id: P15289
gene_symbol: ARSA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ARSA (arylsulfatase A, also called cerebroside-sulfatase or cerebroside-3-sulfatase;
  EC 3.1.6.8) is a lysosomal sulfatase of the glycosphingolipid degradation pathway. It
  hydrolytically removes the 3-O-sulfate from sulfatide (3-O-sulfogalactosylceramide,
  cerebroside-3-sulfate) to give galactosylceramide (cerebroside) plus sulfate, and also
  desulfates other sulfated glycolipids such as seminolipid and lactosylceramide sulfate
  (SM3). Catalysis requires the lipid-presenting activator protein saposin B (a cleavage
  product of PSAP) and a catalytic Calpha-formylglycine residue at Cys69 that is generated
  post-translationally in the endoplasmic reticulum by the formylglycine-generating enzyme
  SUMF1; a Ca2+ ion is bound in the active site. The enzyme is synthesized and matured in
  the ER and delivered to the lysosomal lumen via the mannose-6-phosphate receptor pathway,
  where it acts at acidic pH. Loss of ARSA activity causes intralysosomal accumulation of
  sulfatide and the demyelinating lysosomal storage disorder metachromatic leukodystrophy
  (MLD).
alternative_products:
- name: '1'
  id: P15289-1
- name: '2'
  id: P15289-2
  sequence_note: VSP_046190
existing_annotations:
- term:
    id: GO:0004065
    label: arylsulfatase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Family-level molecular function inferred phylogenetically across the arylsulfatase
      clade. ARSA is a bona fide arylsulfatase that hydrolyzes aryl sulfate esters (used
      as surrogate diagnostic substrates) and, physiologically, the natural sulfatide
      substrate. This is a correct broad MF; the more specific cerebroside-sulfatase term
      captures the physiological reaction.
    action: ACCEPT
    reason: >-
      IBA is well-reviewed and correctly places ARSA in the arylsulfatase family. Retained
      as the broader family MF; the specific physiological MF is GO:0004098.
    supported_by:
    - reference_id: PMID:2562955
      supporting_text: "Transfection of monkey and baby hamster kidney cells resulted in an up to 200-fold increase of the arylsulfatase A activity."
- term:
    id: GO:0004098
    label: cerebroside-sulfatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Specific molecular function: hydrolysis of the 3-O-sulfate of sulfatide
      (cerebroside-3-sulfate) to give cerebroside (galactosylceramide) and sulfate
      (RHEA:21300, EC 3.1.6.8). This is the precise, physiologically correct MF for ARSA
      and is independently supported by direct assay.
    action: ACCEPT
    reason: >-
      Automated RHEA/EC mapping matches the experimentally established reaction and the
      IDA/EXP annotations below.
    supported_by:
    - reference_id: file:human/ARSA/ARSA-uniprot.txt
      supporting_text: "cerebroside-3-sulfate (sulfatide) into cerebroside and sulfate, a"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      ARSA is a lysosomal acid hydrolase; the lysosome is its functional site of action.
      Consistent with the SubCell mapping and with the experimentally supported lysosomal
      localization.
    action: ACCEPT
    reason: >-
      Correct core localization for a lysosomal sulfatase; corroborated by TAS
      (PMID:2562955) and Reactome lysosomal-lumen annotations.
    supported_by:
    - reference_id: PMID:2562955
      supporting_text: "The arylsulfatase A was located in lysosome-like"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      ARSA transits the ER, where the catalytic Calpha-formylglycine is generated before
      lysosomal delivery. This is a maturation/transit compartment rather than the site of
      catalytic function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real localization during biosynthesis (formylglycine generation and folding), but
      not where ARSA performs its physiological reaction; retained as non-core.
    supported_by:
    - reference_id: PMID:9342345
      supporting_text: "the oxidation of its thiol group to an aldehyde is catalyzed in the"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding annotation from a high-throughput interactome-mapping study
      (Stitch-seq). Uninformative about ARSA molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a systematic interactome screen; carries no specific
      functional information and is subsumed by the informative sulfatase MF terms.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: "Next-generation sequencing to generate interactome datasets."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding annotation from a proteome-scale human interactome map. The
      interaction partner (TRIP13) does not inform ARSA's lysosomal sulfatase function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale interactome dataset; uninformative.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: "A proteome-scale map of the human interactome network."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding annotation from an interactome-perturbation study; uninformative
      about ARSA's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from systematic interactome data.
