id: Q13510
gene_symbol: ASAH1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ASAH1 encodes acid ceramidase (N-acylsphingosine amidohydrolase 1; EC
  3.5.1.23), a soluble lysosomal amidohydrolase that catalyzes the last common step
  of sphingolipid/glycosphingolipid degradation, hydrolyzing ceramide into sphingosine
  and a free fatty acid at acidic pH. It is synthesized as a single ~53-55 kDa precursor
  that is autoproteolytically cleaved into disulfide-linked alpha and beta subunits,
  with the N-terminal cysteine of the beta subunit (Cys143) serving as the catalytic
  nucleophile of an N-terminal nucleophile (Ntn) hydrolase; cleavage triggers a conformational
  change that activates the enzyme. It is trafficked to the lysosome via the mannose-6-phosphate
  receptor and requires the sphingolipid activator protein saposin D for activity against
  membrane-embedded ceramide. By controlling the balance of ceramide, sphingosine and
  sphingosine-1-phosphate, it influences downstream sphingolipid signaling (cell proliferation,
  apoptosis, differentiation). Loss-of-function mutations cause the lysosomal storage
  disorder Farber lipogranulomatosis, while hypomorphic alleles cause spinal muscular
  atrophy with progressive myoclonic epilepsy (SMA-PME).
alternative_products:
- name: '1'
  id: Q13510-1
- name: '2'
  id: Q13510-2
  sequence_note: VSP_037504
- name: '3'
  id: Q13510-3
  sequence_note: VSP_037504, VSP_046284, VSP_046285
existing_annotations:
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically-inferred acid ceramidase (N-acylsphingosine amidohydrolase)
      activity. This is the correct, well-supported core molecular function of ASAH1.
    action: ACCEPT
    reason: This is the core, defining molecular function of ASAH1, independently supported
      by direct biochemical assays on the human enzyme (IDA/EXP annotations from PMID:11451951,
      PMID:12815059, PMID:7744740, and others) and by disease genetics. The IBA sits
      at the appropriate level of specificity.
    supported_by:
    - reference_id: PMID:8955159
      supporting_text: hydrolyzes the sphingolipid ceramide into sphingosine and free
        fatty acid
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic subcellular-location mapping to the extracellular region, reflecting
      the low-level secretion of ASAH1.
    action: KEEP_AS_NON_CORE
    reason: A minor portion of newly synthesized acid ceramidase is secreted, but secretion
      is extraordinarily low and the physiological site of function is the lysosome;
      keep as non-core secretome localization rather than a core location.
    supported_by:
    - reference_id: PMID:7744740
      supporting_text: secreted into the medium as a monomeric 47-kDa protein, indicating
        that
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation (transferred from the mouse ortholog Q9WV54) placing
      ASAH1 in the nucleus.
    action: KEEP_AS_NON_CORE
    reason: A nuclear localization has been reported, most probably for isoforms devoid
      of a signal peptide, and specifically for isoform 2 in the adrenocortical NR5A1/SF-1
      corepressor role (PMID:22927646). This is a context/isoform-specific moonlighting
      localization, not the core site of the lysosomal enzyme; keep as non-core.
    supported_by:
    - reference_id: PMID:22927646
      supporting_text: ASAH1 is localized in the nuclei of H295R adrenocortical cells
        and that cyclic
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic subcellular-location mapping to the cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization has been reported, most probably for signal-peptide-devoid
      isoforms (e.g. isoform 2 in the SF-1 corepressor context); not the core lysosomal
      location. Keep as non-core.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation to the lysosome, the core site of ASAH1 function.
    action: ACCEPT
    reason: ASAH1 is a soluble lysosomal hydrolase; lysosomal localization is directly
      demonstrated (IDA PMID:12764132) and is the physiological site of ceramide catabolism.
    supported_by:
    - reference_id: PMID:11451951
      supporting_text: processed to the mature, heterodimeric enzyme (40 + 13 kDa)
        in the
- term:
    id: GO:0006631
    label: fatty acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO electronic annotation to the broad process of fatty acid metabolism,
      reflecting that free fatty acid is a product of ceramide hydrolysis.
