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FUNCTION Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH (PubMed:10610716, PubMed:11451951, PubMed:15655246, PubMed:26898341, PubMed:36752535, PubMed:7744740, PubMed:7852294). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:10610716). Has a higher catalytic efficiency towards C12-ceramides versus other ceramides (PubMed:15655246, PubMed:7744740). Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine (PubMed:12764132, PubMed:12815059). For the reverse synthetic reaction, the natural sphingosine D-erythro isomer is more efficiently utilized as a substrate compared to D-erythro-dihydrosphingosine and D-erythro-phytosphingosine, while the fatty acids with chain lengths of 12 or 14 carbons are the most efficiently used (PubMed:12764132). Also has an N-acylethanolamine hydrolase activity (PubMed:15655246). By regulating the levels of ceramides, sphingosine and sphingosine-1-phosphate in the epidermis, mediates the calcium-induced differentiation of epidermal keratinocytes (PubMed:17713573). Also indirectly regulates tumor necrosis factor/TNF-induced apoptosis (By similarity). By regulating the intracellular balance between ceramides and sphingosine, in adrenocortical cells, probably also acts as a regulator of steroidogenesis (PubMed:22261821).FUNCTION May directly regulate steroidogenesis by binding the nuclear receptor NR5A1 and negatively regulating its transcriptional activity.CATALYTIC ACTIVITY an N-acylsphing-4-enine + H2O = sphing-4-enine + a fatty acidCATALYTIC ACTIVITY a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + H2O = beta-D-glucosyl-(1<->1)-sphing-4-enine + a fatty acidCATALYTIC ACTIVITY a globoside Gb3Cer + H2O = a lysoGb3 + a fatty acidCATALYTIC ACTIVITY a globoside Gb3Cer (d18:1(4E)) + H2O = a lysoGb3(d18:1(4E)) + a fatty acidCATALYTIC ACTIVITY N-dodecanoylsphing-4-enine + H2O = dodecanoate + sphing-4-enineCATALYTIC ACTIVITY N-tetradecanoylsphing-4-enine + H2O = sphing-4-enine + tetradecanoateCATALYTIC ACTIVITY N-hexadecanoylsphing-4-enine + H2O = sphing-4-enine + hexadecanoateCATALYTIC ACTIVITY N-octadecanoylsphing-4-enine + H2O = sphing-4-enine + octadecanoateCATALYTIC ACTIVITY N-dodecanoyl-(4R)-hydroxysphinganine + H2O = (4R)-hydroxysphinganine + dodecanoateCATALYTIC ACTIVITY N-(dodecanoyl)-sphinganine + H2O = dodecanoate + sphinganineCATALYTIC ACTIVITY N-(acetyl)-sphing-4-enine + H2O = sphing-4-enine + acetateCATALYTIC ACTIVITY N-(hexanoyl)sphing-4-enine + H2O = hexanoate + sphing-4-enineCATALYTIC ACTIVITY N-octanoylsphing-4-enine + H2O = octanoate + sphing-4-enineCATALYTIC ACTIVITY N-(9Z-octadecenoyl)-sphing-4-enine + H2O = sphing-4-enine + (9Z)-octadecenoateCATALYTIC ACTIVITY N-dodecanoylethanolamine + H2O = dodecanoate + ethanolamineACTIVITY REGULATION Activated by Ca(2+), Mg(2+) and Na(+) cations (PubMed:12764132). Inhibited by Zn(2+) (PubMed:12764132). Phosphatidylserine and phosphatidic acid stimulate while cardiolipin, phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and sphingomyelin inhibit the reverse ceramide synthase activity (PubMed:12764132). Phosphatidic acid, phosphatidylinositol and C16-ceramide inhibit the ceramidase/hydrolase activity (PubMed:12764132).BIOPHYSICOCHEMICAL PROPERTIES Optimum pH is 3.8-5.0 for the hydrolysis of N-dodecanoylsphing-4-enine (PubMed:12815059, PubMed:7744740). Optimum pH is 5.5-6.5 for the synthesis of N-dodecanoylsphing-4-enine (PubMed:12815059).PATHWAY Lipid metabolism; sphingolipid metabolism.SUBUNIT Heterodimer; disulfide-linked (PubMed:11451951, PubMed:29692406, PubMed:30525581, PubMed:7744740). The heterodimer is composed of the disulfide-linked alpha and beta chains produced by autocatalytic cleavage of the precursor (PubMed:11451951, PubMed:29692406, PubMed:30525581, PubMed:7744740). Isoform 2: May interact with NR5A1 in the nucleus; the direct interaction would negatively regulate NR5A1 transcriptional activity (Probable).INTERACTION Secretion is extremely low and localization to lysosomes is mannose-6-phosphate receptor-dependent.SUBCELLULAR LOCATION A localization to the nucleus and the cytoplasm has also been reported for ASAH1, most probably for isoforms devoid of a signal peptide.ALTERNATIVE PRODUCTS Broadly expressed with higher expression in heart.INDUCTION Up-regulated by Ca(2+).PTM N-glycosylated.PTM Proteolytically cleaved into two chains alpha and beta that remain associated via a disulfide bond (PubMed:11451951, PubMed:29692406, PubMed:30525581, PubMed:7744740). Cleavage gives rise to a conformation change that activates the enzyme. The same catalytic Cys residue mediates the autoproteolytic cleavage and subsequent hydrolysis of lipid substrates (PubMed:29692406, PubMed:30525581). The beta chain may undergo an additional C-terminal processing (PubMed:12815059).DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS Switches substrate specificity upon intralysosomal accumulation of glycosphingolips (PubMed:26898341, PubMed:7852294). Such is the case in Gaucher disease where the regular catabolism of glucosylceramide (GluCer) fails due to the lack of GBA1 activity, its accumulation triggers the alternative catabolism by acid ceramidase which deacylates GluCer producing a free fatty acid and glucosylsphingosine (glucosylsphing-4-enine, GluSph) (PubMed:26898341, PubMed:7852294). Similarly, the intralysosomal accumulation of globoside Gb3 in Fabry disease due to an inactive GLA triggers its alternative catabolism by acid ceramidase, generating lysoGb3 (PubMed:26898341). Formation of lyso-glycosphingolipids might have harmful side-effects and contribute to the pathology, for instance GluSph causes an aberrant activation of mTORC1, suppressing normal lysosomal functions, including the clearance of pathogenic alpha-synuclein species (PubMed:36752535).MISCELLANEOUS Mutagenesis in position: 25:L->A (Loss of interaction with NR5A1).SIMILARITY Belongs to the acid ceramidase family.
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