    supported_by:
    - reference_id: PMID:25910212
      supporting_text: "Widespread macromolecular interaction perturbations in human genetic disorders."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding annotation from an alternative-splicing interactome study;
      uninformative about ARSA function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a high-throughput splice-isoform interactome screen.
    supported_by:
    - reference_id: PMID:26871637
      supporting_text: "Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding annotations from the HuRI human binary interactome map (multiple
      partners including ANXA11, CCDC22, PKN1, TRIP13). None specify a functional molecular
      interaction relevant to ARSA's lysosomal sulfatase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a systematic binary interactome dataset; uninformative
      and subsumed by the specific sulfatase MF terms.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: "A reference map of the human binary protein interactome."
- term:
    id: GO:0004065
    label: arylsulfatase activity
  evidence_type: IDA
  original_reference_id: PMID:25553303
  qualifier: enables
  review:
    summary: >-
      Direct assay of leukocyte ARSA activity, including using a natural sulfatide
      substrate, measured by UPLC-MS/MS. Confirms arylsulfatase A enzymatic activity
      (EC 3.1.6.8) for the human protein.
    action: ACCEPT
    reason: >-
      Experimental direct measurement of ARSA enzymatic activity; supports the core
      catalytic MF at the family level.
    supported_by:
    - reference_id: PMID:25553303
      supporting_text: "measuring arylsulfatase A (ARSA; EC3.1.6.8) activity"
    - reference_id: PMID:25553303
      supporting_text: "using a natural sulfatide substrate"
- term:
    id: GO:0006689
    label: ganglioside catabolic process
  evidence_type: IDA
  original_reference_id: PMID:11919180
  qualifier: involved_in
  review:
    summary: >-
      In Arsa-null mice, ganglio-series sulfatides (e.g. SB1a) accumulate, showing ARSA is
      required to degrade sulfated members of the ganglio-series glycosphingolipid pathway.
      ARSA acts on the sulfated (sulfatide) members rather than on sialylated gangliosides
      per se, so this is an adjacent/peripheral role rather than the core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported experimentally, but ARSA's direct chemistry is desulfation of
      galactosyl-3-sulfate glycolipids; its contribution to the ganglioside catabolic
      pathway is via the sulfated intermediates. Kept as non-core.
    supported_by:
    - reference_id: PMID:11919180
      supporting_text: "Arylsulfatase A is required to degrade SB1a. It is probably the sole"
    - reference_id: PMID:11919180
      supporting_text: "sphingolipid-sulfatase cleaving the galactosyl-3-sulfate bond."
- term:
    id: GO:0036021
    label: endolysosome lumen
  evidence_type: IC
  original_reference_id: PMID:27498570
  qualifier: is_active_in
  review:
    summary: >-
      Curator inference (IC) that ARSA, an acid hydrolase, is active in the endolysosome
      lumen, based on the finding that endolysosomes are the principal intracellular sites
      of acid hydrolase activity. Consistent with ARSA's lysosomal acid-pH-optimum activity.
    action: ACCEPT
    reason: >-
      Correct localization of catalytic activity for an acid hydrolase; endolysosome lumen
      is a valid refinement of the lysosomal site of action.
    supported_by:
    - reference_id: PMID:27498570
      supporting_text: "endolysosomes are the principal organelles in"
- term:
    id: GO:0004098
    label: cerebroside-sulfatase activity
  evidence_type: IDA
  original_reference_id: PMID:24294900
  qualifier: enables
  review:
    summary: >-
      Direct enzymatic assay of ARSA activity toward the natural substrate
      galactosyl-3-sulfate ceramide (sulfatide), establishing the physiological
      cerebroside-sulfatase reaction. This is the core molecular function.
    action: ACCEPT
    reason: >-
      Direct assay against the natural sulfatide substrate; the specific, physiologically
      correct MF for ARSA.
    supported_by:
    - reference_id: PMID:24294900
      supporting_text: "galactosyl-3-sulfate ceramide (or sulfatide), is performed using neat sulfatide"
- term:
    id: GO:0030149
    label: sphingolipid catabolic process
  evidence_type: IDA
  original_reference_id: PMID:32431092
  qualifier: involved_in
  review:
    summary: >-
      ARSA deficiency leads to accumulation of cerebroside sulfate (sulfatide), placing
      ARSA in the sphingolipid (sulfatide) catabolic pathway. This is the correct core
      biological process for the enzyme.