    action: KEEP_AS_NON_CORE
    reason: A free fatty acid is released with sphingosine when ASAH1 hydrolyzes ceramide,
      so this is not wrong, but it is a very general parent process. The core process
      is ceramide/sphingolipid catabolism; keep as non-core.
    supported_by:
    - reference_id: PMID:8955159
      supporting_text: hydrolyzes the sphingolipid ceramide into sphingosine and free
        fatty acid
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (RHEA/EC 3.5.1.23) annotation of the acid ceramidase activity.
    action: ACCEPT
    reason: Correct core molecular function, redundant with and consistent with the
      IBA and experimental annotations of the same term.
    supported_by:
    - reference_id: PMID:8955159
      supporting_text: hydrolyzes the sphingolipid ceramide into sphingosine and free
        fatty acid
- term:
    id: GO:0017064
    label: fatty acid amide hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic annotation of a fatty acid amide hydrolase activity.
    action: KEEP_AS_NON_CORE
    reason: ASAH1 does possess a genuine but low N-acylethanolamine (fatty acid amide)
      hydrolase activity in addition to its principal ceramidase activity, so the term
      is not wrong; however it is a minor secondary activity assigned by family mapping,
      not the core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:15655246
      supporting_text: N-lauroylethanolamine hydrolyzing activity was observed with
        acid ceramidase
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22927646
  qualifier: enables
  review:
    summary: IntAct protein-binding annotation capturing the interaction of ASAH1 (isoform
      2) with the nuclear receptor NR5A1/SF-1.
    action: MARK_AS_OVER_ANNOTATED
    reason: The bare 'protein binding' term is uninformative and does not convey the
      actual biology. The physiologically meaningful interaction is with the nuclear
      receptor NR5A1 (SF-1), through which isoform 2 acts as a transcriptional corepressor
      of steroidogenic genes; a nuclear-receptor-binding / corepressor term would be
      more informative. Per curation policy the IPI is retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:22927646
      supporting_text: ASAH1 suppresses SF-1 activity by directly interacting
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic annotation (transferred from mouse ortholog) to sphingosine
      biosynthesis, reflecting that sphingosine is the direct product of ceramide hydrolysis.
    action: KEEP_AS_NON_CORE
    reason: Sphingosine is produced directly by ASAH1's hydrolysis of ceramide, so
      the enzyme does contribute to sphingosine formation; however this is the product
      side of its catabolic function rather than a distinct biosynthetic role. Keep
      as non-core relative to the core ceramide catabolic process.
    supported_by:
    - reference_id: PMID:10610716
      supporting_text: 'Acid ceramidase (AC) is the lysosomal enzyme that degrades
        ceramide into '
- term:
    id: GO:0046514
    label: ceramide catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic annotation (transferred from mouse ortholog) to ceramide catabolism,
      the core biological process of ASAH1.
    action: ACCEPT
    reason: Ceramide catabolism is the core physiological process ASAH1 mediates; it
      is independently supported by direct/mutational human evidence (PMID:12764132,
      PMID:10610716) and by the disease phenotype (ceramide accumulation in Farber
      disease).
    supported_by:
    - reference_id: PMID:10610716
      supporting_text: 'Acid ceramidase (AC) is the lysosomal enzyme that degrades
        ceramide into '
- term:
    id: GO:0062098
    label: regulation of programmed necrotic cell death
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic annotation (from mouse ortholog Q9WV54) linking ASAH1 to regulation
      of programmed necrotic cell death.
    action: KEEP_AS_NON_CORE
    reason: This is an indirect, by-similarity downstream consequence of ASAH1's control
      of ceramide/sphingosine signaling rather than a direct core function. Retain
      as a non-core regulatory role.
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic annotation (from mouse ortholog) linking ASAH1 to the cellular
      response to TNF.
    action: KEEP_AS_NON_CORE
    reason: UniProt notes ASAH1 indirectly regulates TNF-induced apoptosis (by similarity).
      This is a downstream signaling consequence of altered ceramide levels, not a
      direct core function; keep as non-core.
