Reviewed, UniProtKB/Swiss-Prot P17405 (ASM_HUMAN)

Names and origin

Protein names

Recommended name:
    Sphingomyelin phosphodiesterase
    EC=3.1.4.12
Alternative name(s):
    Acid sphingomyelinase
      Short name=aSMase

Gene names

Name:	SMPD1
Synonyms:	ASM

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	629 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Converts sphingomyelin to ceramide. Also has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol.
Catalytic activity	Sphingomyelin + H2O = N-acylsphingosine + choline phosphate.
Subunit structure	Monomer.
Subcellular location	Lysosome.
Involvement in disease	Defects in SMPD1 are the cause of Niemann-Pick disease type A (NPA) [MIM:257200]; also referred to as the classical infantile form. Niemann-Pick disease is a clinically and genetically heterogeneous recessive disorder. It is caused by the accumulation of sphingomyelin and other metabolically related lipids in the lysosomes, resulting in neurodegeneration starting from early life. Patients may show xanthomas, pigmentation, hepatosplenomegaly, lymphadenopathy and mental retardation. Niemann-Pick disease occurs more frequently among individuals of Ashkenazi Jewish ancestry than in the general population. NPA is characterized by very early onset in infancy and a rapidly progressive course leading to death by three years. Ref.9 Ref.10 Ref.12 Ref.14 Ref.16 Ref.17 Ref.18 Ref.20 Defects in SMPD1 are the cause of Niemann-Pick disease type B (NPB) [MIM:607616]; also referred to as the visceral form. NPB has little if any neurologic involvement and patients may survive into adulthood.
Miscellaneous	There are two types of sphingomyelinases: ASM (acid), and NSM (neutral). Isoform 1 is the most abundant (90%), isoforms 2 (10%) and 3 (<1%) are only found at lower levels. Only isoform 1 is a catalytic active enzyme.
Sequence similarities	Belongs to the acid sphingomyelinase family. Contains 1 saposin B-type domain.

Ontologies

Keywords
Cellular component	Lysosome
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Domain	Signal
Molecular function	Glycosidase Hydrolase
PTM	Disulfide bond Glycoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	nervous system development Traceable author statement. Source: ProtInc signal transduction Traceable author statement. Source: ProtInc sphingomyelin catabolic process Inferred from electronic annotation. Source: InterPro
Cellular component	lysosome Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	hydrolase activity, acting on glycosyl bonds Inferred from electronic annotation. Source: UniProtKB-KW sphingomyelin phosphodiesterase activity Ref.9 Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P17405-1)

Also known as: ASM-1;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P17405-2)

Also known as: ASM-2;

The sequence of this isoform differs from the canonical sequence as follows:
     363-374: IGGFYALSPYPG → YLSSVETQEGKR
     375-418: Missing.

Isoform 3 (identifier: P17405-3)

Also known as: ASM-3;