    action: ACCEPT
    reason: >-
      Sulfatide desulfation is the committed step of sulfatide degradation within
      sphingolipid catabolism; loss of ARSA blocks this catabolic route.
    supported_by:
    - reference_id: PMID:32431092
      supporting_text: "lead to the accumulation of cerebroside sulfate, a glycolipid that forms part of myelin membranes"
- term:
    id: GO:0004098
    label: cerebroside-sulfatase activity
  evidence_type: EXP
  original_reference_id: PMID:10751093
  qualifier: enables
  review:
    summary: >-
      Functional characterization of MLD-causing missense mutants by expression and enzyme
      activity assays confirms that ARSA is the cerebroside-sulfatase whose deficiency
      causes metachromatic leukodystrophy.
    action: ACCEPT
    reason: >-
      Experimental (mutant activity) support for ARSA's cerebroside-sulfatase function; a
      duplicate of the specific core MF and appropriately retained.
    supported_by:
    - reference_id: PMID:10751093
      supporting_text: "Metachromatic leukodystrophy is a lysosomal storage disease caused by the"
    - reference_id: PMID:10751093
      supporting_text: "deficiency of arylsulfatase A."
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: EXP
  original_reference_id: PMID:9342345
  qualifier: located_in
  review:
    summary: >-
      ARSA transits the ER, where the catalytic cysteine (Cys69) is oxidized to
      formylglycine before delivery to the lysosome. Experimental support for ER
      localization during maturation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct maturation compartment (formylglycine generation) but not the physiological
      site of catalysis; retained as non-core.
    supported_by:
    - reference_id: PMID:9342345
      supporting_text: "A linear sequence of 16 residues surrounding the Cys-69"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      Extracellular localization attributed to neutrophil azurophil-granule exocytosis
      (Reactome degranulation pathway). This is a secretory-context/bystander location, not
      ARSA's functional lysosomal site.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Peripheral to ARSA's role as an intracellular lysosomal sulfatase; captured only via
      a granule-exocytosis pathway.
    supported_by:
    - reference_id: Reactome:R-HSA-6798751
      supporting_text: "Exocytosis of azurophil granule lumen proteins"
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      Localization to the neutrophil azurophil granule lumen (a lysosome-related organelle)
      from the Reactome degranulation pathway. Peripheral cell-type-specific location, not
      the core lysosomal function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Cell-type-specific granule membership from a degranulation pathway; not central to
      ARSA's function.
    supported_by:
    - reference_id: Reactome:R-HSA-6798751
      supporting_text: "Exocytosis of azurophil granule lumen proteins"
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      Detection in urinary exosome proteomics. High-throughput proteomic identification in
      a secreted vesicle fraction; a bystander location rather than the functional site.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Proteomic detection in exosomes is common for lysosomal/secreted proteins and does
      not reflect ARSA's core functional localization.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: "In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine."
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1614362
  qualifier: located_in
  review:
    summary: >-
      ER lumen localization during biosynthesis, from the Reactome pathway in which SUMF1
      generates the formylglycine that activates arylsulfatases. Maturation compartment,
      not the catalytic site.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with ER formylglycine generation during maturation; non-core relative to
      lysosomal function.
    supported_by:
    - reference_id: Reactome:R-HSA-1614362
      supporting_text: "SUMF1 mediates the oxidation of cysteine to formylglycine, producing active arylsulfatases"
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2248891
  qualifier: located_in
  review:
    summary: >-
      ER lumen localization from the Reactome pathway describing M6PR-mediated transport of
      activated ARSA to the lysosome. Transit/maturation compartment.
    action: KEEP_AS_NON_CORE
    reason: >-
      Maturation/transit location prior to lysosomal delivery; non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-2248891
      supporting_text: "M6PR transports activated ARSA to the lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1606807
  qualifier: located_in
  review:
    summary: >-
      Lysosomal lumen localization from the Reactome reaction in which ARSA removes sulfate
      from the PSAP(saposin B):sulfatide complex. This is the functional site of ARSA
      catalysis.
    action: ACCEPT
    reason: >-
      Correct core functional compartment (lysosomal lumen) where ARSA acts on sulfatide
      with the saposin B activator.
    supported_by:
    - reference_id: Reactome:R-HSA-1606807
      supporting_text: "ARSA removes sulfate from PSAP(195-273):Sulfatide"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2248891
  qualifier: located_in
  review:
    summary: >-
      Lysosomal lumen localization from the Reactome pathway describing delivery of
      activated ARSA to the lysosome via the mannose-6-phosphate receptor. Correct
      functional destination.
