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Information on EC 3.1.6.8 - cerebroside-sulfatase
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3.1.6.8 cerebroside-sulfataseIUBMB Comments
Hydrolyses galactose-3-sulfate residues in a number of lipids. Also hydrolyses ascorbate 2-sulfate and many phenol sulfates.
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Word Map
- 3.1.6.8
-
metachromatic
- leukodystrophy
- sulfatide
- medicine
- lysosomal
- asa
-
demyelinate
-
sural
-
pseudodeficiency
- nitrocatechol
-
sulfatases
- molecular biology
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
arylsulfatase-a, cerebroside sulfatase, cerebroside sulfate sulfatase, cerebroside-sulfatase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
arylsulfatase A
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-
-
-
ASA
-
-
-
-
cerebroside sulfatase
-
-
-
-
cerebroside sulfate sulfatase
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-
-
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Cerebroside-sulfatase
-
-
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sulfatase, cerebroside
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-
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-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a cerebroside 3-sulfate + H2O = a cerebroside + sulfate
A detailed mechanism for sulfate ester cleavage is proposed, involving an aldehyde hydrate as the functional group.
a cerebroside 3-sulfate + H2O = a cerebroside + sulfate
a detailed mechanism for sulfate ester cleavage is proposed, involving an aldehyde hydrate as the functional group
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of sulfuric ester
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-
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PATHWAY SOURCE
PATHWAYS
SYSTEMATIC NAME
IUBMB Comments
cerebroside-3-sulfate 3-sulfohydrolase
Hydrolyses galactose-3-sulfate residues in a number of lipids. Also hydrolyses ascorbate 2-sulfate and many phenol sulfates.
CAS REGISTRY NUMBER
COMMENTARY
9068-68-2
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
cerebroside 3-sulphate + H2O
cerebroside + sulfate
the enzyme catalyzes the first step in the degradation of the glycolipid cerebroside sulfate
-
?
additional information
?
-
substrate binding and docking study, using crystal structures, PDB IDs 1N2K and 1E2S, overview
-
-
?
4-nitrocatechol sulfate + H2O
4-nitrocatechol + sulfate
artificial substrate, Cys69 is the catalytic residue, and Lys302 and Lys123 act as residues anchoring the sulfate group to the active site, interaction with the enzyme active site, overview
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-
?
cerebroside 3-sulfate + H2O
cerebroside + sulfate
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galactosyl ceramid
?
cerebroside 3-sulfate + H2O
cerebroside + sulfate
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galactosyl ceramide
-
?
cerebroside 3-sulfate + H2O
cerebroside + sulfate
the enzyme catalyzes the first step in the degradation of the glycolipid cerebroside sulfate. Accumulation of cerebroside sulfate is responsible for metachromatic leukodystrophy, a severe autosomal recessive inherited disorder. Good correlation between the type of mutation, deficient arylsulfatase A activity and disease severity is recognized
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-
?
sulfogalactosylceramide + H2O
?
Cys69 is the catalytic residue, and Lys302 and Lys123 act as residues anchoring the sulfate group to the active site, interaction with the enzyme active site, overview
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-
?
sulfogalactosylglycerolipid + H2O
?
Cys69 is the catalytic residue, and Lys302 and Lys123 act as residues anchoring the sulfate group to the active site, interaction with the enzyme active site, overview
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
cerebroside 3-sulphate + H2O
cerebroside + sulfate
the enzyme catalyzes the first step in the degradation of the glycolipid cerebroside sulfate
-
?
cerebroside 3-sulfate + H2O
cerebroside + sulfate
-
galactosyl ceramid
?
cerebroside 3-sulfate + H2O
cerebroside + sulfate
-
galactosyl ceramide
-
?
