UniProt functional annotation for P15289



	UniProt functional annotation for P15289

UniProt code: P15289.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Hydrolyzes cerebroside sulfate. {ECO:0000269|PubMed:10751093, ECO:0000269|PubMed:24294900}.

Catalytic activity: Reaction=H2O + N-acyl-1-beta-D-(3-O-sulfo)-galactosyl-sphing-4-enine = a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + H(+) + sulfate; Xref=Rhea:RHEA:21300, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16189, ChEBI:CHEBI:18390, ChEBI:CHEBI:75956; EC=3.1.6.8; Evidence={ECO:0000269|PubMed:10751093, ECO:0000269|PubMed:24294900}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21301; Evidence={ECO:0000269|PubMed:24294900};

Cofactor: Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:12888274}; Note=Binds 1 Ca(2+) ion per subunit. {ECO:0000269|PubMed:12888274};

Activity regulation: Inhibited by phosphate. The phosphate forms a covalent bond with the active site 3-oxoalanine. {ECO:0000269|PubMed:12888274}.

Biophysicochemical properties: Kinetic parameters: KM=0.099 mM for galactosyl-3-sulfate ceramide {ECO:0000269|PubMed:24294900}; Note=kcat is 0,087 sec(-1) with galactosyl-3-sulfate ceramide as substrate. {ECO:0000269|PubMed:24294900}; pH dependence: Optimum pH is 4.5. {ECO:0000269|PubMed:24294900};

Subunit: Homodimer at neutral pH and homooctamer at acidic pH. Exists both as a single chain of 58 kDa (component A) or as a chain of 50 kDa (component B) linked by disulfide bond(s) to a 7 kDa chain (component C). Interacts with SUMF1. {ECO:0000269|PubMed:12888274, ECO:0000269|PubMed:1352993, ECO:0000269|PubMed:16368756}.

Subcellular location: Endoplasmic reticulum {ECO:0000269|PubMed:9342345}. Lysosome {ECO:0000305|PubMed:2562955}.

Ptm: The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity. This post- translational modification is severely defective in multiple sulfatase deficiency (MSD). {ECO:0000269|PubMed:7628016, ECO:0000269|PubMed:9342345}.

Disease: Metachromatic leukodystrophy (MLD) [MIM:250100]: An autosomal recessive disease caused by abnormal intralysosomal accumulation of cerebroside-3-sulfate in central and peripheral nervous systems, as well as other organs. MLD is clinically characterized by leukodystrophy, progressive demyelination and a variety of neurological symptoms, including gait disturbances, ataxias, optical atrophy, dementia, seizures, and spastic tetraparesis. Decreased arylsulfatase A activity is detected in urine, leukocytes, and fibroblasts of affected individuals. Several forms of the disease can be distinguished according to the age at onset and disease severity: late infantile, juvenile and adult forms, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency. Individuals with pseudoarylsulfatase A deficiency have low arylsulfatase A activity but lack neurological manifestations and are apparently healthy. {ECO:0000269|PubMed:10220151, ECO:0000269|PubMed:10381328, ECO:0000269|PubMed:10477432, ECO:0000269|PubMed:10533072, ECO:0000269|PubMed:10751093, ECO:0000269|PubMed:11020646, ECO:0000269|PubMed:11061266, ECO:0000269|PubMed:11456299, ECO:0000269|PubMed:11941485, ECO:0000269|PubMed:12503099, ECO:0000269|PubMed:12788103, ECO:0000269|PubMed:1353340, ECO:0000269|PubMed:14517960, ECO:0000269|PubMed:14680985, ECO:0000269|PubMed:15026521, ECO:0000269|PubMed:15326627, ECO:0000269|PubMed:15710861, ECO:0000269|PubMed:1670590, ECO:0000269|PubMed:1673291, ECO:0000269|PubMed:1678251, ECO:0000269|PubMed:18693274, ECO:0000269|PubMed:19606494, ECO:0000269|PubMed:20339381, ECO:0000269|PubMed:21265945, ECO:0000269|PubMed:2574462, ECO:0000269|PubMed:7581401, ECO:0000269|PubMed:7825603, ECO:0000269|PubMed:7860068, ECO:0000269|PubMed:7902317, ECO:0000269|PubMed:7906588, ECO:0000269|PubMed:7909527, ECO:0000269|PubMed:8095918, ECO:0000269|PubMed:8101038, ECO:0000269|PubMed:8101083, ECO:0000269|PubMed:8104633, ECO:0000269|PubMed:8891236, ECO:0000269|PubMed:9090526, ECO:0000269|PubMed:9272717, ECO:0000269|PubMed:9452102, ECO:0000269|PubMed:9490297, ECO:0000269|PubMed:9600244, ECO:0000269|PubMed:9819708}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Multiple sulfatase deficiency (MSD) [MIM:272200]: A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. {ECO:0000269|PubMed:15146462}. Note=The protein represented in this entry is involved in disease pathogenesis. Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1 (PubMed:15146462). SUMF1 mutations result in defective post- translational modification of ARSA at residue Cys-69 that is not converted to 3-oxoalanine (PubMed:7628016). {ECO:0000269|PubMed:15146462, ECO:0000269|PubMed:7628016}.

Miscellaneous: The metal cofactor was first identified as magnesium ion, based on the structure of the recombinant protein, but when purified from human placenta, the protein contains 1 calcium ion per subunit.

Similarity: Belongs to the sulfatase family. {ECO:0000305}.

Sequence caution: Sequence=AAB03341.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=BAH11167.1; Type=Erroneous initiation; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Hydrolyzes cerebroside sulfate. {ECO:0000269\|PubMed:10751093, ECO:0000269\|PubMed:24294900}.


