ASAH1 encodes acid ceramidase, a soluble lysosomal N-terminal nucleophile hydrolase that cleaves ceramide into sphingosine and a free fatty acid at acidic pH. A glycosylated precursor undergoes autocleavage into disulfide-linked alpha and beta subunits, exposing catalytic Cys143 at the beta-subunit N terminus. Mannose-6-phosphate-dependent trafficking delivers the enzyme to the endolysosomal system, where saposin D facilitates access to membrane ceramide. Acid ceramidase shapes cellular ceramide and sphingosine pools; substrate preferences depend on ceramide structure and assay conditions. Cellular studies also support glycosphingolipid deacylation when lysosomal glycosidases are deficient. Secreted and nuclear pools occur in particular settings, including an interaction with the nuclear receptor SF-1 in adrenocortical cells. Pathogenic ASAH1 variants cause a spectrum including Farber disease and spinal muscular atrophy with or without progressive myoclonic epilepsy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0017040 N-acylsphingosine amidohydrolase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the phylogenetically inferred acid-ceramidase activity as core. Reason: Direct human enzyme purification and expression establish ceramide hydrolysis. The preserved PAINT ancestral assertion agrees with this evidence. Q13510 in WITH/FROM is a human descendant supporting the inference, not circular evidence. Neither donor count nor pairwise similarity is used to evaluate the inference; the tree and alignment were not independently replayed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002005684 UNRESOLVED Exact PAINT node scope and MSA were not independently reconstructed. Human ASAH1 biochemistry corroborates the transferred function, which is distinct from verifying the ancestral placement. No target-specific evidence challenges the curator inference. 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: Retain the mapped extracellular pool as contextual localization. Reason: Human fibroblast biosynthesis experiments show secretion of a minor precursor pool. Amplified CHO expression instead secretes most recombinant enzyme, so low secretion is not universal. The SL-0243 mapping is compatible with these observations; the dominant physiological catalytic compartment remains lysosomal. Non-core does not mean that every secreted molecule is nonfunctional. Supporting Evidence: PMID:7744740 A minor portion of newly synthesized acid ceramidase was secreted into the medium as a monomeric 47-kDa protein |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain context-dependent nuclear localization. Reason: The combined mapping preserves mouse Q9WV54, its Ensembl protein and SL-0191. Independent human H295R experiments in PMID:22927646 report nuclear ASAH1. The studied constructs and endogenous signal were not mapped to modern splice product 2, so no isoform-specific claim follows. The exact mouse donor annotation chain was not reconstructed. Supporting Evidence: PMID:22927646 ASAH1 is localized in the nuclei of H295R adrenocortical cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain contextual cytoplasmic localization from the UniProt mapping. Reason: The SL-0086 source records a cytoplasmic pool in addition to the principal lysosomal location. This broad location is retained as non-core without assigning a signal-peptide-free splice product or claiming that the H295R experiment identified modern isoform 2. |
| 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 endosomes/lysosomes. |
| 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: Retain Rhea/EC-derived ceramidase activity as core. Reason: The preserved nine Rhea identifiers and EC:3.5.1.23 map ceramide amide hydrolysis, independently established with human ASAH1. Agreement with experimental rows corroborates the biochemical function; it is not a reason to discard the distinct electronic source assertion. 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: Retain secondary fatty-acid amide hydrolysis. Reason: PMID:15655246 explicitly reports N-lauroylethanolamine hydrolysis by acid ceramidase, in addition to its principal ceramidase activity. The InterPro mapping is compatible with this secondary substrate activity. The NAAA-focused title does not make the ASAH1 result a paralog error; relative physiological contributions are not established by the assay. 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... | MODIFY | Summary: Refine SF-1 binding to nuclear receptor binding. Reason: The cited study reports human ASAH1 association with NR5A1/SF-1 in H295R cells, tagged-protein assays and cell-free receptor binding in Fig. 3. The identified partner is a nuclear receptor, supporting GO:0016922 rather than a generic binding term. This refinement retains the original IPI source and does not identify an endogenous modern splice isoform. Receptor binding is contextual to the adrenocortical regulatory role. Proposed replacements: nuclear receptor binding Supporting Evidence: PMID:22927646 ASAH1 suppresses SF-1 activity by directly interacting with the receptor. |
