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).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0017040 N-acylsphingosine amidohydrolase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred acid ceramidase (N-acylsphingosine amidohydrolase) activity. This is the correct, well-supported core molecular function of ASAH1. 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. Supporting Evidence: PMID:8955159 hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic subcellular-location mapping to the extracellular region, reflecting the low-level secretion of ASAH1. 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. Supporting Evidence: PMID:7744740 secreted into the medium as a monomeric 47-kDa protein, indicating that |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation (transferred from the mouse ortholog Q9WV54) placing ASAH1 in the nucleus. 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. Supporting Evidence: PMID:22927646 ASAH1 is localized in the nuclei of H295R adrenocortical cells and that cyclic |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic subcellular-location mapping to the cytoplasm. 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. |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation to the lysosome, the core site of ASAH1 function. Reason: ASAH1 is a soluble lysosomal hydrolase; lysosomal localization is directly demonstrated (IDA PMID:12764132) and is the physiological site of ceramide catabolism. Supporting Evidence: PMID:11451951 processed to the mature, heterodimeric enzyme (40 + 13 kDa) in the |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO electronic annotation to the broad process of fatty acid metabolism, reflecting that free fatty acid is a product of ceramide hydrolysis. 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. Supporting Evidence: PMID:8955159 hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (RHEA/EC 3.5.1.23) annotation of the acid ceramidase activity. Reason: Correct core molecular function, redundant with and consistent with the IBA and experimental annotations of the same term. Supporting Evidence: PMID:8955159 hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid |
| GO:0017064 fatty acid amide hydrolase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO electronic annotation of a fatty acid amide hydrolase activity. 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. Supporting Evidence: PMID:15655246 N-lauroylethanolamine hydrolyzing activity was observed with acid ceramidase |
| GO:0005515 protein binding | IPI PMID:22927646 Acid ceramidase (ASAH1) represses steroidogenic factor 1-dep... | MARK AS OVER ANNOTATED | Summary: IntAct protein-binding annotation capturing the interaction of ASAH1 (isoform 2) with the nuclear receptor NR5A1/SF-1. 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. Supporting Evidence: PMID:22927646 ASAH1 suppresses SF-1 activity by directly interacting |
| GO:0046512 sphingosine biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (transferred from mouse ortholog) to sphingosine biosynthesis, reflecting that sphingosine is the direct product of ceramide hydrolysis. 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. Supporting Evidence: PMID:10610716 Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into |
| GO:0046514 ceramide catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic annotation (transferred from mouse ortholog) to ceramide catabolism, the core biological process of ASAH1. 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). Supporting Evidence: PMID:10610716 Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into |
| GO:0062098 regulation of programmed necrotic cell death | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (from mouse ortholog Q9WV54) linking ASAH1 to regulation of programmed necrotic cell death. 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. |
| GO:0071356 cellular response to tumor necrosis factor | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (from mouse ortholog) linking ASAH1 to the cellular response to TNF. 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. |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-based electronic annotation to the general process of sphingolipid metabolism. 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. Supporting Evidence: PMID:8955159 Ceramide is an essential component of all sphingolipids |
| GO:0036021 endolysosome lumen | IC PMID:27498570 Endolysosomes Are the Principal Intracellular Sites of Acid ... | ACCEPT | 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. 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. Supporting Evidence: PMID:27498570 endolysosomes are the principal sites of intracellular acid hydrolase activity |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IDA PMID:11451951 Human acid ceramidase: processing, glycosylation, and lysoso... | ACCEPT | Summary: Direct assay of acid ceramidase activity on recombinant/mutant human enzyme (glycosylation/processing study). 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. Supporting Evidence: PMID:11451951 processed to the mature, heterodimeric enzyme (40 + 13 kDa) in the |