Catalytic activity:		Reaction=H2O + N-acyl-1-beta-D-(3-O-sulfo)-galactosyl-sphing-4-enine = a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + H(+) + sulfate; Xref=Rhea:RHEA:21300, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16189, ChEBI:CHEBI:18390, ChEBI:CHEBI:75956; EC=3.1.6.8; Evidence={ECO:0000269\|PubMed:10751093, ECO:0000269\|PubMed:24294900}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21301; Evidence={ECO:0000269\|PubMed:24294900};
Cofactor:		Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000269\|PubMed:12888274}; Note=Binds 1 Ca(2+) ion per subunit. {ECO:0000269\|PubMed:12888274};
Activity regulation:		Inhibited by phosphate. The phosphate forms a covalent bond with the active site 3-oxoalanine. {ECO:0000269\|PubMed:12888274}.
Biophysicochemical properties:		Kinetic parameters: KM=0.099 mM for galactosyl-3-sulfate ceramide {ECO:0000269\|PubMed:24294900}; Note=kcat is 0,087 sec(-1) with galactosyl-3-sulfate ceramide as substrate. {ECO:0000269\|PubMed:24294900}; pH dependence: Optimum pH is 4.5. {ECO:0000269\|PubMed:24294900};
Subunit:		Homodimer at neutral pH and homooctamer at acidic pH. Exists both as a single chain of 58 kDa (component A) or as a chain of 50 kDa (component B) linked by disulfide bond(s) to a 7 kDa chain (component C). Interacts with SUMF1. {ECO:0000269\|PubMed:12888274, ECO:0000269\|PubMed:1352993, ECO:0000269\|PubMed:16368756}.
Subcellular location:		Endoplasmic reticulum {ECO:0000269\|PubMed:9342345}. Lysosome {ECO:0000305\|PubMed:2562955}.
Ptm:		The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity. This post- translational modification is severely defective in multiple sulfatase deficiency (MSD). {ECO:0000269\|PubMed:7628016, ECO:0000269\|PubMed:9342345}.
Disease:		Metachromatic leukodystrophy (MLD) [MIM:250100]: An autosomal recessive disease caused by abnormal intralysosomal accumulation of cerebroside-3-sulfate in central and peripheral nervous systems, as well as other organs. MLD is clinically characterized by leukodystrophy, progressive demyelination and a variety of neurological symptoms, including gait disturbances, ataxias, optical atrophy, dementia, seizures, and spastic tetraparesis. Decreased arylsulfatase A activity is detected in urine, leukocytes, and fibroblasts of affected individuals. Several forms of the disease can be distinguished according to the age at onset and disease severity: late infantile, juvenile and adult forms, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency. Individuals with pseudoarylsulfatase A deficiency have low arylsulfatase A activity but lack neurological manifestations and are apparently healthy. {ECO:0000269\|PubMed:10220151, ECO:0000269\|PubMed:10381328, ECO:0000269\|PubMed:10477432, ECO:0000269\|PubMed:10533072, ECO:0000269\|PubMed:10751093, ECO:0000269\|PubMed:11020646, ECO:0000269\|PubMed:11061266, ECO:0000269\|PubMed:11456299, ECO:0000269\|PubMed:11941485, ECO:0000269\|PubMed:12503099, ECO:0000269\|PubMed:12788103, ECO:0000269\|PubMed:1353340, ECO:0000269\|PubMed:14517960, ECO:0000269\|PubMed:14680985, ECO:0000269\|PubMed:15026521, ECO:0000269\|PubMed:15326627, ECO:0000269\|PubMed:15710861, ECO:0000269\|PubMed:1670590, ECO:0000269\|PubMed:1673291, ECO:0000269\|PubMed:1678251, ECO:0000269\|PubMed:18693274, ECO:0000269\|PubMed:19606494, ECO:0000269\|PubMed:20339381, ECO:0000269\|PubMed:21265945, ECO:0000269\|PubMed:2574462, ECO:0000269\|PubMed:7581401, ECO:0000269\|PubMed:7825603, ECO:0000269\|PubMed:7860068, ECO:0000269\|PubMed:7902317, ECO:0000269\|PubMed:7906588, ECO:0000269\|PubMed:7909527, ECO:0000269\|PubMed:8095918, ECO:0000269\|PubMed:8101038, ECO:0000269\|PubMed:8101083, ECO:0000269\|PubMed:8104633, ECO:0000269\|PubMed:8891236, ECO:0000269\|PubMed:9090526, ECO:0000269\|PubMed:9272717, ECO:0000269\|PubMed:9452102, ECO:0000269\|PubMed:9490297, ECO:0000269\|PubMed:9600244, ECO:0000269\|PubMed:9819708}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Multiple sulfatase deficiency (MSD) [MIM:272200]: A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. {ECO:0000269\|PubMed:15146462}. Note=The protein represented in this entry is involved in disease pathogenesis. Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1 (PubMed:15146462). SUMF1 mutations result in defective post- translational modification of ARSA at residue Cys-69 that is not converted to 3-oxoalanine (PubMed:7628016). {ECO:0000269\|PubMed:15146462, ECO:0000269\|PubMed:7628016}.
Miscellaneous:		The metal cofactor was first identified as magnesium ion, based on the structure of the recombinant protein, but when purified from human placenta, the protein contains 1 calcium ion per subunit.
Similarity:		Belongs to the sulfatase family. {ECO:0000305}.
Sequence caution:		Sequence=AAB03341.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=BAH11167.1; Type=Erroneous initiation; Evidence={ECO:0000305};