cerebroside 3-sulfate + H2O
cerebroside + sulfate
the enzyme catalyzes the first step in the degradation of the glycolipid cerebroside sulfate. Accumulation of cerebroside sulfate is responsible for metachromatic leukodystrophy, a severe autosomal recessive inherited disorder. Good correlation between the type of mutation, deficient arylsulfatase A activity and disease severity is recognized
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metachromatic leukodystrophy, MLD, is a rare inherited lysosomal storage disorder caused by the deficiency of arylsulfatase A, ARSA
physiological function
ARSA is involved in the catabolism of membrane sulfatides into galactosylceramide
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ARSA_HUMAN
507
0
53588
Swiss-Prot
Secretory Pathway (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
50000
50000
enzyme is synthesized as a preprotein with 507 amino acids, the mature protein has 489 amino acids with a calculated mass of 52000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
octamer
additional information
The dimer-octamer equilibrium is regulated by the pH and may be explained by a switch function of Glu424. Glu424 in the conformation suitable for the intramolecular hydrogen bonds to Gln460. Glu424 in the conformation suitable for the intermolecular hydrogen bonds to Phe398
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of mutant C69A a nd C69S in complex with p-nitrocatechol sulfate
crystal structure of mutant C69A in complex with p-nitrocatechol sulfate, Protein Data Bank: 1E1Z and 1E2S, and crystal structure of mutant C69S in complex with p-nitrocatechol sulfate, Protein Data Bank: 1E33 and 1E3C
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A212P
naturally occuring ARSA polymorphism, causes a severe peripheral neuropathy phenotype
C168stop
naturally occuring ARSA polymorphism, causes a severe peripheral neuropathy phenotype
C69A
The inactive mutant in complex with p-nitrocatechol sulfate mimics a reaction intermediate during sulfate ester hydrolysis by the active enzyme, without the covalent bond to the key side-chain C-alpha-formylglycine
C69S
D407fs
naturally occuring ARSA polymorphism, causes a severe peripheral neuropathy phenotype
E253K/T391S
mutations contribute to sum of the enzyme activity reduction ascribed to each mutation
E307K
naturally occuring ARSA polymorphism, causes a mild peripheral neuropathy phenotype
H138D
naturally occuring ARSA polymorphism, causes a mild peripheral neuropathy phenotype
H231Q
mutation identified in three patients belonging to a consanguineous family with late-infantile metachromatic leukodystrophy disorder MLD. The mutation leads to changes in the pre-mRNA secondary structure and in the ArsA protein structure
L52P
naturally occuring ARSA polymorphism, causes a severe peripheral neuropathy phenotype
P426L/N350S/96A>G
mutations contribute to sum of the enzyme activity reduction ascribed to each mutation
S406G
naturally occuring ARSA polymorphism, causes a severe peripheral neuropathy phenotype
T304M
naturally occuring ARSA polymorphism, causes a severe peripheral neuropathy phenotype
additional information
C69S
the mutant is able to bind covalently to the substrate and hydrolyse it, but is unable to release the resulting sulfate
C69S
present at significantly higher levels in both conditioned media and within the cell when compared with wild type
additional information
study of disease-causing mutations, severe phenotype of this patient depends not only on the two disease-causing mutations, but also to some extent on the pseudodeficiency mutations
additional information
the frameshift mutations g.445_446dupG and g.2590_2591dupC are associated with metachromatic leukodystrophy and lead 0.3% or 10% of wild type ARSA activity, respectively
additional information
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the frameshift mutations g.445_446dupG and g.2590_2591dupC are associated with metachromatic leukodystrophy and lead 0.3% or 10% of wild type ARSA activity, respectively
additional information
characterization of pathogenic variants c.98T > C, c.195delC, c.229G > C, c.545C > G, c.674A > G, c.852T > A, and c.1274A > G, which were found when sequencing a cohort of 31 German metachromatic leukodystrophy families. Upon expression in immortalized, human multipotent mesenchymal stromal cells prepared from a patient deficient in ARSA activity, the seven mutants show ARSA activity of less than 10% when compared with wild type
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
the ARSA gene is a small gene located on chromosome 22q13 that spans 8 exons and encodes a 507-aminoacid peptide, it is transcribed into three mRNA species, a major one of 2.1 kb and two less abundant species of 3.7 and 4.8 kb. DNA and amino acid sequence determination and analysis of natural mutants. Recombinant expression in HeLa cells using lentiviral vectors, containing mutated ARSA alleles, the vectors stably integrate into the host genome. expression of mutated alleles in murine ARSA-/- fibroblasts
transient expression experiments on COS7 cells transfected with enzyme cDNAs carrying the mutations separately and in the combination found in the patient's alleles
transient expression experiments on COS7 cells transfected with enzyme cDNAs carrying the mutations separately and in the combination found in the patients alleles
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
metachromatic leukodystrophy is caused by deficient activity of arylsulfatase A
medicine
characterization of pathogenic variants C490R, P428L, N284K, P428L, H425R, Y225C and P428L, which were found when sequencing a cohort of 31 German metachromatic leukodystrophy families. Upon expression in immortalized, human multipotent mesenchymal stromal cells prepared from a patient deficient in ARSA activity, the seven mutants show ARSA activity of less than 10% when compared with wild type
medicine
mutation H231Q occurs in three patients belonging to a consanguineous family with late-infantile metachromatic leukodystrophy disorder MLD. The mutation leads to changes in the pre-mRNA secondary structure and in the ArsA protein structure
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Lukatela, G.; Krauss, N.; Theis, K.; Selmer, T.; Gieselmann, V.; von Figura, K.; Saenger, W.
Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis
Biochemistry
37
3654-3664
1998
Homo sapiens (P15289)
Vagedes, P.; Saenger, W.; Knapp, E.W.
Driving forces of protein association: the dimer-octamer equilibrium in arylsulfatase A
Biophys. J.
83
3066-3078
2002
Homo sapiens (P15289)
Regis, S.; Corsolini, F.; Stroppiano, M.; Cusano, R.; Filocamo, M.
Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity
Hum. Genet.
110
351-355
2002
Homo sapiens (P15289)
von Bulow, R.; Schmidt, B.; Dierks, T.; von Figura, K.; Uson, I.
Crystal structure of an enzyme-substrate complex provides insight into the interaction between human arylsulfatase A and its substrates during catalysis
J. Mol. Biol.
305
269-277
2001
Homo sapiens (P15289)
Christianson, T.M.; Starr, C.M.; Zankel, T.C.
Overexpression of inactive arylsulfatase mutants and in vitro activation by light-dependent oxidation with vanadate
Biochem. J.
382
581-587
2004
Homo sapiens (P15289)
Lugowska, A.; Wlodarski, P.; Ploski, R.; Mierzewska, H.; Dudzinska, M.; Matheisel, A.; Swietochowska, H.; Tylki-Szymanska, A.
Molecular and clinical consequences of novel mutations in the arylsulfatase A gene
Clin. Genet.
75
57-64
2009
Homo sapiens (P15289), Homo sapiens
Schenk, M.; Koppisetty, C.A.; Santos, D.C.; Carmona, E.; Bhatia, S.; Nyholm, P.G.; Tanphaichitr, N.
Interaction of arylsulfatase-A (ASA) with its natural sulfoglycolipid substrates: a computational and site-directed mutagenesis study
Glycoconj. J.
26
1029-1045
2009
Homo sapiens (P15289), Sus scrofa (Q8WNR3)
Cesani, M.; Capotondo, A.; Plati, T.; Sergi, L.S.; Fumagalli, F.; Roncarolo, M.G.; Naldini, L.; Comi, G.; Sessa, M.; Biffi, A.
Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy
Hum. Mutat.
30
E936-E945
2009
Homo sapiens (P15289)
Boehringer, J.; Santer, R.; Schumacher, N.; Gieseke, F.; Cornils, K.; Pechan, M.; Kustermann-Kuhn, B.; Handgretinger, R.; Schoels, L.; Harzer, K.; Kraegeloh-Mann, I.; Mueller, I.
Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells
Hum. Mutat.
38
1511-1520
2017
Homo sapiens (P15289)
Issa, A.B.; Feki, F.K.; Jdila, M.B.; Khabou, B.; Rhouma, B.B.; Ammar-Keskes, L.; Triki, C.; Fakhfakh, F.
Clinical, molecular, and computational analysis showed a novel homozygous mutation among the substrate-binding site of ARSA protein in consanguineous family with late-infantile MLD
J. Mol. Neurosci.
66
17-25
2018
Homo sapiens (P15289)
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