UniProt functional annotation for P17405



	UniProt functional annotation for P17405

UniProt code: P17405.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Converts sphingomyelin to ceramide (PubMed:1840600, PubMed:18815062, PubMed:27659707, PubMed:25920558, PubMed:25339683, PubMed:33163980, PubMed:12563314). Exists as two enzymatic forms that arise from alternative trafficking of a single protein precursor, one that is targeted to the endolysosomal compartment, whereas the other is released extracellularly (PubMed:21098024, PubMed:9660788, PubMed:20807762). However, in response to various forms of stress, lysosomal exocytosis may represent a major source of the secretory form (PubMed:20530211, PubMed:12563314, PubMed:20807762, PubMed:9393854, PubMed:22573858). {ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:1840600, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:21098024, ECO:0000269|PubMed:22573858, ECO:0000269|PubMed:25339683, ECO:0000269|PubMed:25920558, ECO:0000269|PubMed:27659707, ECO:0000269|PubMed:33163980, ECO:0000269|PubMed:9393854, ECO:0000269|PubMed:9660788, ECO:0000305}.

Function: In the lysosomes, converts sphingomyelin to ceramide (PubMed:20807762, PubMed:21098024). Plays an important role in the export of cholesterol from the intraendolysosomal membranes (PubMed:25339683). Also has phospholipase C activities toward 1,2- diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol (PubMed:25339683). Modulates stress-induced apoptosis through the production of ceramide (PubMed:8706124). {ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:21098024, ECO:0000269|PubMed:25339683, ECO:0000269|PubMed:8706124}.

Function: When secreted, modulates cell signaling with its ability to reorganize the plasma membrane by converting sphingomyelin to ceramide (PubMed:12563314, PubMed:20807762, PubMed:17303575). Secreted form is increased in response to stress and inflammatory mediators such as IL1B, IFNG or TNF as well as upon infection with bacteria and viruses. Produces the release of ceramide in the outer leaflet of the plasma membrane playing a central role in host defense (PubMed:12563314, PubMed:20807762, PubMed:9393854). Ceramide reorganizes these rafts into larger signaling platforms that are required to internalize P. aeruginosa, induce apoptosis and regulate the cytokine response in infected cells (PubMed:12563314). In wounded cells, the lysosomal form is released extracellularly in the presence of Ca(2+) and promotes endocytosis and plasma membrane repair (PubMed:20530211). {ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:17303575, ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:9393854}.

Function: [Isoform 2]: Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity. {ECO:0000269|PubMed:1840600, ECO:0000305}.

Function: [Isoform 3]: Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity. {ECO:0000269|PubMed:1840600, ECO:0000305}.

Function: (Microbial infection) Secretion is activated by bacteria such as P. aeruginos, N. gonorrhoeae and others, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection. {ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:9393854, ECO:0000305|PubMed:31155842}.

Function: (Microbial infection) Secretion is activated by human coronaviruses SARS-CoV and SARS-CoV-2 as well as Zaire ebolavirus, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection. {ECO:0000269|PubMed:22573858, ECO:0000269|PubMed:33163980}.

Catalytic activity: Reaction=a sphingomyelin + H2O = an N-acylsphing-4-enine + H(+) + phosphocholine; Xref=Rhea:RHEA:19253, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17636, ChEBI:CHEBI:52639, ChEBI:CHEBI:295975; EC=3.1.4.12; Evidence={ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:1718266, ECO:0000269|PubMed:1840600, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:22573858, ECO:0000269|PubMed:26084044, ECO:0000269|PubMed:27349982, ECO:0000269|PubMed:33163980, ECO:0000269|PubMed:8702487, ECO:0000269|PubMed:8706124}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19254; Evidence={ECO:0000305|PubMed:12563314, ECO:0000305|PubMed:1840600, ECO:0000305|PubMed:22573858, ECO:0000305|PubMed:33163980, ECO:0000305|PubMed:8706124};

