI:CHEBI:16953, CC ChEBI:CHEBI:29991, ChEBI:CHEBI:30089; CC Evidence={ECO:0000269|PubMed:12706335, ECO:0000269|PubMed:17027983, CC ECO:0000269|PubMed:18293939, ECO:0000269|PubMed:24036223, CC ECO:0000269|PubMed:8252036}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59409; CC Evidence={ECO:0000305|PubMed:8252036}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:17194761, ECO:0000269|PubMed:18293939}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:17194761, CC ECO:0000269|PubMed:18293939}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC Vmax=1.2 nmol/h/mg enzyme {ECO:0000269|PubMed:28101991}; CC -!- SUBUNIT: Homodimer. {ECO:0000305|PubMed:17194761, CC ECO:0000305|PubMed:18293939}. CC -!- INTERACTION: CC P45381; Q96HD9: ACY3; NbExp=15; IntAct=EBI-750475, EBI-3916242; CC P45381; P45381: ASPA; NbExp=2; IntAct=EBI-750475, EBI-750475; CC P45381; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-750475, EBI-350590; CC P45381; Q68J44: DUSP29; NbExp=3; IntAct=EBI-750475, EBI-1054321; CC P45381; Q14145: KEAP1; NbExp=4; IntAct=EBI-750475, EBI-751001; CC P45381; O75925: PIAS1; NbExp=3; IntAct=EBI-750475, EBI-629434; CC P45381; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-750475, EBI-947187; CC P45381; Q9H347: UBQLN3; NbExp=3; IntAct=EBI-750475, EBI-25832660; CC P45381; Q8IYU4: UBQLNL; NbExp=3; IntAct=EBI-750475, EBI-12295223; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9R1T5}. Nucleus CC {ECO:0000250|UniProtKB:Q9R1T5}. CC -!- TISSUE SPECIFICITY: Brain white matter, skeletal muscle, kidney, CC adrenal glands, lung and liver. {ECO:0000269|PubMed:8252036}. CC -!- DISEASE: Canavan disease (CAND) [MIM:271900]: A rare neurodegenerative CC condition of infancy or childhood characterized by white matter CC vacuolization and demyelination that gives rise to a spongy appearance. CC The clinical features are onset in early infancy, atonia of neck CC muscles, hypotonia, hyperextension of legs and flexion of arms, CC blindness, severe mental defect, megalocephaly, and death by 18 months CC on the average. {ECO:0000269|PubMed:10407784, CC ECO:0000269|PubMed:10564886, ECO:0000269|PubMed:10909858, CC ECO:0000269|PubMed:12205125, ECO:0000269|PubMed:12638939, CC ECO:0000269|PubMed:12706335, ECO:0000269|PubMed:24036223, CC ECO:0000269|PubMed:28101991, ECO:0000269|PubMed:7599639, CC ECO:0000269|PubMed:7668285, ECO:0000269|PubMed:8023850, CC ECO:0000269|PubMed:8252036, ECO:0000269|PubMed:8659549, CC ECO:0000269|PubMed:9452117}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the AspA/AstE family. Aspartoacylase subfamily. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; S67156; AAB29190.1; -; mRNA. DR EMBL; BC029128; AAH29128.1; -; mRNA. DR CCDS; CCDS11028.1; -. DR PIR; S38538; S38538. DR RefSeq; NP_000040.1; NM_000049.2. DR RefSeq; NP_001121557.1; NM_001128085.1. DR RefSeq; XP_016880150.1; XM_017024661.1. DR PDB; 2I3C; X-ray; 2.80 A; A/B=2-313. DR PDB; 2O4H; X-ray; 2.70 A; A/B=1-313. DR PDB; 2O53; X-ray; 2.70 A; A/B=1-313. DR PDB; 2Q51; X-ray; 2.80 A; A/B=2-313. DR PDB; 4MRI; X-ray; 2.80 A; A/B=1-313. DR PDB; 4MXU; X-ray; 2.60 A; A/B=1-313. DR PDB; 4NFR; X-ray; 3.00 A; A/B=1-313. DR PDB; 4TNU; X-ray; 2.90 A; A/B=1-313. DR PDBsum; 2I3C; -. DR PDBsum; 2O4H; -. DR PDBsum; 2O53; -. DR PDBsum; 2Q51; -. DR PDBsum; 4MRI; -. DR PDBsum; 4MXU; -. DR PDBsum; 4NFR; -. DR PDBsum; 4TNU; -. DR AlphaFoldDB; P45381; -. DR SMR; P45381; -. DR BioGRID; 106935; 11. DR DIP; DIP-60793N; -. DR IntAct; P45381; 13. DR STRING; 9606.ENSP00000263080; -. DR DrugBank; DB00128; Aspartic acid. DR DrugBank; DB01593; Zinc. DR DrugBank; DB14487; Zinc acetate. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR DrugCentral; P45381; -. DR iPTMnet; P45381; -. DR PhosphoSitePlus; P45381; -. DR BioMuta; ASPA; -. DR MassIVE; P45381; -. DR PaxDb; 9606-ENSP00000263080; -. DR PeptideAtlas; P45381; -. DR ProteomicsDB; 55676; -. DR Antibodypedia; 10844; 334 antibodies from 32 providers. DR DNASU; 443; -. DR Ensembl; ENST00000263080.3; ENSP00000263080.2; ENSG00000108381.11. DR Ensembl; ENST00000456349.6; ENSP00000409976.2; ENSG00000108381.11. DR GeneID; 443; -. DR KEGG; hsa:443; -. DR MANE-Select; ENST00000263080.3; ENSP00000263080.2; NM_000049.4; NP_000040.1. DR AGR; HGNC:756; -. DR CTD; 443; -. DR DisGeNET; 443; -. DR GeneCards; ASPA; -. DR GeneReviews; ASPA; -. DR HGNC; HGNC:756; ASPA. DR HPA; ENSG00000108381; Tissue enhanced (brain, kidney). DR MalaCards; ASPA; -. DR MIM; 271900; phenotype. DR MIM; 608034; gene. DR neXtProt; NX_P45381; -. DR OpenTargets; ENSG00000108381; -. DR Orphanet; 314918; Mild Canavan disease. DR Orphanet; 314911; Severe Canavan disease. DR PharmGKB; PA25055; -. DR VEuPathDB; HostDB:ENSG00000108381; -. DR eggNOG; ENOG502QRAK; Eukaryota. DR GeneTree; ENSGT00390000001189; -. DR HOGENOM; CLU_083292_0_0_1; -. DR InParanoid; P45381; -. DR OMA; THGNEIN; -. DR OrthoDB; 35794at2759; -. DR PhylomeDB; P45381; -. DR TreeFam; TF328708; -. DR BioCyc; MetaCyc:HS03094-MONOMER; -. DR BRENDA; 3.5.1.15; 2681. DR PathwayCommons; P45381; -. DR Reactome; R-HSA-8963693; Aspartate and asparagine metabolism. DR SignaLink; P45381; -. DR SIGNOR; P45381; -. DR BioGRID-ORCS; 443; 5 hits in 1148 CRISPR screens. DR ChiTaRS; ASPA; human. DR EvolutionaryTrace; P45381; -. DR GenomeRNAi; 443; -. DR Pharos; P45381; Tbio. DR PRO; PR:P45381; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P45381; Protein. DR Bgee; ENSG00000108381; Expressed in corpus callosum and 166 other cell types or tissues. DR ExpressionAtlas; P45381; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0019807; F:aspartoacylase activity; IDA:UniProtKB. DR GO; GO:0016811; F:hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides; IBA:GO_Central. DR GO; GO:0016788; F:hydrolase activity, acting on ester bonds; IEA:InterPro. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0006083; P:acetate metabolic process; IEA:Ensembl. DR GO; GO:0006531; P:aspartate metabolic process; IEA:Ensembl. DR GO; GO:0022010; P:central nervous system myelination; IEA:Ensembl. DR GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; IEA:Ensembl. DR CDD; cd06909; M14_ASPA; 1. DR Gene3D; 2.20.25.160; -; 1. DR Gene3D; 3.40.630.10; Zn peptidases; 1. DR HAMAP; MF_00704; Aspartoacylase; 1. DR InterPro; IPR016708; Aspartoacylase. DR InterPro; IPR007036; Aste_AspA. DR PANTHER; PTHR15162; ASPARTOACYLASE; 1. DR PANTHER; PTHR15162:SF9; ASPARTOACYLASE; 1. DR Pfam; PF04952; AstE_AspA; 1. DR PIRSF; PIRSF018001; Aspartoacylase; 1. DR SUPFAM; SSF53187; Zn-dependent exopeptidases; 1. DR Genevisible; P45381; HS. PE 1: Evidence at protein level; KW 3D-structure; Cytoplasm; Disease variant; Hydrolase; Leukodystrophy; KW Metal-binding; Nucleus; Reference proteome; Zinc. FT CHAIN 1..313 FT /note="Aspartoacylase" FT /id="PRO_0000216871" FT ACT_SITE 178 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000305|PubMed:17027983, FT ECO:0000305|PubMed:18293939, ECO:0007744|PDB:2O4H" FT BINDING 21 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:17027983, FT ECO:0000269|PubMed:18293939, ECO:0007744|PDB:2O4H, FT ECO:0007744|PDB:2O53" FT BINDING 24 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:17027983, FT ECO:0000269|PubMed:18293939, ECO:0007744|PDB:2O4H, FT