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-based electronic annotation to the general process of sphingolipid
      metabolism.
    action: KEEP_AS_NON_CORE
    reason: Correct but broad; ASAH1's specific role is ceramide/sphingolipid catabolism,
      which is captured by more precise terms. Keep the general parent as non-core.
    supported_by:
    - reference_id: PMID:8955159
      supporting_text: Ceramide is an essential component of all sphingolipids
- 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 ASAH1, as an acid hydrolase, is active in the
      endolysosome lumen, based on the finding that endolysosomes are the principal
      sites of acid hydrolase activity.
    action: ACCEPT
    reason: Consistent with ASAH1 being a soluble luminal acid hydrolase; the IC correctly
      places its activity in the acid-hydrolase-active endolysosomal lumen. Retained
      alongside the core lysosome/lysosomal lumen location.
    supported_by:
    - reference_id: PMID:27498570
      supporting_text: endolysosomes are the principal sites of intracellular acid
        hydrolase activity
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: IDA
  original_reference_id: PMID:11451951
  qualifier: enables
  review:
    summary: Direct assay of acid ceramidase activity on recombinant/mutant human enzyme
      (glycosylation/processing study).
    action: ACCEPT
    reason: Direct experimental support for the core molecular function; N-glycosylation-site
      mutagenesis (e.g. N173Q, N259Q, N342Q) abolishes ceramide catabolic activity,
      demonstrating the assayed ceramidase function.
    supported_by:
    - reference_id: PMID:11451951
      supporting_text: processed to the mature, heterodimeric enzyme (40 + 13 kDa)
        in the
- term:
    id: GO:0030149
    label: sphingolipid catabolic process
  evidence_type: IDA
  original_reference_id: PMID:11451951
  qualifier: involved_in
  review:
    summary: Direct-assay annotation placing ASAH1 in sphingolipid catabolism.
    action: ACCEPT
    reason: Ceramide is the central sphingolipid, and its ASAH1-mediated degradation
      is a core step of sphingolipid catabolism. Well supported; a valid (slightly
      more general) core-process parent of ceramide catabolic process.
    supported_by:
    - reference_id: PMID:8955159
      supporting_text: Ceramide is an essential component of all sphingolipids
- term:
    id: GO:0006685
    label: sphingomyelin catabolic process
  evidence_type: IDA
  original_reference_id: PMID:11451951
  qualifier: involved_in
  review:
    summary: Direct-assay annotation to sphingomyelin catabolism.
    action: KEEP_AS_NON_CORE
    reason: ASAH1 acts downstream of sphingomyelinase in the sphingolipid degradation
      pathway (it degrades the ceramide produced from sphingomyelin) and physically/functionally
      associates with acid sphingomyelinase (PMID:12815059). ASAH1 does not itself
      hydrolyze sphingomyelin; its participation in sphingomyelin catabolism is indirect,
      so keep as non-core.
    supported_by:
    - reference_id: PMID:12815059
      supporting_text: media from the overexpressing hamster cells had increased acid
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:12638942
  qualifier: enables
  review:
    summary: Acid ceramidase activity assayed in Farber disease patient mutation analysis
      (COS-1 expression of mutant cDNAs).
    action: ACCEPT
    reason: Direct experimental support for the core molecular function; Farber-causing
      variants (V97E, G235R, 96delV) reduce measured acid ceramidase activity to 2-37%
      of control, confirming the assayed activity.
    supported_by:
    - reference_id: PMID:12638942
      supporting_text: accumulation of ceramide in tissues due to acid ceramidase deficiency
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:15655246
  qualifier: enables
  review:
    summary: Experimental characterization of acid ceramidase activity alongside the
      related NAAA enzyme.
    action: ACCEPT
    reason: Direct experimental support for the core ceramidase activity; this study
      compares ASAH1 (acid ceramidase) with NAAA and confirms ceramide-hydrolyzing
      activity of acid ceramidase.
    supported_by:
    - reference_id: PMID:15655246
      supporting_text: N-lauroylethanolamine hydrolyzing activity was observed with
        acid ceramidase
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:22703880
  qualifier: enables
  review:
    summary: Acid ceramidase activity assayed for the SMA-PME T42M variant.
    action: ACCEPT
    reason: Direct experimental support for the core molecular function; the SMA-PME
      T42M mutant retains only ~32% of normal acid ceramidase activity, confirming
      the assayed ceramidase function and its disease relevance.