Catalytic activity: Reaction=H2O + N-(octadecanoyl)-sphing-4-enine-1-phosphocholine = H(+) + N-octadecanoylsphing-4-enine + phosphocholine; Xref=Rhea:RHEA:54284, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:72961, ChEBI:CHEBI:83358, ChEBI:CHEBI:295975; Evidence={ECO:0000269|PubMed:25339683}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54285; Evidence={ECO:0000269|PubMed:25339683};

Catalytic activity: Reaction=1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1,2- dihexadecanoyl-sn-glycerol + H(+) + phosphocholine; Xref=Rhea:RHEA:45304, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:72999, ChEBI:CHEBI:82929, ChEBI:CHEBI:295975; Evidence={ECO:0000269|PubMed:25339683}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45305; Evidence={ECO:0000305};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:8702487, ECO:0000269|PubMed:9660788}; Note=Binds 2 Zn(2+) ions per subunit (PubMed:27349982, PubMed:27725636). {ECO:0000269|PubMed:27349982, ECO:0000269|PubMed:27725636, ECO:0000269|PubMed:8702487, ECO:0000269|PubMed:9660788};

Activity regulation: Hydrolysis of liposomal sphingomyelin is stimulated by incorporation of diacylglycerol (DAG), ceramide and free fatty acids into the liposomal membranes (PubMed:25339683). Phosphatidylcholine hydrolysis is inhibited by incorporation of cholesterol, ceramide, DAG, monoacylglycerol and fatty acids (PubMed:25339683). Antidepressants, namely amitriptyline, imipramine, desipramine, fluoxetine, sertraline, escitalopram, and maprotiline inhibit sphingomyelin phosphodiesterase activity (PubMed:33163980, PubMed:22573858). {ECO:0000269|PubMed:22573858, ECO:0000269|PubMed:25339683, ECO:0000269|PubMed:33163980}.

Activity regulation: (Microbial infection) The secretory form is activated by P. aeruginosa, this activation results in the release of ceramide in the outer leaflet of the plasma membrane. {ECO:0000269|PubMed:12563314}.

Activity regulation: (Microbial infection) The secretory form is activated by human coronavirus SARS-CoV-2, this activation results in the release of ceramide in the outer leaflet of the plasma membrane. {ECO:0000269|PubMed:33163980}.

Subunit: Monomer. Interacts with SORT1; the interaction is required for SMPD1 targeting to lysosomes (PubMed:16787399). {ECO:0000269|PubMed:16787399, ECO:0000269|PubMed:27349982}.

Subcellular location: Lysosome {ECO:0000269|PubMed:16787399, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:27659707, ECO:0000269|PubMed:9660788}. Lipid droplet {ECO:0000269|PubMed:25339683}. Secreted {ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:16787399, ECO:0000269|PubMed:17303575, ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:22573858, ECO:0000269|PubMed:27659707, ECO:0000269|PubMed:8702487, ECO:0000269|PubMed:9030779, ECO:0000269|PubMed:9660788}. Note=The secreted form is induced in a time- and dose-dependent by IL1B and TNF as well as stress and viral infection. This increase of the secreted form seems to be due to exocytosis of the lysosomal form and is Ca(2+)-dependent (PubMed:20807762, PubMed:22573858, PubMed:20530211). Secretion is dependent of phosphorylation at Ser-510 (PubMed:17303575). Secretion is induced by inflammatory mediators such as IL1B, IFNG or TNF as well as infection with bacteria and viruses (PubMed:12563314, PubMed:20807762). {ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:17303575, ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:22573858}.

Ptm: Proteolytically processed (PubMed:21098024, PubMed:9030779). Mature lysosomal form arises from C-terminal proteolytic processing of pro-sphingomyelin phosphodiesterase (PubMed:21098024). {ECO:0000269|PubMed:21098024, ECO:0000269|PubMed:9030779}.

Ptm: Both lysosomal and secreted forms are glycosylated but they show a differential pattern of glycosylation. {ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:9030779}.

