ASAH1

This gene encodes a heterodimeric protein consisting of a nonglycosylated alpha subunit and a glycosylated beta subunit that is cleaved to the mature enzyme posttranslationally. The encoded protein catalyzes the synthesis and degradation of ceramide into sphingosine and fatty acid. Mutations in this gene have been associated with a lysosomal storage disorder known as Farber disease. Multiple transcript variants encoding several distinct isoforms have been identified for this gene. [provided by RefSeq]

N-acylsphingosine amidohydrolase (acid ceramidase) 1

Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH (PubMed:10610716, PubMed:7744740, PubMed:15655246, PubMed:11451951).
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:7744740, PubMed:15655246).
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).
Has also 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).
Isoform 2: May directly regulate steroidogenesis by binding the nuclear receptor NR5A1 and negatively regulating its transcriptional activity.

Cellular response to tumor necrosis factor Source: UniProtKB
Ceramide biosynthetic process Source: UniProtKB
Ceramide catabolic process Source: UniProtKB
Fatty acid metabolic process Source: InterPro
Glycosphingolipid metabolic process Source: Reactome
Keratinocyte differentiation Source: UniProtKB
Negative regulation of nucleic acid-templated transcription Source: UniProtKB
Neutrophil degranulation Source: Reactome
Regulation of programmed necrotic cell death Source: UniProtKB
Regulation of steroid biosynthetic process Source: UniProtKB
Sphingosine biosynthetic process Source: UniProtKB

Lysosome; Secreted. Secretion is extremely low and localization to lysosomes is mannose-6-phosphate receptor-dependent.
Isoform 2: Cytoplasm; Nucleus. A localization to the nucleus and the cytoplasm has also been reported for ASAH1, most probably for isoforms devoid of a signal peptide.

Farber lipogranulomatosis (FRBRL): An autosomal recessive lysosomal storage disorder characterized by subcutaneous lipid-loaded nodules, excruciating pain in the joints and extremities, and marked accumulation of ceramide in lysosomes. Disease severity is variable. The most severe disease subtype is a rare neonatal form with death occurring before 1 year of age.
Spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME): An autosomal recessive neuromuscular disorder characterized by childhood onset of motor deficits and progressive myoclonic seizures, after normal developmental milestones. Proximal muscle weakness and generalized muscular atrophy are due to degeneration of spinal motor neurons. Myoclonic epilepsy is generally resistant to conventional therapy. The disease course is progressive and leads to respiratory muscle involvement and severe handicap or early death from respiratory insufficiency.

N-glycosylated.
Proteolytically cleaved into two chains alpha and beta that remain associated via a disulfide bond (PubMed:7744740, PubMed:11451951, PubMed:30525581, PubMed:29692406). 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:30525581, PubMed:29692406). The beta chain may undergo an additional C-terminal processing (PubMed:12815059).