| 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 sphingosine and fatty acid. |
| 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 sphingosine and fatty acid. |
| GO:0062098 regulation of programmed necrotic cell death | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain contextual regulated necrotic cell death regulation. Reason: The preserved mouse Q9WV54 annotation supports this contextual regulatory role, retained as non-core relative to lysosomal ceramide hydrolysis. The exact donor annotation chain was not reconstructed. PMID:10974027 provides related human-ASAH1/mouse-L929 evidence for protection from TNF-induced death, but its authors describe atypical apoptosis without cell swelling or membrane rupture. It therefore remains an additional contextual reference and is not attached as evidence for the exact programmed-necrotic-death class. |
| GO:0071356 cellular response to tumor necrosis factor | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain contextual cellular response to TNF regulation. Reason: Human ASAH1 overexpression protects mouse L929 cells from TNF-induced death, supporting a contextual cellular response to TNF. This corroborates the retained mouse Q9WV54 transfer while leaving its original source chain intact. The experimental setting does not establish a general human-tissue response or a particular RIPK/MLKL mechanism. Retain as non-core relative to lysosomal ceramide hydrolysis. Supporting Evidence: PMID:10974027 overexpression of AC in murine fibrosarcoma L929 cells protects against TNF-induced cell death. |
| 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 hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid. |
| GO:0036021 endolysosome lumen | IC PMID:27498570 Endolysosomes Are the Principal Intracellular Sites of Acid ... | ACCEPT | Summary: Retain the curator inference of activity in the endolysosome lumen. Reason: ASAH1 is a luminal acid hydrolase, and the cited compartment study supports the inference that acid hydrolases act in endolysosomes. It measured compartment-class hydrolase activity, not a new ASAH1-specific experiment. The original IC object and the restored object carrying GO:0036019 in WITH/FROM remain separately preserved. 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: Retain activity measured in the human acid-ceramidase processing study. Reason: The study assayed catalytic activity alongside human enzyme glycosylation and maturation. Its abstract reports that removal of glycosylation sites 1, 3 and 5 impairs heterodimer formation, while removal of sites 2, 4 and 6 leaves processing and activity unaffected. The complete mutant-specific activity series was not read here; the curated activity is retained with independent human biochemical corroboration. Supporting Evidence: PMID:11451951 The elimination of sites 2, 4, and 6 has no influence on lysosomal processing or enzymatic activity of recombinant ceramidase. |
| GO:0030149 sphingolipid catabolic process | IDA PMID:11451951 Human acid ceramidase: processing, glycosylation, and lysoso... | ACCEPT | Summary: Retain ASAH1 participation in sphingolipid catabolism. Reason: ASAH1 itself performs ceramide amide hydrolysis, a degradation step in sphingolipid metabolism. The original processing-study IDA is retained; the independent human cloning/activity paper corroborates the catalytic assignment. The specific ceramide-catabolic core is used in the synthesis. Supporting Evidence: PMID:8955159 hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid. |
| GO:0006685 sphingomyelin catabolic process | IDA PMID:11451951 Human acid ceramidase: processing, glycosylation, and lysoso... | KEEP AS NON CORE | Summary: Retain downstream enzymatic participation in sphingomyelin breakdown as non-core. Reason: ASAH1 cleaves the ceramide produced after sphingomyelinase acts. Performing a later catalytic step is still participation in the pathway; this does not imply direct sphingomyelin hydrolysis by ASAH1. The original PMID:11451951 IDA is retained, with PMID:12815059 independently characterizing recombinant human ceramidase and its functional association with acid sphingomyelinase. Supporting Evidence: PMID:12815059 had an acidic pH optimum (4.5), and followed normal Michaelis-Menten kinetics using 14C- and BODIPY-labeled C12-ceramide as substrates. |