Ptm: Phosphorylated at Ser-510 by PRKCD upon stress stimuli. Phosphorylation is required for secretion. {ECO:0000269|PubMed:17303575, ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:9030779}.

Polymorphism: A common polymorphism arises from a variable number of hexanucleotide repeat sequence within the signal peptide region. {ECO:0000269|PubMed:18088425}.

Disease: Niemann-Pick disease A (NPDA) [MIM:257200]: An early-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Niemann-Pick disease type A is a primarily neurodegenerative disorder characterized by onset within the first year of life, mental retardation, digestive disorders, failure to thrive, major hepatosplenomegaly, and severe neurologic symptoms. The severe neurological disorders and pulmonary infections lead to an early death, often around the age of four. Clinical features are variable. A phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. {ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:1391960, ECO:0000269|PubMed:15221801, ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:1618760, ECO:0000269|PubMed:1718266, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:19405096, ECO:0000269|PubMed:2023926, ECO:0000269|PubMed:20386867, ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888, ECO:0000269|PubMed:23430884, ECO:0000269|PubMed:26499107, ECO:0000269|PubMed:27338287, ECO:0000269|PubMed:8680412, ECO:0000269|PubMed:8693491, ECO:0000269|PubMed:9266408, ECO:0000269|PubMed:9660788}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Niemann-Pick disease B (NPDB) [MIM:607616]: A late-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Clinical signs involve only visceral organs. The most constant sign is hepatosplenomegaly which can be associated with pulmonary symptoms. Patients remain free of neurologic manifestations. However, a phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. In Niemann-Pick disease type B, onset of the first symptoms occurs in early childhood and patients can survive into adulthood. {ECO:0000269|PubMed:12369017, ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:1301192, ECO:0000269|PubMed:15241805, ECO:0000269|PubMed:16010684, ECO:0000269|PubMed:1618760, ECO:0000269|PubMed:16472269, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:1885770, ECO:0000269|PubMed:19050888, ECO:0000269|PubMed:19405096, ECO:0000269|PubMed:20386867, ECO:0000269|PubMed:21098024, ECO:0000269|PubMed:21621718, ECO:0000269|PubMed:22613662, ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888, ECO:0000269|PubMed:23430512, ECO:0000269|PubMed:25920558, ECO:0000269|PubMed:26084044, ECO:0000269|PubMed:26499107, ECO:0000269|PubMed:27338287, ECO:0000269|PubMed:27659707, ECO:0000269|PubMed:8051942, ECO:0000269|PubMed:8664904}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: There are two types of sphingomyelinases: ASM (acid), and NSM (neutral).

Miscellaneous: [Isoform 1]: Most abundant (90%).

Miscellaneous: [Isoform 2]: Intermediate abundance (10%). {ECO:0000305}.

Miscellaneous: [Isoform 3]: Low abundance (<1%). {ECO:0000305}.

Similarity: Belongs to the acid sphingomyelinase family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Converts sphingomyelin to ceramide (PubMed:1840600, PubMed:18815062, PubMed:27659707, PubMed:25920558, PubMed:25339683, PubMed:33163980, PubMed:12563314). Exists as two enzymatic forms that arise from alternative trafficking of a single protein precursor, one that is targeted to the endolysosomal compartment, whereas the other is released extracellularly (PubMed:21098024, PubMed:9660788, PubMed:20807762). However, in response to various forms of stress, lysosomal exocytosis may represent a major source of the secretory form (PubMed:20530211, PubMed:12563314, PubMed:20807762, PubMed:9393854, PubMed:22573858). {ECO:0000269\|PubMed:12563314, ECO:0000269\|PubMed:1840600, ECO:0000269\|PubMed:18815062, ECO:0000269\|PubMed:20530211, ECO:0000269\|PubMed:20807762, ECO:0000269\|PubMed:21098024, ECO:0000269\|PubMed:22573858, ECO:0000269\|PubMed:25339683, ECO:0000269\|PubMed:25920558, ECO:0000269\|PubMed:27659707, ECO:0000269\|PubMed:33163980, ECO:0000269\|PubMed:9393854, ECO:0000269\|PubMed:9660788, ECO:0000305}.