| GO:0030149 sphingolipid catabolic process | IDA PMID:11451951 Human acid ceramidase: processing, glycosylation, and lysoso... | ACCEPT | Summary: Direct-assay annotation placing ASAH1 in sphingolipid catabolism. 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. Supporting Evidence: PMID:8955159 Ceramide is an essential component of all sphingolipids |
| GO:0006685 sphingomyelin catabolic process | IDA PMID:11451951 Human acid ceramidase: processing, glycosylation, and lysoso... | KEEP AS NON CORE | Summary: Direct-assay annotation to sphingomyelin catabolism. 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. Supporting Evidence: PMID:12815059 media from the overexpressing hamster cells had increased acid |
| GO:0017040 N-acylsphingosine amidohydrolase activity | EXP PMID:12638942 Mutation analysis of the acid ceramidase gene in Japanese pa... | ACCEPT | Summary: Acid ceramidase activity assayed in Farber disease patient mutation analysis (COS-1 expression of mutant cDNAs). 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. Supporting Evidence: PMID:12638942 accumulation of ceramide in tissues due to acid ceramidase deficiency |
| GO:0017040 N-acylsphingosine amidohydrolase activity | EXP PMID:15655246 Molecular characterization of N-acylethanolamine-hydrolyzing... | ACCEPT | Summary: Experimental characterization of acid ceramidase activity alongside the related NAAA enzyme. 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. Supporting Evidence: PMID:15655246 N-lauroylethanolamine hydrolyzing activity was observed with acid ceramidase |
| GO:0017040 N-acylsphingosine amidohydrolase activity | EXP PMID:22703880 Spinal muscular atrophy associated with progressive myocloni... | ACCEPT | Summary: Acid ceramidase activity assayed for the SMA-PME T42M variant. 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. Supporting Evidence: PMID:22703880 acid-ceramidase activity was only 32% of that generated |
| GO:0017040 N-acylsphingosine amidohydrolase activity | EXP PMID:27026573 ASAH1 variant causing a mild SMA phenotype with no myoclonic... | ACCEPT | Summary: Acid ceramidase activity assayed for a mild SMA (T42A) ASAH1 variant. Reason: Direct experimental support for the core molecular function; biochemical study of a hypomorphic ASAH1 variant confirms reduced acid ceramidase (ceramide degradation) activity. Supporting Evidence: PMID:27026573 ASAH1 gene encodes for acid ceramidase that is involved in the degradation of |
| GO:0017040 N-acylsphingosine amidohydrolase activity | EXP PMID:29692406 Structural basis for the activation of acid ceramidase. | ACCEPT | Summary: Structure-function study of acid ceramidase activation, including catalytic assays. 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. Supporting Evidence: PMID:29692406 Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into |
| GO:0017040 N-acylsphingosine amidohydrolase activity | EXP PMID:8955159 Molecular cloning and characterization of a full-length comp... | ACCEPT | Summary: Experimental characterization of cloned human acid ceramidase; transient expression increased AC activity ~10-fold. Reason: Direct experimental support for the core molecular function; the founding molecular cloning paper demonstrates ceramide-hydrolyzing activity of the expressed human enzyme. Supporting Evidence: PMID:8955159 hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid |
| GO:0062098 regulation of programmed necrotic cell death | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity annotation (from mouse ortholog Q9WV54) to regulation of programmed necrotic cell death. 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. |
| GO:0071356 cellular response to tumor necrosis factor | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity annotation (from mouse ortholog) to the cellular response to TNF. 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. |
| GO:0030216 keratinocyte differentiation | IMP PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | KEEP AS NON CORE | Summary: Knockdown study showing acid ceramidase (with alkaline ceramidase haCER1) mediates calcium-induced differentiation of human epidermal keratinocytes. 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. Supporting Evidence: PMID:17713573 keratin 1 and involucrin in HEKs. In addition, the acid ceramidase (AC) was also |
| GO:0050810 regulation of steroid biosynthetic process | IMP PMID:22261821 Acid ceramidase (ASAH1) is a global regulator of steroidogen... | KEEP AS NON CORE | Summary: shRNA knockdown in H295R adrenocortical cells shows ASAH1 regulates steroidogenic capacity and adrenocortical gene expression. 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. Supporting Evidence: PMID:22261821 catalyzing the hydrolysis of Cer into SPH |