| 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 Expression of mutated acid ceramidase cDNA in COS-1 cells showed acid ceramidase activity decreased to 35%, 2% and 37% of control value |
| GO:0017040 N-acylsphingosine amidohydrolase activity | EXP PMID:15655246 Molecular characterization of N-acylethanolamine-hydrolyzing... | ACCEPT | Summary: Retain the acid-ceramidase activity in the comparative NAAA study. Reason: The comparative study includes human acid-ceramidase expression and ceramide-substrate controls alongside N-lauroylethanolamine assays. Selected original Methods/Results were independently read through an indexed transcription of the author paper; the article link and exact reading scope are recorded in the reference assessment and notes. The normal local record is abstract-only and emphasizes the secondary NAE activity. The attached PMID:8955159 passage independently corroborates ceramide hydrolysis; it is not represented as a quote from PMID:15655246. Supporting Evidence: PMID:8955159 hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid. |
| 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 by normal cDNA. |
| 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 Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | EXP PMID:29692406 Structural basis for the activation of acid ceramidase. | ACCEPT | Summary: Retain directly assayed human acid-ceramidase activity. Reason: The structural study includes active human enzyme and ceramide-liposome assays, with catalytic and membrane-interaction mutants. Inactive proenzyme structures came from naked mole rat and minke whale. Ceramide positioning was modeled rather than observed in a substrate-bound crystal structure. Saposin D enhances membrane-substrate activity; the experiments do not establish an obligatory stable enzyme-saposin complex. Supporting Evidence: PMID:29692406 Autocleavage triggers a conformational change exposing a hydrophobic channel leading to the active site. PMID:41570988 However, saposin D was not included in our in vitro assay. |
| 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: Retain contextual regulated necrotic cell death regulation. Reason: The preserved mouse Q9WV54 annotation supports this contextual regulatory role, retained as non-core relative to lysosomal ceramide hydrolysis. The exact donor annotation chain was not reconstructed. PMID:10974027 provides related human-ASAH1/mouse-L929 evidence for protection from TNF-induced death, but its authors describe atypical apoptosis without cell swelling or membrane rupture. It therefore remains an additional contextual reference and is not attached as evidence for the exact programmed-necrotic-death class. |
| GO:0071356 cellular response to tumor necrosis factor | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain contextual cellular response to TNF regulation. Reason: Human ASAH1 overexpression protects mouse L929 cells from TNF-induced death, supporting a contextual cellular response to TNF. This corroborates the retained mouse Q9WV54 transfer while leaving its original source chain intact. The experimental setting does not establish a general human-tissue response or a particular RIPK/MLKL mechanism. Retain as non-core relative to lysosomal ceramide hydrolysis. Supporting Evidence: PMID:10974027 overexpression of AC in murine fibrosarcoma L929 cells protects against TNF-induced cell death. |
| GO:0030216 keratinocyte differentiation | IMP PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | KEEP AS NON CORE | Summary: Retain the calcium-induced human keratinocyte differentiation context. Reason: PMID:17713573 reports that acid-ceramidase knockdown attenuates calcium-induced keratin 1 and involucrin expression. This supports the existing non-core regulatory process. In the separate 2026 study, several differentiation markers were comparable after 14 days of differentiation in knockout and control keratinocytes. Different perturbations and culture conditions limit generalization; that result does not by itself refute the earlier study. Supporting Evidence: PMID:17713573 its knockdown attenuated the Ca2+(o)-induced expression of keratin 1 and involucrin in HEKs. PMID:41570988 These results suggest that the differentiation of ASAH1 KO keratinocytes proceeds normally. |