Function:		In the lysosomes, converts sphingomyelin to ceramide (PubMed:20807762, PubMed:21098024). Plays an important role in the export of cholesterol from the intraendolysosomal membranes (PubMed:25339683). Also has phospholipase C activities toward 1,2- diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol (PubMed:25339683). Modulates stress-induced apoptosis through the production of ceramide (PubMed:8706124). {ECO:0000269\|PubMed:20807762, ECO:0000269\|PubMed:21098024, ECO:0000269\|PubMed:25339683, ECO:0000269\|PubMed:8706124}.



Function:		When secreted, modulates cell signaling with its ability to reorganize the plasma membrane by converting sphingomyelin to ceramide (PubMed:12563314, PubMed:20807762, PubMed:17303575). Secreted form is increased in response to stress and inflammatory mediators such as IL1B, IFNG or TNF as well as upon infection with bacteria and viruses. Produces the release of ceramide in the outer leaflet of the plasma membrane playing a central role in host defense (PubMed:12563314, PubMed:20807762, PubMed:9393854). Ceramide reorganizes these rafts into larger signaling platforms that are required to internalize P. aeruginosa, induce apoptosis and regulate the cytokine response in infected cells (PubMed:12563314). In wounded cells, the lysosomal form is released extracellularly in the presence of Ca(2+) and promotes endocytosis and plasma membrane repair (PubMed:20530211). {ECO:0000269\|PubMed:12563314, ECO:0000269\|PubMed:17303575, ECO:0000269\|PubMed:20530211, ECO:0000269\|PubMed:20807762, ECO:0000269\|PubMed:9393854}.



Function:		[Isoform 2]: Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity. {ECO:0000269\|PubMed:1840600, ECO:0000305}.



Function:		[Isoform 3]: Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity. {ECO:0000269\|PubMed:1840600, ECO:0000305}.



Function:		(Microbial infection) Secretion is activated by bacteria such as P. aeruginos, N. gonorrhoeae and others, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection. {ECO:0000269\|PubMed:12563314, ECO:0000269\|PubMed:9393854, ECO:0000305\|PubMed:31155842}.



Function:		(Microbial infection) Secretion is activated by human coronaviruses SARS-CoV and SARS-CoV-2 as well as Zaire ebolavirus, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection. {ECO:0000269\|PubMed:22573858, ECO:0000269\|PubMed:33163980}.