ECO:0007744|PDB:2O53" FT BINDING 63 FT /ligand="N-acetyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:16953" FT /evidence="ECO:0000269|PubMed:18293939, FT ECO:0007744|PDB:2O4H" FT BINDING 70 FT /ligand="N-acetyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:16953" FT /evidence="ECO:0000269|PubMed:18293939, FT ECO:0007744|PDB:2O4H" FT BINDING 71 FT /ligand="N-acetyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:16953" FT /evidence="ECO:0000269|PubMed:18293939, FT ECO:0007744|PDB:2O4H, ECO:0007744|PDB:2O53" FT BINDING 116 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:17027983, FT ECO:0000269|PubMed:18293939, ECO:0007744|PDB:2O4H, FT ECO:0007744|PDB:2O53" FT BINDING 164 FT /ligand="N-acetyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:16953" FT /evidence="ECO:0000269|PubMed:18293939, FT ECO:0007744|PDB:2O4H" FT BINDING 168 FT /ligand="N-acetyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:16953" FT /evidence="ECO:0000269|PubMed:18293939, FT ECO:0007744|PDB:2O4H" FT BINDING 288 FT /ligand="N-acetyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:16953" FT /evidence="ECO:0000269|PubMed:18293939, FT ECO:0007744|PDB:2O4H" FT SITE 63 FT /note="Transition state stabilizer" FT /evidence="ECO:0000305|PubMed:17027983, FT ECO:0000305|PubMed:18293939, ECO:0007744|PDB:2O4H" FT VARIANT 16 FT /note="I -> T (in CAND; <0.5% residual enzyme activity; FT dbSNP:rs769653717)" FT /evidence="ECO:0000269|PubMed:10407784, FT ECO:0000269|PubMed:8659549" FT /id="VAR_039079" FT VARIANT 21 FT /note="H -> P (in CAND)" FT /evidence="ECO:0000269|PubMed:10909858" FT /id="VAR_016778" FT VARIANT 24 FT /note="E -> G (in CAND; dbSNP:rs104894551)" FT /evidence="ECO:0000269|PubMed:12638939" FT /id="VAR_016782" FT VARIANT 24 FT /note="E -> K (in CAND; <1% residual enzyme activity)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078086" FT VARIANT 27 FT /note="G -> R (in CAND; 3% residual enzyme activity; FT dbSNP:rs766328537)" FT /evidence="ECO:0000269|PubMed:10407784, FT ECO:0000269|PubMed:8659549" FT /id="VAR_039080" FT VARIANT 30 FT /note="L -> P (in CAND; <1% residual enzyme activity; FT dbSNP:rs1555538144)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078087" FT VARIANT 57 FT /note="A -> T (in CAND)" FT /evidence="ECO:0000269|PubMed:10909858" FT /id="VAR_016779" FT VARIANT 57 FT /note="A -> V (in CAND; <1% residual enzyme activity; FT dbSNP:rs1555538148)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078088" FT VARIANT 63 FT /note="R -> T (in CAND; <1% residual enzyme activity; FT dbSNP:rs1555538151)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078089" FT VARIANT 68 FT /note="D -> A (in CAND)" FT /evidence="ECO:0000269|PubMed:12638939" FT /id="VAR_016783" FT VARIANT 69 FT /note="L -> R (in CAND; <1% residual enzyme activity; FT dbSNP:rs776777887)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078090" FT VARIANT 101 FT /note="G -> V (in CAND; <1% residual enzyme activity)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078091" FT VARIANT 114 FT /note="D -> E (in CAND; <0.5% residual enzyme activity)" FT /evidence="ECO:0000269|PubMed:8659549" FT /id="VAR_039081" FT VARIANT 114 FT /note="D -> Y (in CAND; dbSNP:rs1446467099)" FT /evidence="ECO:0000269|PubMed:12205125" FT /id="VAR_016784" FT VARIANT 123 FT /note="G -> E (in CAND; about 25% residual enzyme activity; FT dbSNP:rs1057521115)" FT /evidence="ECO:0000269|PubMed:8659549" FT /id="VAR_039082" FT VARIANT 129 FT /note="E -> K (in CAND; <1% residual enzyme activity; FT dbSNP:rs773049803)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078092" FT