    supported_by:
    - reference_id: PMID:22703880
      supporting_text: acid-ceramidase activity was only 32% of that generated
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:27026573
  qualifier: enables
  review:
    summary: Acid ceramidase activity assayed for a mild SMA (T42A) ASAH1 variant.
    action: ACCEPT
    reason: Direct experimental support for the core molecular function; biochemical
      study of a hypomorphic ASAH1 variant confirms reduced acid ceramidase (ceramide
      degradation) activity.
    supported_by:
    - reference_id: PMID:27026573
      supporting_text: 'ASAH1 gene encodes for acid ceramidase that is involved in
        the degradation of '
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:29692406
  qualifier: enables
  review:
    summary: Structure-function study of acid ceramidase activation, including catalytic
      assays.
    action: ACCEPT
    reason: Direct experimental/structural support for the core molecular function;
      crystal structures and mutagenesis of catalytic residues (Cys143 nucleophile,
      Asp162, Arg333) establish the acid ceramidase mechanism.
    supported_by:
    - reference_id: PMID:29692406
      supporting_text: 'Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane
        ceramide into '
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:8955159
  qualifier: enables
  review:
    summary: Experimental characterization of cloned human acid ceramidase; transient
      expression increased AC activity ~10-fold.
    action: ACCEPT
    reason: Direct experimental support for the core molecular function; the founding
      molecular cloning paper demonstrates ceramide-hydrolyzing activity of the expressed
      human enzyme.
    supported_by:
    - reference_id: PMID:8955159
      supporting_text: hydrolyzes the sphingolipid ceramide into sphingosine and free
        fatty acid
- term:
    id: GO:0062098
    label: regulation of programmed necrotic cell death
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity annotation (from mouse ortholog Q9WV54) to regulation
      of programmed necrotic cell death.
    action: KEEP_AS_NON_CORE
    reason: Duplicate of the IEA/GO_REF:0000107 annotation of the same term; an indirect
      by-similarity signaling role downstream of ceramide, not a direct core function.
      Keep as non-core.
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity annotation (from mouse ortholog) to the cellular response
      to TNF.
    action: KEEP_AS_NON_CORE
    reason: Duplicate of the IEA annotation of the same term; an indirect signaling
      consequence of ceramide regulation, not a direct core function. Keep as non-core.
- term:
    id: GO:0030216
    label: keratinocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:17713573
  qualifier: involved_in
  review:
    summary: Knockdown study showing acid ceramidase (with alkaline ceramidase haCER1)
      mediates calcium-induced differentiation of human epidermal keratinocytes.
    action: KEEP_AS_NON_CORE
    reason: A genuine, tissue-specific physiological role mediated by ASAH1's control
      of sphingosine/S1P levels, but downstream of and secondary to its core catabolic
      activity; keep as a non-core process.
    supported_by:
    - reference_id: PMID:17713573
      supporting_text: keratin 1 and involucrin in HEKs. In addition, the acid ceramidase
        (AC) was also
- term:
    id: GO:0050810
    label: regulation of steroid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:22261821
  qualifier: involved_in
  review:
    summary: shRNA knockdown in H295R adrenocortical cells shows ASAH1 regulates steroidogenic
      capacity and adrenocortical gene expression.
    action: KEEP_AS_NON_CORE
    reason: A real but context-specific (adrenocortical) regulatory role, mediated
      through ASAH1's control of the ceramide/sphingosine/S1P balance and, for isoform
      2, direct SF-1 corepression; secondary to the core catabolic function. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:22261821
      supporting_text: catalyzing the hydrolysis of Cer into SPH
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:11451951
  qualifier: located_in
  review:
    summary: Direct observation of low-level secreted acid ceramidase.
    action: KEEP_AS_NON_CORE
    reason: Secretion of ASAH1 is real but extraordinarily low, and the core site of
      function is the lysosome; keep the extracellular localization as non-core.
    supported_by:
    - reference_id: PMID:11451951
      supporting_text: Secretion of hAC by either fibroblasts or acid ceramidase
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: IDA
  original_reference_id: PMID:12815059
  qualifier: enables
  review:
    summary: Direct assay of acid ceramidase activity on purified recombinant human
      enzyme (Michaelis-Menten kinetics with C12-ceramide).