Catalytic activity:		Reaction=a sphingomyelin + H2O = an N-acylsphing-4-enine + H(+) + phosphocholine; Xref=Rhea:RHEA:19253, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17636, ChEBI:CHEBI:52639, ChEBI:CHEBI:295975; EC=3.1.4.12; Evidence={ECO:0000269\|PubMed:12563314, ECO:0000269\|PubMed:15877209, ECO:0000269\|PubMed:1718266, ECO:0000269\|PubMed:1840600, ECO:0000269\|PubMed:18815062, ECO:0000269\|PubMed:22573858, ECO:0000269\|PubMed:26084044, ECO:0000269\|PubMed:27349982, ECO:0000269\|PubMed:33163980, ECO:0000269\|PubMed:8702487, ECO:0000269\|PubMed:8706124}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19254; Evidence={ECO:0000305\|PubMed:12563314, ECO:0000305\|PubMed:1840600, ECO:0000305\|PubMed:22573858, ECO:0000305\|PubMed:33163980, ECO:0000305\|PubMed:8706124};
Catalytic activity:		Reaction=H2O + N-(octadecanoyl)-sphing-4-enine-1-phosphocholine = H(+) + N-octadecanoylsphing-4-enine + phosphocholine; Xref=Rhea:RHEA:54284, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:72961, ChEBI:CHEBI:83358, ChEBI:CHEBI:295975; Evidence={ECO:0000269\|PubMed:25339683}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54285; Evidence={ECO:0000269\|PubMed:25339683};
Catalytic activity:		Reaction=1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1,2- dihexadecanoyl-sn-glycerol + H(+) + phosphocholine; Xref=Rhea:RHEA:45304, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:72999, ChEBI:CHEBI:82929, ChEBI:CHEBI:295975; Evidence={ECO:0000269\|PubMed:25339683}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45305; Evidence={ECO:0000305};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:8702487, ECO:0000269\|PubMed:9660788}; Note=Binds 2 Zn(2+) ions per subunit (PubMed:27349982, PubMed:27725636). {ECO:0000269\|PubMed:27349982, ECO:0000269\|PubMed:27725636, ECO:0000269\|PubMed:8702487, ECO:0000269\|PubMed:9660788};
Activity regulation:		Hydrolysis of liposomal sphingomyelin is stimulated by incorporation of diacylglycerol (DAG), ceramide and free fatty acids into the liposomal membranes (PubMed:25339683). Phosphatidylcholine hydrolysis is inhibited by incorporation of cholesterol, ceramide, DAG, monoacylglycerol and fatty acids (PubMed:25339683). Antidepressants, namely amitriptyline, imipramine, desipramine, fluoxetine, sertraline, escitalopram, and maprotiline inhibit sphingomyelin phosphodiesterase activity (PubMed:33163980, PubMed:22573858). {ECO:0000269\|PubMed:22573858, ECO:0000269\|PubMed:25339683, ECO:0000269\|PubMed:33163980}.
Activity regulation:		(Microbial infection) The secretory form is activated by P. aeruginosa, this activation results in the release of ceramide in the outer leaflet of the plasma membrane. {ECO:0000269\|PubMed:12563314}.
Activity regulation:		(Microbial infection) The secretory form is activated by human coronavirus SARS-CoV-2, this activation results in the release of ceramide in the outer leaflet of the plasma membrane. {ECO:0000269\|PubMed:33163980}.
Subunit:		Monomer. Interacts with SORT1; the interaction is required for SMPD1 targeting to lysosomes (PubMed:16787399). {ECO:0000269\|PubMed:16787399, ECO:0000269\|PubMed:27349982}.
Subcellular location:		Lysosome {ECO:0000269\|PubMed:16787399, ECO:0000269\|PubMed:18815062, ECO:0000269\|PubMed:20530211, ECO:0000269\|PubMed:20807762, ECO:0000269\|PubMed:27659707, ECO:0000269\|PubMed:9660788}. Lipid droplet {ECO:0000269\|PubMed:25339683}. Secreted {ECO:0000269\|PubMed:12563314, ECO:0000269\|PubMed:16787399, ECO:0000269\|PubMed:17303575, ECO:0000269\|PubMed:20530211, ECO:0000269\|PubMed:20807762, ECO:0000269\|PubMed:22573858, ECO:0000269\|PubMed:27659707, ECO:0000269\|PubMed:8702487, ECO:0000269\|PubMed:9030779, ECO:0000269\|PubMed:9660788}. Note=The secreted form is induced in a time- and dose-dependent by IL1B and TNF as well as stress and viral infection. This increase of the secreted form seems to be due to exocytosis of the lysosomal form and is Ca(2+)-dependent (PubMed:20807762, PubMed:22573858, PubMed:20530211). Secretion is dependent of phosphorylation at Ser-510 (PubMed:17303575). Secretion is induced by inflammatory mediators such as IL1B, IFNG or TNF as well as infection with bacteria and viruses (PubMed:12563314, PubMed:20807762). {ECO:0000269\|PubMed:12563314, ECO:0000269\|PubMed:17303575, ECO:0000269\|PubMed:20530211, ECO:0000269\|PubMed:20807762, ECO:0000269\|PubMed:22573858}.