VARIANT 143 FT /note="I -> T (in CAND; dbSNP:rs777936704)" FT /evidence="ECO:0000269|PubMed:9452117" FT /id="VAR_004995" FT VARIANT 152 FT /note="C -> R (in CAND; loss of activity; FT dbSNP:rs104894548)" FT /evidence="ECO:0000269|PubMed:7599639" FT /id="VAR_004996" FT VARIANT 152 FT /note="C -> W (in CAND)" FT /evidence="ECO:0000269|PubMed:12638939" FT /id="VAR_016785" FT VARIANT 152 FT /note="C -> Y (in CAND; <0.5% residual enzyme activity)" FT /evidence="ECO:0000269|PubMed:8659549" FT /id="VAR_039083" FT VARIANT 168 FT /note="R -> C (in CAND; undetectable enzyme activity; FT dbSNP:rs937670540)" FT /evidence="ECO:0000269|PubMed:8659549" FT /id="VAR_039084" FT VARIANT 168 FT /note="R -> H (in CAND; dbSNP:rs770706390)" FT /evidence="ECO:0000269|PubMed:10909858" FT /id="VAR_016780" FT VARIANT 170 FT /note="I -> T (in CAND; 5.5% residual enzyme activity; FT dbSNP:rs144321760)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078093" FT VARIANT 176..177 FT /note="Missing (in CAND)" FT /evidence="ECO:0000269|PubMed:7668285" FT /id="VAR_004997" FT VARIANT 177 FT /note="I -> T (in CAND; Loss of catalytic activity)" FT /evidence="ECO:0000269|PubMed:24036223" FT /id="VAR_078094" FT VARIANT 180 FT /note="G -> V (in CAND; <1% residual enzyme activity; FT dbSNP:rs1014551540)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078095" FT VARIANT 181 FT /note="P -> T (in CAND; dbSNP:rs786204572)" FT /evidence="ECO:0000269|PubMed:10909858" FT /id="VAR_016781" FT VARIANT 183 FT /note="P -> H (in CAND; dbSNP:rs1555539857)" FT /evidence="ECO:0000269|PubMed:10407784" FT /id="VAR_039085" FT VARIANT 186 FT /note="V -> F (in CAND)" FT /evidence="ECO:0000269|PubMed:10407784" FT /id="VAR_039086" FT VARIANT 195 FT /note="M -> R (in CAND)" FT /evidence="ECO:0000269|PubMed:10407784" FT /id="VAR_039087" FT VARIANT 204 FT /note="D -> H (in CAND; 12% residual enzyme activity)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078096" FT VARIANT 231 FT /note="Y -> C (in CAND; dbSNP:rs104894550)" FT /evidence="ECO:0000269|PubMed:10564886" FT /id="VAR_016786" FT VARIANT 244 FT /note="H -> R (in CAND; dbSNP:rs1057516995)" FT /evidence="ECO:0000269|PubMed:12638939" FT /id="VAR_016787" FT VARIANT 248 FT /note="Q -> R (in CAND; <1% residual enzyme activity)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078097" FT VARIANT 249 FT /note="D -> V (in CAND; dbSNP:rs104894552)" FT /evidence="ECO:0000269|PubMed:12205125, FT ECO:0000269|PubMed:12638939" FT /id="VAR_016788" FT VARIANT 274 FT /note="G -> R (in CAND; dbSNP:rs761064915)" FT /evidence="ECO:0000269|PubMed:10407784, FT ECO:0000269|PubMed:7668285" FT /id="VAR_004998" FT VARIANT 280 FT /note="P -> L (in CAND; dbSNP:rs1555541310)" FT /evidence="ECO:0000269|PubMed:10407784" FT /id="VAR_039088" FT VARIANT 280 FT /note="P -> S (in CAND; dbSNP:rs750505963)" FT /evidence="ECO:0000269|PubMed:10407784" FT /id="VAR_039089" FT VARIANT 285 FT /note="E -> A (in CAND; predominant mutation in Ashkenazi FT Jewish population; 99% loss of activity; dbSNP:rs28940279)" FT /evidence="ECO:0000269|PubMed:12706335, FT ECO:0000269|PubMed:28101991, ECO:0000269|PubMed:8023850, FT ECO:0000269|PubMed:8252036, ECO:0000269|PubMed:8659549" FT /id="VAR_004999" FT VARIANT 286 FT /note="A -> D (in CAND; <1% residual enzyme activity; FT dbSNP:rs1414684396)" FT /evidence="ECO:0000269|PubMed:28101991" FT /id="VAR_078098" FT VARIANT 287 FT /note="A -> T (in CAND; dbSNP:rs774323189)" FT /evidence="ECO:0000269|PubMed:10407784" FT /id="VAR_039090" FT VARIANT 295 FT /note="F -> S (in CAND)" FT /evidence="ECO:0000269|PubMed:10407784, FT