    action: ACCEPT
    reason: Direct experimental support for the core molecular function on the purified
      recombinant enzyme.
    supported_by:
    - reference_id: PMID:12815059
      supporting_text: The purified enzyme also catalyzed ceramide synthesis in vitro
        using
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12815059
  qualifier: involved_in
  review:
    summary: Direct-assay annotation to sphingosine biosynthesis (sphingosine is the
      product of ceramide hydrolysis).
    action: KEEP_AS_NON_CORE
    reason: Sphingosine is the direct product of ASAH1 ceramide hydrolysis, so the
      enzyme contributes to sphingosine formation, but this is the product side of
      catabolism rather than a distinct biosynthetic role. Keep as non-core.
    supported_by:
    - reference_id: PMID:12815059
      supporting_text: The purified enzyme also catalyzed ceramide synthesis in vitro
        using
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12815059
  qualifier: involved_in
  review:
    summary: Direct assay showing the purified enzyme also catalyzes the reverse (ceramide
      synthase) reaction in vitro.
    action: KEEP_AS_NON_CORE
    reason: ASAH1 has a genuine reverse ceramide-synthesizing activity in vitro (and
      in situ), but its physiological (in vivo) contribution to ceramide biosynthesis
      is uncertain relative to dedicated ceramide synthases; keep as a non-core activity.
    supported_by:
    - reference_id: PMID:12815059
      supporting_text: The purified enzyme also catalyzed ceramide synthesis in vitro
        using
- term:
    id: GO:0046514
    label: ceramide catabolic process
  evidence_type: IDA
  original_reference_id: PMID:12815059
  qualifier: involved_in
  review:
    summary: Direct-assay annotation to ceramide catabolism, the core process of ASAH1.
    action: ACCEPT
    reason: Core biological process, directly supported by the biochemical demonstration
      of ceramide hydrolysis by the purified human enzyme.
    supported_by:
    - reference_id: PMID:12815059
      supporting_text: BODIPY-labeled C12-ceramide as substrates
- term:
    id: GO:0016811
    label: hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in
      linear amides
  evidence_type: IDA
  original_reference_id: PMID:15655246
  qualifier: enables
  review:
    summary: Direct-assay annotation to the general amidohydrolase class term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a broad parent of the specific N-acylsphingosine amidohydrolase
      activity (GO:0017040) already annotated. The specific term captures the function;
      the general class term is redundant/over-general.
    proposed_replacement_terms:
    - id: GO:0017040
      label: N-acylsphingosine amidohydrolase activity
    supported_by:
    - reference_id: PMID:15655246
      supporting_text: N-lauroylethanolamine hydrolyzing activity was observed with
        acid ceramidase
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:7744740
  qualifier: located_in
  review:
    summary: Direct observation that a minor portion of acid ceramidase is secreted
      as a monomeric protein.
    action: KEEP_AS_NON_CORE
    reason: Secreted acid ceramidase is a minor species; the mature functional enzyme
      acts in the lysosome. Keep extracellular localization as non-core.
    supported_by:
    - reference_id: PMID:7744740
      supporting_text: secreted into the medium as a monomeric 47-kDa protein, indicating
        that
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:12764132
  qualifier: located_in
  review:
    summary: Direct demonstration of lysosomal localization of acid ceramidase.
    action: ACCEPT
    reason: The lysosome is the core site of ASAH1 function; this direct-assay annotation
      establishes the physiologically relevant location.
    supported_by:
    - reference_id: PMID:12764132
      supporting_text: this reaction occurs in situ as well as in vitro
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IDA
  original_reference_id: PMID:12764132
  qualifier: located_in
  negated: true
  review:
    summary: Informative NOT annotation excluding early endosome localization.
    action: ACCEPT
    reason: A curated negative (NOT located_in early endosome) that usefully constrains
      ASAH1's localization to the lysosomal compartment; retain as-is.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:12764132
  qualifier: located_in
  negated: true
  review:
    summary: Informative NOT annotation excluding endoplasmic reticulum localization.
    action: ACCEPT
    reason: A curated negative (NOT located_in ER) that usefully constrains the mature
      enzyme's steady-state localization away from the ER; retain as-is.