Ptm:		Proteolytically processed (PubMed:21098024, PubMed:9030779). Mature lysosomal form arises from C-terminal proteolytic processing of pro-sphingomyelin phosphodiesterase (PubMed:21098024). {ECO:0000269\|PubMed:21098024, ECO:0000269\|PubMed:9030779}.
Ptm:		Both lysosomal and secreted forms are glycosylated but they show a differential pattern of glycosylation. {ECO:0000269\|PubMed:20807762, ECO:0000269\|PubMed:9030779}.
Ptm:		Phosphorylated at Ser-510 by PRKCD upon stress stimuli. Phosphorylation is required for secretion. {ECO:0000269\|PubMed:17303575, ECO:0000269\|PubMed:20807762, ECO:0000269\|PubMed:9030779}.
Polymorphism:		A common polymorphism arises from a variable number of hexanucleotide repeat sequence within the signal peptide region. {ECO:0000269\|PubMed:18088425}.
Disease:		Niemann-Pick disease A (NPDA) [MIM:257200]: An early-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Niemann-Pick disease type A is a primarily neurodegenerative disorder characterized by onset within the first year of life, mental retardation, digestive disorders, failure to thrive, major hepatosplenomegaly, and severe neurologic symptoms. The severe neurological disorders and pulmonary infections lead to an early death, often around the age of four. Clinical features are variable. A phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. {ECO:0000269\|PubMed:12556236, ECO:0000269\|PubMed:1391960, ECO:0000269\|PubMed:15221801, ECO:0000269\|PubMed:15877209, ECO:0000269\|PubMed:1618760, ECO:0000269\|PubMed:1718266, ECO:0000269\|PubMed:18815062, ECO:0000269\|PubMed:19405096, ECO:0000269\|PubMed:2023926, ECO:0000269\|PubMed:20386867, ECO:0000269\|PubMed:22818240, ECO:0000269\|PubMed:23252888, ECO:0000269\|PubMed:23430884, ECO:0000269\|PubMed:26499107, ECO:0000269\|PubMed:27338287, ECO:0000269\|PubMed:8680412, ECO:0000269\|PubMed:8693491, ECO:0000269\|PubMed:9266408, ECO:0000269\|PubMed:9660788}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Niemann-Pick disease B (NPDB) [MIM:607616]: A late-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Clinical signs involve only visceral organs. The most constant sign is hepatosplenomegaly which can be associated with pulmonary symptoms. Patients remain free of neurologic manifestations. However, a phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. In Niemann-Pick disease type B, onset of the first symptoms occurs in early childhood and patients can survive into adulthood. {ECO:0000269\|PubMed:12369017, ECO:0000269\|PubMed:12556236, ECO:0000269\|PubMed:1301192, ECO:0000269\|PubMed:15241805, ECO:0000269\|PubMed:16010684, ECO:0000269\|PubMed:1618760, ECO:0000269\|PubMed:16472269, ECO:0000269\|PubMed:18815062, ECO:0000269\|PubMed:1885770, ECO:0000269\|PubMed:19050888, ECO:0000269\|PubMed:19405096, ECO:0000269\|PubMed:20386867, ECO:0000269\|PubMed:21098024, ECO:0000269\|PubMed:21621718, ECO:0000269\|PubMed:22613662, ECO:0000269\|PubMed:22818240, ECO:0000269\|PubMed:23252888, ECO:0000269\|PubMed:23430512, ECO:0000269\|PubMed:25920558, ECO:0000269\|PubMed:26084044, ECO:0000269\|PubMed:26499107, ECO:0000269\|PubMed:27338287, ECO:0000269\|PubMed:27659707, ECO:0000269\|PubMed:8051942, ECO:0000269\|PubMed:8664904}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		There are two types of sphingomyelinases: ASM (acid), and NSM (neutral).
Miscellaneous:		[Isoform 1]: Most abundant (90%).
Miscellaneous:		[Isoform 2]: Intermediate abundance (10%). {ECO:0000305}.
Miscellaneous:		[Isoform 3]: Low abundance (<1%). {ECO:0000305}.
Similarity:		Belongs to the acid sphingomyelinase family. {ECO:0000305}.