    action: ACCEPT
    reason: >-
      Consistent with M6PR-mediated lysosomal targeting; the lysosomal lumen is ARSA's
      functional site.
    supported_by:
    - reference_id: Reactome:R-HSA-2248891
      supporting_text: "M6PR transports activated ARSA to the lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840949
  qualifier: located_in
  review:
    summary: >-
      Lysosomal lumen localization from the Reactome reaction in which ARSA removes sulfate
      from SM3 (a sulfated glycolipid), reinforcing the lysosomal lumen as the site of
      catalysis.
    action: ACCEPT
    reason: >-
      Correct functional compartment; supports lysosomal-lumen localization of ARSA
      catalysis.
    supported_by:
    - reference_id: Reactome:R-HSA-9840949
      supporting_text: "ARSA removes sulfate from SM3"
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:12888274
  qualifier: enables
  review:
    summary: >-
      The crystal structure of endogenous human ARSA shows a Ca2+ ion in the active site
      (one per subunit), coordinating the substrate sulfate and the catalytic formylglycine.
      Structural cofactor binding, not the core catalytic MF.
    action: ACCEPT
    reason: >-
      Direct structural evidence for an active-site Ca2+; a genuine (non-core) cofactor
      binding function that supports catalysis.
    supported_by:
    - reference_id: PMID:12888274
      supporting_text: "present in the active site of arylsulfatase A isolated from human placenta is"
    - reference_id: file:human/ARSA/ARSA-uniprot.txt
      supporting_text: "Binds 1 Ca(2+) ion per subunit."
- term:
    id: GO:0008484
    label: sulfuric ester hydrolase activity
  evidence_type: IDA
  original_reference_id: PMID:15962010
  qualifier: enables
  review:
    summary: >-
      General sulfatase (sulfuric ester hydrolase) activity, whose generation depends on
      the SUMF1-catalyzed formylglycine modification (regulated by SUMF2). Correct but this
      is a broad parent MF subsumed by the specific arylsulfatase/cerebroside-sulfatase terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      True but overly general; the informative MF terms (GO:0004065, GO:0004098) already
      capture ARSA's sulfatase activity at greater specificity.
    supported_by:
    - reference_id: PMID:15962010
      supporting_text: "highly conserved cysteine located within their active site into formylglycine."
- term:
    id: GO:0004065
    label: arylsulfatase activity
  evidence_type: TAS
  original_reference_id: PMID:2562955
  qualifier: enables
  review:
    summary: >-
      Cloning/expression paper establishing that the ARSA cDNA encodes arylsulfatase A
      enzymatic activity (up to 200-fold increase on transfection). Author-asserted MF.
    action: ACCEPT
    reason: >-
      TAS support for ARSA arylsulfatase activity, consistent with the IDA/IBA MF
      annotations.
    supported_by:
    - reference_id: PMID:2562955
      supporting_text: "Transfection of monkey and baby hamster kidney cells resulted in an up to 200-fold increase of the arylsulfatase A activity."
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: TAS
  original_reference_id: PMID:2562955
  qualifier: located_in
  review:
    summary: >-
      ARSA localizes to lysosomes and is delivered there in a mannose-6-phosphate
      receptor-dependent manner. Correct core localization.
    action: ACCEPT
    reason: >-
      Author-asserted lysosomal localization consistent with M6PR-dependent targeting and
      the enzyme's acid-hydrolase role.
    supported_by:
    - reference_id: PMID:2562955
      supporting_text: "transported to dense lysosomes in a mannose 6-phosphate"
core_functions:
- description: >-
    Lysosomal cerebroside-sulfatase (arylsulfatase A): hydrolytically removes the
    3-O-sulfate from sulfatide (galactosyl-3-sulfate ceramide) to yield galactosylceramide
    plus sulfate, acting on the saposin-B-presented lipid substrate in the lysosomal lumen
    to drive sulfatide/sphingolipid catabolism.