| GO:0005576 extracellular region | IDA PMID:11451951 Human acid ceramidase: processing, glycosylation, and lysoso... | KEEP AS NON CORE | Summary: Direct observation of low-level secreted acid ceramidase. 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. Supporting Evidence: PMID:11451951 Secretion of hAC by either fibroblasts or acid ceramidase |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IDA PMID:12815059 Purification and characterization of recombinant, human acid... | ACCEPT | Summary: Direct assay of acid ceramidase activity on purified recombinant human enzyme (Michaelis-Menten kinetics with C12-ceramide). Reason: Direct experimental support for the core molecular function on the purified recombinant enzyme. Supporting Evidence: PMID:12815059 The purified enzyme also catalyzed ceramide synthesis in vitro using |
| GO:0046512 sphingosine biosynthetic process | IDA PMID:12815059 Purification and characterization of recombinant, human acid... | KEEP AS NON CORE | Summary: Direct-assay annotation to sphingosine biosynthesis (sphingosine is the product of ceramide hydrolysis). 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. Supporting Evidence: PMID:12815059 The purified enzyme also catalyzed ceramide synthesis in vitro using |
| GO:0046513 ceramide biosynthetic process | IDA PMID:12815059 Purification and characterization of recombinant, human acid... | KEEP AS NON CORE | Summary: Direct assay showing the purified enzyme also catalyzes the reverse (ceramide synthase) reaction in vitro. 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. Supporting Evidence: PMID:12815059 The purified enzyme also catalyzed ceramide synthesis in vitro using |
| GO:0046514 ceramide catabolic process | IDA PMID:12815059 Purification and characterization of recombinant, human acid... | ACCEPT | Summary: Direct-assay annotation to ceramide catabolism, the core process of ASAH1. Reason: Core biological process, directly supported by the biochemical demonstration of ceramide hydrolysis by the purified human enzyme. Supporting Evidence: PMID:12815059 BODIPY-labeled C12-ceramide as substrates |
| GO:0016811 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides | IDA PMID:15655246 Molecular characterization of N-acylethanolamine-hydrolyzing... | MARK AS OVER ANNOTATED | Summary: Direct-assay annotation to the general amidohydrolase class term. 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 replacements: N-acylsphingosine amidohydrolase activity Supporting Evidence: PMID:15655246 N-lauroylethanolamine hydrolyzing activity was observed with acid ceramidase |
| GO:0005576 extracellular region | IDA PMID:7744740 Purification, characterization, and biosynthesis of human ac... | KEEP AS NON CORE | Summary: Direct observation that a minor portion of acid ceramidase is secreted as a monomeric protein. Reason: Secreted acid ceramidase is a minor species; the mature functional enzyme acts in the lysosome. Keep extracellular localization as non-core. Supporting Evidence: PMID:7744740 secreted into the medium as a monomeric 47-kDa protein, indicating that |
| GO:0005764 lysosome | IDA PMID:12764132 The reverse activity of human acid ceramidase. | ACCEPT | Summary: Direct demonstration of lysosomal localization of acid ceramidase. Reason: The lysosome is the core site of ASAH1 function; this direct-assay annotation establishes the physiologically relevant location. Supporting Evidence: PMID:12764132 this reaction occurs in situ as well as in vitro |
| GO:0005769 early endosome | IDA NOT PMID:12764132 The reverse activity of human acid ceramidase. | ACCEPT | Summary: Informative NOT annotation excluding early endosome localization. Reason: A curated negative (NOT located_in early endosome) that usefully constrains ASAH1's localization to the lysosomal compartment; retain as-is. |
| GO:0005783 endoplasmic reticulum | IDA NOT PMID:12764132 The reverse activity of human acid ceramidase. | ACCEPT | Summary: Informative NOT annotation excluding endoplasmic reticulum localization. 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. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IMP PMID:10610716 The human acid ceramidase gene (ASAH): structure, chromosoma... | ACCEPT | Summary: Mutant-phenotype evidence; Farber-causing variants (E138V, R254G, P362R) cause loss of ceramidase activity. Reason: Direct genetic support for the core molecular function; disease variants abolishing acid ceramidase activity confirm the assigned function. Supporting Evidence: PMID:10610716 Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IDA PMID:12764132 The reverse activity of human acid ceramidase. | ACCEPT | Summary: Direct assay of acid ceramidase (forward and reverse) activity on the recombinant human enzyme. Reason: Direct experimental support for the core molecular function. Supporting Evidence: PMID:12764132 this reaction occurs in situ as well as in vitro |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IDA PMID:7744740 Purification, characterization, and biosynthesis of human ac... | ACCEPT | Summary: Direct assay of acid ceramidase activity on enzyme purified from human urine (Km 149 uM, Vmax 136 nmol/mg/h with N-lauroylsphingosine). Reason: Direct experimental support for the core molecular function on the natively purified enzyme. Supporting Evidence: PMID:7744740 apparent Km of 149 microM and a Vmax of 136 nmol/mg/h using |