| GO:0050810 regulation of steroid biosynthetic process | IMP PMID:22261821 Acid ceramidase (ASAH1) is a global regulator of steroidogen... | KEEP AS NON CORE | Summary: Retain regulation of steroidogenic capacity in human adrenocortical cells. Reason: ASAH1 silencing in H295R cells changes steroidogenic gene expression and increases basal and cAMP-dependent steroid secretion. The study supports a context-specific regulatory process rather than direct catalysis of a steroid-synthesis reaction. No modern isoform-2 assignment is made; receptor-binding evidence comes from the separate PMID:22927646 study. Supporting Evidence: PMID:22261821 ASAH1 silencing increased basal and cAMP-dependent cortisol and dehydroepiandrosterone secretion |
| GO:0005576 extracellular region | IDA PMID:11451951 Human acid ceramidase: processing, glycosylation, and lysoso... | KEEP AS NON CORE | Summary: Retain low-level secretion observed in the specified fibroblast/COS setting. Reason: The source reports exceptionally low secretion in fibroblasts and acid-ceramidase-cDNA-transfected COS cells and tests M6P-dependent trafficking. This is an experimental context, not a universal secretion limit: other overexpression systems release much more enzyme. The extracellular pool is retained as non-core. Supporting Evidence: PMID:11451951 Secretion of hAC by either fibroblasts or acid ceramidase cDNA-transfected COS cells is extraordinarily low. |
| 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 had an acidic pH optimum (4.5), and followed normal Michaelis-Menten kinetics using 14C- and BODIPY-labeled C12-ceramide as substrates. |
| 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 had an acidic pH optimum (4.5), and followed normal Michaelis-Menten kinetics using 14C- and BODIPY-labeled C12-ceramide as substrates. |
| 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 14C-labeled C12 fatty acid and sphingosine as substrates. |
| 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 had an acidic pH optimum (4.5), and followed normal Michaelis-Menten kinetics using 14C- and 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... | MODIFY | Summary: Refine the broad linear-amide hydrolase term to fatty acid amide hydrolase activity. Reason: The cited comparative paper assays N-lauroylethanolamine hydrolysis by human acid ceramidase. GO:0017064 specifically describes fatty-acid amide hydrolysis and captures this secondary activity. Replacing the broad class only with ceramidase would omit the distinct substrate tested. Broadness alone is not evidence that the original amide-hydrolysis claim is incorrect. Proposed replacements: fatty acid amide hydrolase 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: Retain the secreted precursor observed in human fibroblasts. Reason: Metabolically labeled skin fibroblasts secreted a minor monomeric precursor pool, while mature heterodimer generation was associated with endosomal/lysosomal compartments. The source supports contextual extracellular location, without proving that secreted enzyme is always inactive or that its abundance is low in every expression system. Supporting Evidence: PMID:7744740 A minor portion of newly synthesized acid ceramidase was secreted into the medium as a monomeric 47-kDa protein |
| GO:0005764 lysosome | IDA PMID:12764132 The reverse activity of human acid ceramidase. | ACCEPT | Summary: Retain lysosomal localization in human fibroblasts. Reason: ASAH1 colocalizes with LAMP2 in normal human skin fibroblasts, supporting its principal lysosomal location. The independent reviewer read the indexed original localization Results and Fig. 7 caption; the original article URL is recorded in the reference assessment and notes. The separate M6P-targeting study supplies the attached local-cache quotation. Neither the figure image nor the complete article was read, and the local PMID:12764132 record remains abstract-only. Supporting Evidence: PMID:11451951 processed to the mature, heterodimeric enzyme (40 + 13 kDa) in the endosomes/lysosomes. |
| GO:0005769 early endosome | IDA NOT PMID:12764132 The reverse activity of human acid ceramidase. | ACCEPT | Summary: Retain the condition-specific NOT localization assertion. Reason: The indexed original localization Results and Fig. 7 caption report little or no colocalization with EEA1 in normal human skin fibroblasts under the tested growth conditions. Retain the curated NOT flag for early endosomes within that assay context. This steady-state observation does not exclude transit during biosynthesis or trafficking. The article URL and selected-text reading scope are recorded in the reference assessment and notes; figure pixels were not inspected. |