  molecular_function:
    id: GO:0004098
    label: cerebroside-sulfatase activity
  directly_involved_in:
  - id: GO:0030149
    label: sphingolipid catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:24294900
    supporting_text: "galactosyl-3-sulfate ceramide (or sulfatide), is performed using neat sulfatide"
  - reference_id: file:human/ARSA/ARSA-uniprot.txt
    supporting_text: "cerebroside-3-sulfate (sulfatide) into cerebroside and sulfate, a"
  - reference_id: PMID:32431092
    supporting_text: "lead to the accumulation of cerebroside sulfate, a glycolipid that forms part of myelin membranes"
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/ARSA/ARSA-uniprot.txt
  title: UniProtKB entry P15289 (ARSA_HUMAN), Arylsulfatase A
  findings: []
- id: PMID:10751093
  title: Characterization of four arylsulfatase A missense mutations G86D, Y201C,
    D255H, and E312D causing metachromatic leukodystrophy.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Functional characterization of MLD missense mutants; confirms ARSA is the
      cerebroside-sulfatase deficient in MLD.
- id: PMID:11919180
  title: 'Kidney sulfatides in mouse models of inherited glycosphingolipid disorders:
    determination by nano-electrospray ionization tandem mass spectrometry.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      In vivo Arsa-null mouse data; establishes ARSA as the sphingolipid-sulfatase cleaving
      the galactosyl-3-sulfate bond.
- id: PMID:12888274
  title: Crystal structure of a covalent intermediate of endogenous human arylsulfatase
    A.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Structure shows active-site Ca2+ and the formylglycine covalent intermediate.
- id: PMID:15962010
  title: Sulphatase activities are regulated by the interaction of sulphatase-modifying
    factor 1 with SUMF2.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Establishes SUMF1-generated formylglycine as required for sulfatase activity;
      relevant to ARSA maturation, general to sulfatases.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome method paper; source of a generic protein-binding IPI.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteomic detection of ARSA in urinary exosomes; bystander localization.
- id: PMID:24294900
  title: 'A new analytical bench assay for the determination of arylsulfatase a activity
    toward galactosyl-3-sulfate ceramide: implication for metachromatic leukodystrophy
    diagnosis.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct assay of ARSA against natural sulfatide substrate; supports the specific
      cerebroside-sulfatase MF.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale interactome map; source of a generic protein-binding IPI.
- id: PMID:25553303
  title: Ultra-performance liquid chromatography-tandem mass spectrometry measurement
    of leukocyte arylsulfatase A activity using a natural substrate.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct measurement of leukocyte ARSA activity using a natural sulfatide substrate.
- id: PMID:2562955
  title: Cloning and expression of human arylsulfatase A.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning/expression establishing ARSA enzymatic activity and M6PR-dependent lysosomal
      targeting.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Interactome-perturbation study; source of a generic protein-binding IPI.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Splice-isoform interactome screen; source of a generic protein-binding IPI.
- id: PMID:27498570
  title: Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Basis for the IC that ARSA (an acid hydrolase) is active in the endolysosome lumen.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome map; source of multiple generic protein-binding IPIs.
- id: PMID:32431092
  title: 'Arylsulfatase A pseudodeficiency in Mexico: Enzymatic activity and haplotype
    analysis.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      ARSA deficiency leads to cerebroside-sulfate accumulation; supports the sphingolipid
      catabolic BP.
- id: PMID:9342345
  title: 'Conversion of cysteine to formylglycine: a protein modification in the endoplasmic
    reticulum.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows the ARSA Cys69->formylglycine conversion occurs in the ER; supports ER
      maturation localization.
- id: Reactome:R-HSA-1606807
  title: ARSA removes sulfate from PSAP(195-273):Sulfatide
  findings: []
- id: Reactome:R-HSA-1614362
  title: SUMF1 mediates the oxidation of cysteine to formylglycine, producing active
    arylsulfatases
  findings: []
- id: Reactome:R-HSA-2248891
  title: M6PR transports activated ARSA to the lysosome
  findings: []
- id: Reactome:R-HSA-6798751
  title: Exocytosis of azurophil granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9840949
  title: ARSA removes sulfate from SM3
  findings: []
suggested_questions:
- question: >-
    Beyond sulfatide and SM3/seminolipid, what is the full physiological substrate spectrum
    of ARSA in vivo, and how strictly does it depend on saposin B versus other sphingolipid
    activator proteins?
suggested_experiments:
- description: >-
    Quantitative substrate-profiling (lipidomics) of ARSA-deficient versus wild-type
    lysosomes to define the in vivo sulfated-glycolipid substrate range and the saposin-B
    dependence of each reaction.
  experiment_type: lipidomics