ACY2_HUMAN
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 03-AUG-2022, entry version 193.
DE RecName: Full=Aspartoacylase;
DE EC=3.5.1.15 {ECO:0000269|PubMed:24036223, ECO:0000269|PubMed:28101991};
DE AltName: Full=Aminoacylase-2;
DE Short=ACY-2;
GN Name=ASPA; Synonyms=ACY2, ASP;
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], 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 CHARACTERIZATION, CHARACTERIZATION OF VARIANT CAND ALA-285, AND MUTAGENESIS
RP 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 CATALYTIC ACTIVITY, ZINC-BINDING SITES, ACTIVE SITE, AND MUTAGENESIS OF
RP 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]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) IN COMPLEXES WITH ZINC IONS;
RP PHOSPHATE AND N-PHOSPHONOMETHYL-L-ASPARTATE, COFACTOR, SUBUNIT, AND
RP MUTAGENESIS OF ARG-71; 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, 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 act as a
CC scavenger of NAA from body fluids.
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:17027983, ECO:0000269|PubMed:24036223,
CC ECO:0000269|PubMed:28101991};
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. Nucleus {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Brain white matter, skeletal muscle, kidney,
CC adrenal glands, lung and liver.
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}.
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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; 12.
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; P45381; -.
DR PeptideAtlas; P45381; -.
DR PRIDE; P45381; -.
DR ProteomicsDB; 55676; -.
DR Antibodypedia; 10844; 291 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 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; 1074294at2759; -.
DR PhylomeDB; P45381; -.
DR TreeFam; TF328708; -.
DR BioCyc; MetaCyc:HS03094-MON; -.
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 1069 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 164 other tissues.
DR ExpressionAtlas; P45381; baseline and differential.
DR Genevisible; P45381; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004046; F:aminoacylase activity; TAS:ProtInc.
DR GO; GO:0019807; F:aspartoacylase activity; IEA:UniProtKB-EC.
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:0006533; P:aspartate catabolic process; TAS:ProtInc.
DR GO; GO:0022010; P:central nervous system myelination; IEA:Ensembl.
DR GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; IEA:Ensembl.
DR HAMAP; MF_00704; Aspartoacylase; 1.
DR InterPro; IPR016708; Aspartoacylase.
DR InterPro; IPR007036; Aste_AspA.
DR Pfam; PF04952; AstE_AspA; 1.
DR PIRSF; PIRSF018001; Aspartoacylase; 1.
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 /evidence="ECO:0000269|PubMed:17027983"
FT BINDING 21
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT BINDING 24
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT BINDING 63
FT /ligand="substrate"
FT BINDING 70..71
FT /ligand="substrate"
FT BINDING 116
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT BINDING 164..168
FT /ligand="substrate"
FT BINDING 178
FT /ligand="substrate"
FT BINDING 288
FT /ligand="substrate"
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