| GO:0005783 endoplasmic reticulum | IDA NOT PMID:12764132 The reverse activity of human acid ceramidase. | ACCEPT | Summary: Retain the condition-specific NOT localization assertion. Reason: The indexed original localization Results and Fig. 7 caption report little or no colocalization with BiP in normal human skin fibroblasts under the tested growth conditions. Retain the curated NOT flag for the endoplasmic reticulum within that assay context. This steady-state observation does not exclude transit during biosynthesis or trafficking. The article URL and selected-text reading scope are recorded in the reference assessment and notes; figure pixels were not inspected. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IMP PMID:10610716 The human acid ceramidase gene (ASAH): structure, chromosoma... | ACCEPT | Summary: Retain mutant-phenotype evidence for acid-ceramidase activity. Reason: The cited human gene study expressed E138V, R254G and P362R variants and observed markedly reduced enzymatic activity despite similar protein expression. This supports the enzyme assignment; the abstract does not establish that every variant abolishes activity completely. Supporting Evidence: PMID:10610716 their enzymatic activity was markedly reduced, confirming their authenticity. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IDA PMID:12764132 The reverse activity of human acid ceramidase. | ACCEPT | Summary: Retain acid-ceramidase activity in the forward/reverse reaction study. Reason: The source explicitly reports ceramide hydrolysis by the purified recombinant human enzyme while characterizing the reverse reaction. The accepted ceramidase term names the forward hydrolytic activity; reverse synthesis remains a separate contextual process assertion. Supporting Evidence: PMID:12764132 In addition to ceramide hydrolysis, the purified enzyme was able to catalyze ceramide synthesis |
| 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 The purified enzyme had an apparent Km of 149 microM and a Vmax of 136 nmol/mg/h using N-lauroylsphingosine as substrate. |
| 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 sphingosine and fatty acid. |
| 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 provide evidence that this reaction occurs in situ as well as in vitro. |
| GO:0046514 ceramide catabolic process | IMP PMID:10610716 The human acid ceramidase gene (ASAH): structure, chromosoma... | ACCEPT | Summary: Retain the core ceramide-catabolic process. Reason: ASAH1 directly hydrolyzes ceramide. The patient-variant study reports markedly reduced enzyme activity, consistent with the established ceramide-storage phenotype. This is a catalytic participant, not merely a molecule required as another enzyme's substrate. Complete abolition of every variant's activity is not asserted. Supporting Evidence: PMID:10610716 Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into sphingosine and fatty acid. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798745 | KEEP AS NON CORE | Summary: Retain the modeled extracellular region location as non-core. Reason: The independently inspected Reactome event R-HSA-6798745 connects input set R-HSA-6800171 with extracellular output set R-HSA-6806432; both processed human Q13510 chains are explicit members. This checks the TAS source hierarchy, not independent replication of the underlying proteomics. The location is retained as contextual cargo localization without inferring that ASAH1 catalyzes exocytosis or is necessarily a nonfunctional bystander. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: Retain the modeled extracellular region location as non-core. Reason: The independently inspected Reactome event R-HSA-6800434 connects input set R-HSA-6800431 with extracellular output set R-HSA-6806481; both processed human Q13510 chains are explicit members. This checks the TAS source hierarchy, not independent replication of the underlying proteomics. The location is retained as contextual cargo localization without inferring that ASAH1 catalyzes exocytosis or is necessarily a nonfunctional bystander. |
| GO:1904724 tertiary granule lumen | TAS Reactome:R-HSA-6798745 | KEEP AS NON CORE | Summary: Retain the modeled tertiary granule lumen location as non-core. Reason: The independently inspected Reactome event R-HSA-6798745 connects input set R-HSA-6800171 with extracellular output set R-HSA-6806432; both processed human Q13510 chains are explicit members. This checks the TAS source hierarchy, not independent replication of the underlying proteomics. The location is retained as contextual cargo localization without inferring that ASAH1 catalyzes exocytosis or is necessarily a nonfunctional bystander. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: Retain the modeled ficolin-1-rich granule lumen location as non-core. Reason: The independently inspected Reactome event R-HSA-6800434 connects input set R-HSA-6800431 with extracellular output set R-HSA-6806481; both processed human Q13510 chains are explicit members. This checks the TAS source hierarchy, not independent replication of the underlying proteomics. The location is retained as contextual cargo localization without inferring that ASAH1 catalyzes exocytosis or is necessarily a nonfunctional bystander. |