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: IMP
  original_reference_id: PMID:10610716
  qualifier: enables
  review:
    summary: Mutant-phenotype evidence; Farber-causing variants (E138V, R254G, P362R)
      cause loss of ceramidase activity.
    action: ACCEPT
    reason: Direct genetic support for the core molecular function; disease variants
      abolishing acid ceramidase activity confirm the assigned function.
    supported_by:
    - reference_id: PMID:10610716
      supporting_text: 'Acid ceramidase (AC) is the lysosomal enzyme that degrades
        ceramide into '
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: IDA
  original_reference_id: PMID:12764132
  qualifier: enables
  review:
    summary: Direct assay of acid ceramidase (forward and reverse) activity on the
      recombinant human enzyme.
    action: ACCEPT
    reason: Direct experimental support for the core molecular function.
    supported_by:
    - reference_id: PMID:12764132
      supporting_text: this reaction occurs in situ as well as in vitro
- term:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  evidence_type: IDA
  original_reference_id: PMID:7744740
  qualifier: enables
  review:
    summary: Direct assay of acid ceramidase activity on enzyme purified from human
      urine (Km 149 uM, Vmax 136 nmol/mg/h with N-lauroylsphingosine).
    action: ACCEPT
    reason: Direct experimental support for the core molecular function on the natively
      purified enzyme.
    supported_by:
    - reference_id: PMID:7744740
      supporting_text: 'apparent Km of 149 microM and a Vmax of 136 nmol/mg/h using'
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:10610716
  qualifier: involved_in
  review:
    summary: Mutant-phenotype annotation to sphingosine biosynthesis (product formation).
    action: KEEP_AS_NON_CORE
    reason: Sphingosine is the direct product of ceramide hydrolysis; loss-of-function
      variants reduce sphingosine formation, but this is the product side of catabolism
      rather than a distinct biosynthetic role. Keep as non-core.
    supported_by:
    - reference_id: PMID:10610716
      supporting_text: 'Acid ceramidase (AC) is the lysosomal enzyme that degrades
        ceramide into '
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12764132
  qualifier: involved_in
  review:
    summary: Direct assay of the reverse (ceramide-synthesizing) activity of acid ceramidase.
    action: KEEP_AS_NON_CORE
    reason: The reverse ceramide synthase activity is genuine in vitro and in situ,
      but its physiological contribution to ceramide biosynthesis relative to dedicated
      ceramide synthases is uncertain; keep as non-core.
    supported_by:
    - reference_id: PMID:12764132
      supporting_text: purified enzyme was able to catalyze ceramide synthesis using
        [14C]lauric acid
- term:
    id: GO:0046514
    label: ceramide catabolic process
  evidence_type: IMP
  original_reference_id: PMID:10610716
  qualifier: involved_in
  review:
    summary: Mutant-phenotype annotation to ceramide catabolism; Farber variants abolish
      ceramide degradation.
    action: ACCEPT
    reason: Core biological process, supported by disease genetics (loss of ceramide
      degradation and ceramide accumulation in Farber disease).
    supported_by:
    - reference_id: PMID:10610716
      supporting_text: 'Acid ceramidase (AC) is the lysosomal enzyme that degrades
        ceramide into '
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798745
  qualifier: located_in
  review:
    summary: Reactome annotation placing ASAH1 in the extracellular region via neutrophil
      tertiary-granule exocytosis.
    action: KEEP_AS_NON_CORE
    reason: Reflects release of ASAH1 during neutrophil degranulation; a secretome/bystander
      localization, not the core lysosomal site of function. Keep as non-core.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: Reactome annotation placing ASAH1 in the extracellular region via ficolin-rich
      granule exocytosis.
    action: KEEP_AS_NON_CORE
    reason: Secretome/degranulation-associated localization, not the core lysosomal
      site of function. Keep as non-core.
- term:
    id: GO:1904724
    label: tertiary granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798745
  qualifier: located_in
  review:
    summary: Reactome annotation to the neutrophil tertiary granule lumen.
    action: KEEP_AS_NON_CORE
    reason: A neutrophil granule localization consistent with a lysosome-related secretory
      organelle, but not the core site of ASAH1's ceramidase function; keep as non-core.
