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ASAH1

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). 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.

Involvement in disease

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.

None

The disease is caused by variants affecting the gene represented in this entry.

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.

None

The disease is caused by variants affecting the gene represented in this entry.

Pathway

Lipid metabolism; sphingolipid metabolism.

Post-translational modifications

N-glycosylated.

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).

Sequence Similarities

Belongs to the acid ceramidase family.

Tissue Specificity

Broadly expressed with higher expression in heart.

Cellular localization

Alternative names

ASAH, HSD-33, HSD33, ASAH1, Acid ceramidase, AC, ACDase, Acid CDase, Acylsphingosine deacylase, Glycosylceramide deacylase, N-acylethanolamine hydrolase ASAH1, N-acylsphingosine amidohydrolase, Putative 32 kDa heart protein, PHP32

swissprot:Q13510 omim:613468 entrezGene:427

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