| GO:0005576 extracellular region | IDA PMID:25645918 Human neutrophils secrete bioactive paucimannosidic proteins... | KEEP AS NON CORE | Summary: Retain the curated extracellular location with target-specific limits. Reason: Human ASAH1 secretion is independently established by enzyme biosynthesis studies. The exact ASAH1 glycopeptide or target row in the cited neutrophil study was not inspected, so its sputum/azurophilic assignment is not claimed as independently verified. Retain the broadly corroborated extracellular localization as non-core and defer to the experimental curator; do not infer a bystander function. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | Summary: Detected in an extracellular-vesicle proteome, but the detection does not establish that this protein is an EV constituent. Reason: Lysosomal lumenal acid ceramidase; UniProt notes secretion is extremely low. Secreted or lumenal protein (UniProt). MISEV2018 (PMID:30637094) category 5 allows such proteins onto EVs through specific or promiscuous (proteoglycan, lipid) receptors on the EV surface, but asks that their identification be backed by evidence of that association. A bulk EV proteome cannot separate surface binding from co-isolation, and this protein's annotations record no experimental proteoglycan, heparin or lipid binding, and its own review keeps no experimental cell-surface or plasma-membrane pool. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: KEEP_AS_NON_CORE.) |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: Detected in an extracellular-vesicle proteome, but the detection does not establish that this protein is an EV constituent. Reason: Lysosomal lumenal acid ceramidase; UniProt notes secretion is extremely low. Secreted or lumenal protein (UniProt). MISEV2018 (PMID:30637094) category 5 allows such proteins onto EVs through specific or promiscuous (proteoglycan, lipid) receptors on the EV surface, but asks that their identification be backed by evidence of that association. A bulk EV proteome cannot separate surface binding from co-isolation, and this protein's annotations record no experimental proteoglycan, heparin or lipid binding, and its own review keeps no experimental cell-surface or plasma-membrane pool. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: 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 sphingosine |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9859104 | ACCEPT | Summary: Retain the lysosomal-lumen product location recorded in the expression event. Reason: R-HSA-9859104 concerns MITF-M-dependent ASAH1 expression. The resulting enzyme's lysosomal-lumen location agrees with independent trafficking and enzyme evidence; it does not place transcription itself in that compartment. Retain the distinct TAS source assertion as core localization. Supporting Evidence: PMID:29692406 Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into sphingosine |
| GO:0036021 endolysosome lumen | IC PMID:27498570 Endolysosomes Are the Principal Intracellular Sites of Acid ... | ACCEPT | Summary: Retain the curator inference of activity in the endolysosome lumen. Reason: ASAH1 is a luminal acid hydrolase, and the cited compartment study supports the inference that acid hydrolases act in endolysosomes. It measured compartment-class hydrolase activity, not a new ASAH1-specific experiment. The original IC object and the restored object carrying GO:0036019 in WITH/FROM remain separately preserved. Supporting Evidence: PMID:27498570 endolysosomes are the principal sites of intracellular acid hydrolase activity |
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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?
Q: Under which lysosomal glycosidase-deficiency conditions should ASAH1-mediated glycosphingolipid deacylation be represented as a separate GO process annotation? PMID:26898341 supports an alternative cellular route; term ancestry, overlap with existing annotations and the appropriate disease-context scope need assessment before proposing a new process.
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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