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: Reactome annotation to the neutrophil ficolin-1-rich granule lumen.
    action: KEEP_AS_NON_CORE
    reason: A neutrophil granule localization (lysosome-related secretory organelle),
      not the core functional site; keep as non-core.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:25645918
  qualifier: located_in
  review:
    summary: Proteomic detection of ASAH1 among secreted paucimannosidic proteins from
      neutrophil azurophilic granules in infected sputum.
    action: KEEP_AS_NON_CORE
    reason: Extracellular/secretome detection during neutrophil activation; a bystander
      localization rather than the core lysosomal site of function. Keep as non-core.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of ASAH1 in prostatic-secretion urinary
      exosomes.
    action: KEEP_AS_NON_CORE
    reason: Large-scale exosome proteomics localization; reflects the fraction of ASAH1
      that is secreted/exosome-associated, not the core lysosomal functional site.
      Keep as non-core.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of ASAH1 in urinary exosomes.
    action: KEEP_AS_NON_CORE
    reason: Large-scale exosome proteomics localization; bystander/secretome detection,
      not the core lysosomal functional site. Keep as non-core.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1606602
  qualifier: located_in
  review:
    summary: Reactome annotation ('ASAH1 hydrolyzes ceramide') placing the enzyme in
      the lysosomal lumen.
    action: ACCEPT
    reason: The lysosomal lumen is the precise core location of this soluble luminal
      hydrolase and the site of its ceramide-catabolic reaction. Retain as core location.
    supported_by:
    - reference_id: PMID:29692406
      supporting_text: 'Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane
        ceramide into '
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9859104
  qualifier: located_in
  review:
    summary: Reactome (MITF-M-dependent ASAH1 expression) annotation to the lysosomal
      lumen.
    action: ACCEPT
    reason: Duplicate lysosomal-lumen localization; the lysosomal lumen is the core
      functional site of ASAH1. Retain.
    supported_by:
    - reference_id: PMID:29692406
      supporting_text: 'Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane
        ceramide into '
core_functions:
- description: Acid ceramidase is a soluble lysosomal amidohydrolase that hydrolyzes
    ceramide (N-acylsphingosine) into sphingosine and a free fatty acid at acidic pH,
    catalyzing the terminal, common step of sphingolipid/glycosphingolipid degradation.
    It acts as a heterodimer of autoproteolytically generated, disulfide-linked alpha
    and beta subunits (catalytic Cys143 nucleophile) and requires saposin D for activity
    on membrane ceramide.
  molecular_function:
    id: GO:0017040
    label: N-acylsphingosine amidohydrolase activity
  directly_involved_in:
  - id: GO:0046514
    label: ceramide catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:8955159
    supporting_text: hydrolyzes the sphingolipid ceramide into sphingosine and free
      fatty acid
  - reference_id: PMID:10610716
    supporting_text: 'Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide
      into '
  - reference_id: PMID:29692406
    supporting_text: 'Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane
      ceramide into '
proposed_new_terms: []
suggested_questions:
- question: What is the physiological (in vivo) significance of the reverse ceramide-synthase
    activity of ASAH1 relative to dedicated ceramide synthases (CerS1-6)?
- question: How much of the SMA-PME versus Farber disease phenotypic spectrum is explained
    by residual acid ceramidase activity versus tissue-specific substrate handling?
suggested_experiments:
- description: Tissue-specific conditional Asah1 knockouts (e.g. motor neuron vs skin)
    to dissect the SMA-PME versus Farber phenotypes.
- description: Quantify the in vivo contribution of ASAH1 reverse (ceramide synthase)
    activity using isotope-labeled sphingosine/fatty acid flux in cells with and without
    ASAH1.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/ASAH1/ASAH1-uniprot.txt
  title: UniProtKB entry Q13510 (ASAH1_HUMAN), acid ceramidase
  findings:
  - statement: Lysosomal ceramidase that hydrolyzes ceramide into sphingosine and
      free fatty acids at acidic pH; synthesized as a precursor autocatalytically cleaved
      into disulfide-linked alpha and beta subunits; requires saposin-D.
    supporting_text: Lysosomal ceramidase that hydrolyzes sphingolipid ceramides
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Canonical UniProt record for the reviewed gene; used for function,
      subunit processing, catalytic mechanism, localization, and disease.