| GO:0046512 sphingosine biosynthetic process | IMP PMID:10610716 The human acid ceramidase gene (ASAH): structure, chromosoma... | KEEP AS NON CORE | Summary: Mutant-phenotype annotation to sphingosine biosynthesis (product formation). 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. Supporting Evidence: PMID:10610716 Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into |
| GO:0046513 ceramide biosynthetic process | IDA PMID:12764132 The reverse activity of human acid ceramidase. | KEEP AS NON CORE | Summary: Direct assay of the reverse (ceramide-synthesizing) activity of acid ceramidase. 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. Supporting Evidence: PMID:12764132 purified enzyme was able to catalyze ceramide synthesis using [14C]lauric acid |
| GO:0046514 ceramide catabolic process | IMP PMID:10610716 The human acid ceramidase gene (ASAH): structure, chromosoma... | ACCEPT | Summary: Mutant-phenotype annotation to ceramide catabolism; Farber variants abolish ceramide degradation. Reason: Core biological process, supported by disease genetics (loss of ceramide degradation and ceramide accumulation in Farber disease). Supporting Evidence: PMID:10610716 Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798745 | KEEP AS NON CORE | Summary: Reactome annotation placing ASAH1 in the extracellular region via neutrophil tertiary-granule exocytosis. Reason: Reflects release of ASAH1 during neutrophil degranulation; a secretome/bystander localization, not the core lysosomal site of function. Keep as non-core. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: Reactome annotation placing ASAH1 in the extracellular region via ficolin-rich granule exocytosis. Reason: Secretome/degranulation-associated localization, not the core lysosomal site of function. Keep as non-core. |
| GO:1904724 tertiary granule lumen | TAS Reactome:R-HSA-6798745 | KEEP AS NON CORE | Summary: Reactome annotation to the neutrophil tertiary granule lumen. 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. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: Reactome annotation to the neutrophil ficolin-1-rich granule lumen. Reason: A neutrophil granule localization (lysosome-related secretory organelle), not the core functional site; keep as non-core. |
| GO:0005576 extracellular region | IDA PMID:25645918 Human neutrophils secrete bioactive paucimannosidic proteins... | KEEP AS NON CORE | Summary: Proteomic detection of ASAH1 among secreted paucimannosidic proteins from neutrophil azurophilic granules in infected sputum. Reason: Extracellular/secretome detection during neutrophil activation; a bystander localization rather than the core lysosomal site of function. Keep as non-core. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of ASAH1 in prostatic-secretion urinary exosomes. 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. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of ASAH1 in urinary exosomes. Reason: Large-scale exosome proteomics localization; bystander/secretome detection, not the core lysosomal functional site. Keep as non-core. |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1606602 | ACCEPT | Summary: Reactome annotation ('ASAH1 hydrolyzes ceramide') placing the enzyme in the lysosomal lumen. 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. Supporting Evidence: PMID:29692406 Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9859104 | ACCEPT | Summary: Reactome (MITF-M-dependent ASAH1 expression) annotation to the lysosomal lumen. Reason: Duplicate lysosomal-lumen localization; the lysosomal lumen is the core functional site of ASAH1. Retain. Supporting Evidence: PMID:29692406 Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into |
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Download this section (compressed HTML)Q: What is the physiological (in vivo) significance of the reverse ceramide-synthase activity of ASAH1 relative to dedicated ceramide synthases (CerS1-6)?
Q: How much of the SMA-PME versus Farber disease phenotypic spectrum is explained by residual acid ceramidase activity versus tissue-specific substrate handling?
Experiment: Tissue-specific conditional Asah1 knockouts (e.g. motor neuron vs skin) to dissect the SMA-PME versus Farber phenotypes.
Experiment: Quantify the in vivo contribution of ASAH1 reverse (ceramide synthase) activity using isotope-labeled sphingosine/fatty acid flux in cells with and without ASAH1.
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