ECO:0000269|PubMed:7668285" FT /id="VAR_005000" FT VARIANT 305 FT /note="A -> E (in CAND; pan-European origin; most prevalent FT among non-Jewish CAND patients; probably the most ancient FT mutation; loss of activity; dbSNP:rs28940574)" FT /evidence="ECO:0000269|PubMed:10407784, FT ECO:0000269|PubMed:7668285, ECO:0000269|PubMed:8023850, FT ECO:0000269|PubMed:8659549" FT /id="VAR_005001" FT VARIANT 310 FT /note="C -> G (in dbSNP:rs376854191)" FT /evidence="ECO:0000269|PubMed:8659549" FT /id="VAR_039091" FT MUTAGEN 71 FT /note="R->K: Reduces activity by 99%." FT /evidence="ECO:0000269|PubMed:18293939" FT MUTAGEN 164 FT /note="Y->F: Reduces activity by 99%." FT /evidence="ECO:0000269|PubMed:18293939" FT MUTAGEN 168 FT /note="R->K: Reduces activity by 99%." FT /evidence="ECO:0000269|PubMed:18293939" FT MUTAGEN 178 FT /note="E->A: Reduces activity by 99%." FT /evidence="ECO:0000269|PubMed:17027983, FT ECO:0000269|PubMed:18293939" FT MUTAGEN 178 FT /note="E->D: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:17027983, FT ECO:0000269|PubMed:18293939" FT MUTAGEN 178 FT /note="E->Q: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:17027983, FT ECO:0000269|PubMed:18293939" FT MUTAGEN 285 FT /note="E->D: 5-fold decrease in activity." FT /evidence="ECO:0000269|PubMed:12706335" FT MUTAGEN 288 FT /note="Y->F: Reduces activity by 99%." FT /evidence="ECO:0000269|PubMed:18293939" FT STRAND 14..18 FT /evidence="ECO:0007829|PDB:4MXU" FT HELIX 25..34 FT /evidence="ECO:0007829|PDB:4MXU" FT HELIX 39..41 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 48..53 FT /evidence="ECO:0007829|PDB:4MXU" FT HELIX 55..59 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 65..67 FT /evidence="ECO:0007829|PDB:4MXU" FT HELIX 69..71 FT /evidence="ECO:0007829|PDB:4MXU" FT HELIX 75..78 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 84..86 FT /evidence="ECO:0007829|PDB:4TNU" FT HELIX 88..100 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 105..108 FT /evidence="ECO:0007829|PDB:2O4H" FT STRAND 110..117 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 119..121 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 123..129 FT /evidence="ECO:0007829|PDB:4MXU" FT HELIX 134..147 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 152..156 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 160..162 FT /evidence="ECO:0007829|PDB:2O4H" FT HELIX 167..170 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 171..181 FT /evidence="ECO:0007829|PDB:4MXU" FT HELIX 189..210 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 218..229 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 237..239 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 241..243 FT /evidence="ECO:0007829|PDB:2O53" FT TURN 245..249 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 259..263 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 269..271 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 274..276 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 278..282 FT /evidence="ECO:0007829|PDB:4MXU" FT HELIX 286..288 FT /evidence="ECO:0007829|PDB:4MXU" FT TURN 289..292 FT /evidence="ECO:0007829|PDB:4MXU" FT STRAND 294..305 FT /evidence="ECO:0007829|PDB:4MXU" SQ SEQUENCE 313 AA; 35735 MW; 33C0B9B07839E7F5 CRC64; MTSCHIAEEH IQKVAIFGGT HGNELTGVFL VKHWLENGAE IQRTGLEVKP FITNPRAVKK CTRYIDCDLN RIFDLENLGK KMSEDLPYEV RRAQEINHLF GPKDSEDSYD IIFDLHNTTS NMGCTLILED SRNNFLIQMF HYIKTSLAPL PCYVYLIEHP SLKYATTRSI AKYPVGIEVG PQPQGVLRAD ILDQMRKMIK HALDFIHHFN EGKEFPPCAI EVYKIIEKVD YPRDENGEIA AIIHPNLQDQ DWKPLHPGDP MFLTLDGKTI PLGGDCTVYP VFVNEAAYYE KKEAFAKTTK LTLNAKSIRC CLH //