- id: PMID:10610716
  title: 'The human acid ceramidase gene (ASAH): structure, chromosomal location,
    mutation analysis, and expression.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines AC as the lysosomal enzyme degrading ceramide to sphingosine
      and fatty acid; Farber variants abolish activity.
- id: PMID:11451951
  title: 'Human acid ceramidase: processing, glycosylation, and lysosomal targeting.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Precursor processing to heterodimer, M6P-dependent lysosomal targeting,
      very low secretion, glycosylation-site mutagenesis.
- id: PMID:12638942
  title: Mutation analysis of the acid ceramidase gene in Japanese patients with Farber
    disease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Farber variants reduce measured acid ceramidase activity to 2-37%
      of control.
- id: PMID:12764132
  title: The reverse activity of human acid ceramidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Characterizes forward hydrolysis and the reverse ceramide-synthase
      activity; lysosomal localization; excludes early endosome/ER.
- id: PMID:12815059
  title: Purification and characterization of recombinant, human acid ceramidase.
    Catalytic reactions and interactions with acid sphingomyelinase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Purified recombinant enzyme kinetics; reverse synthesis; functional
      association with acid sphingomyelinase.
- id: PMID:15655246
  title: Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase,
    a novel member of the choloylglycine hydrolase family with structural and functional
    similarity to acid ceramidase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes low N-acylethanolamine hydrolase activity of acid ceramidase
      and structural similarity to NAAA.
- id: PMID:17713573
  title: Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates
    calcium-induced differentiation of epidermal keratinocytes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: AC knockdown attenuates calcium-induced keratinocyte differentiation
      (non-core, tissue-specific role).
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale exosome proteomics; supports non-core secretome/exosome
      localization only.
- id: PMID:22261821
  title: Acid ceramidase (ASAH1) is a global regulator of steroidogenic capacity and
    adrenocortical gene expression.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: ASAH1 knockdown alters steroidogenic gene expression via Cer/SPH/S1P
      balance (non-core regulatory role).
- id: PMID:22703880
  title: Spinal muscular atrophy associated with progressive myoclonic epilepsy is
    caused by mutations in ASAH1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes ASAH1 as the SMA-PME gene; T42M retains ~32% activity.
- id: PMID:22927646
  title: Acid ceramidase (ASAH1) represses steroidogenic factor 1-dependent gene transcription
    in H295R human adrenocortical cells by binding to the receptor.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Isoform-2 nuclear ASAH1 binds NR5A1/SF-1 and represses transcription;
      basis for the 'protein binding' IPI (over-annotated bare term).
- 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: Exosome proteomics; supports non-core secretome/exosome localization
      only.
- id: PMID:25645918
  title: Human neutrophils secrete bioactive paucimannosidic proteins from azurophilic
    granules into pathogen-infected sputum.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Neutrophil secretome proteomics; supports non-core extracellular
      localization only.
- id: PMID:27026573
  title: 'ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a
    clinical, biochemical and molecular study.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Hypomorphic ASAH1 variant causing mild SMA; confirms ceramide-degradation
      function.
- id: PMID:27498570
  title: Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports the IC that acid hydrolases (including ASAH1) are active
      in the endolysosome lumen.
- id: PMID:29692406
  title: Structural basis for the activation of acid ceramidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Crystal structures of proenzyme and autocleaved forms; catalytic
      mechanism; saposin-D-facilitated membrane substrate delivery.
- id: PMID:7744740
  title: Purification, characterization, and biosynthesis of human acid ceramidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Native purification; alpha/beta subunits from a single precursor;
      kinetics; low secretion.
- id: PMID:8955159
  title: Molecular cloning and characterization of a full-length complementary DNA
    encoding human acid ceramidase. Identification Of the first molecular lesion causing
    Farber disease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding cloning paper; AC hydrolyzes ceramide to sphingosine and
      free fatty acid; first Farber lesion.
- id: Reactome:R-HSA-1606602
  title: ASAH1 hydrolyzes ceramide
  findings: []
- id: Reactome:R-HSA-6798745
  title: Exocytosis of tertiary granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9859104
  title: MITF-M-dependent ASAH1 expression
  findings: []