The sequence of this isoform differs from the canonical sequence as follows:
     363-418: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 46	46
	Chain	47 – 629	583	Sphingomyelin phosphodiesterase		PRO_0000002323
Regions
	Domain	85 – 169	85	Saposin B-type
Amino acid modifications
	Glycosylation	86	1	N-linked (GlcNAc...) Ref.7
	Glycosylation	175	1	N-linked (GlcNAc...) Ref.7
	Glycosylation	335	1	N-linked (GlcNAc...) Ref.7
	Glycosylation	395	1	N-linked (GlcNAc...) Ref.7
	Glycosylation	520	1	N-linked (GlcNAc...) Ref.7
	Disulfide bond	89 ↔ 165		By similarity
	Disulfide bond	92 ↔ 157		By similarity
	Disulfide bond	120 ↔ 131		Ref.8
	Disulfide bond	221 ↔ 226		Ref.8
	Disulfide bond	227 ↔ 250		Ref.8
	Disulfide bond	385 ↔ 431		Ref.8
	Disulfide bond	584 ↔ 588		Ref.8
	Disulfide bond	594 ↔ 607		Ref.8
Natural variations
	Alternative sequence	363 – 418	56	Missing in isoform 3.		VSP_000333
	Alternative sequence	363 – 374	12	IGGFY…SPYPG → YLSSVETQEGKR in isoform 2.		VSP_000331
	Alternative sequence	375 – 418	44	Missing in isoform 2.		VSP_000332
	Natural variant	36	1	V → A: dbSNP rs1050228. Ref.3		VAR_038191
	Natural variant	157	1	C → R Seems to be less active. Ref.4		VAR_011387
	Natural variant	242	1	G → R in NPB. Ref.14		VAR_005058
	Natural variant	246	1	E → Q in NPA; 30% residual activity. Ref.18		VAR_005059
	Natural variant	248	1	S → R in NPA. Ref.20		VAR_015287
	Natural variant	302	1	L → P in NPA; in 23% of NPA Ashkenazi Jewish patients. Ref.12		VAR_005060
	Natural variant	316	1	V → E: dbSNP rs12575136.		VAR_054642
	Natural variant	319	1	H → Y in NPA. Ref.20		VAR_015288
	Natural variant	322	1	T → I: dbSNP rs1050233. Ref.1 Ref.6		VAR_054643
	Natural variant	371	1	P → S in NPB. Ref.20		VAR_015289
	Natural variant	382	1	M → I in NPA. Ref.14		VAR_005061
	Natural variant	383	1	N → S in NPB. Ref.14		VAR_005062
	Natural variant	389	1	N → T in NPA. Ref.16		VAR_005063
	Natural variant	391	1	W → G in NPB; low sphingomyelin degradation rates. Ref.15		VAR_005064
	Natural variant	421	1	H → Y in NPB. Ref.19		VAR_015290
	Natural variant	436	1	S → R in NPB. Ref.13		VAR_005065
	Natural variant	446	1	Y → C in NPA. Ref.17		VAR_011388
	Natural variant	463	1	F → S in NPA. Ref.20		VAR_015291
	Natural variant	475	1	P → L in NPA. Ref.20		VAR_015292
	Natural variant	496	1	R → L in NPA; in 32% of NPA Ashkenazi Jewish patients. Ref.10		VAR_005066
	Natural variant	506	1	G → R: dbSNP rs1050239. Ref.1 Ref.6 Ref.2		VAR_054644
	Natural variant	537	1	Y → H in NPA. Ref.20		VAR_015293
	Natural variant	577	1	G → S in NPA. Ref.9		VAR_005067
	Natural variant	608	1	Missing in NPB; prevalent among NPB patients from the North African Maghreb region. Ref.20 Ref.11		VAR_005068
Experimental info
	Sequence conflict	35 – 36	2	Missing in CAA42584. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (ASM-1) [UniParc]. Last modified March 3, 2009. Version 4. Checksum: C9888CB8359C42AC	FASTA	629	69,752
	10 20 30 40 50 60 MPRYGASLRQ SCPRSGREQG QDGTAGAPGL LWMGLVLALA LALALALSDS RVLWAPAEAH 70 80 90 100 110 120 PLSPQGHPAR LHRIVPRLRD VFGWGNLTCP ICKGLFTAIN LGLKKEPNVA RVGSVAIKLC 130 140 150 160 170 180 NLLKIAPPAV CQSIVHLFED DMVEVWRRSV LSPSEACGLL LGSTCGHWDI FSSWNISLPT 190 200 210 220 230 240 VPKPPPKPPS PPAPGAPVSR ILFLTDLHWD HDYLEGTDPD CADPLCCRRG SGLPPASRPG 250 260 270 280 290 300 AGYWGEYSKC DLPLRTLESL LSGLGPAGPF DMVYWTGDIP AHDVWHQTRQ DQLRALTTVT 310 320 330 340 350 360 ALVRKFLGPV PVYPAVGNHE STPVNSFPPP FIEGNHSSRW LYEAMAKAWE PWLPAEALRT 370 380 390 400 410 420 LRIGGFYALS PYPGLRLISL NMNFCSRENF WLLINSTDPA GQLQWLVGEL QAAEDRGDKV 430 440 450 460 470 480 HIIGHIPPGH CLKSWSWNYY RIVARYENTL AAQFFGHTHV DEFEVFYDEE TLSRPLAVAF 490 500 510 520 530 540 LAPSATTYIG LNPGYRVYQI DGNYSGSSHV VLDHETYILN LTQANIPGAI PHWQLLYRAR 550 560 570 580 590 600 ETYGLPNTLP TAWHNLVYRM RGDMQLFQTF WFLYHKGHPP SEPCGTPCRL ATLCAQLSAR 610 620 ADSPALCRHL MPDGSLPEAQ SLWPRPLFC
	Isoform 2 (ASM-2). Checksum: A5FC9FE28C0D3E42	FASTA	585	64,889
	10 20 30 40 50 60 MPRYGASLRQ SCPRSGREQG QDGTAGAPGL LWMGLVLALA LALALALSDS RVLWAPAEAH 70 80 90 100 110 120 PLSPQGHPAR LHRIVPRLRD VFGWGNLTCP ICKGLFTAIN LGLKKEPNVA RVGSVAIKLC 130 140 150 160 170 180 NLLKIAPPAV CQSIVHLFED DMVEVWRRSV LSPSEACGLL LGSTCGHWDI FSSWNISLPT 190 200 210 220 230 240 VPKPPPKPPS PPAPGAPVSR ILFLTDLHWD HDYLEGTDPD CADPLCCRRG SGLPPASRPG 250 260 270 280 290 300 AGYWGEYSKC DLPLRTLESL LSGLGPAGPF DMVYWTGDIP AHDVWHQTRQ DQLRALTTVT 310 320 330 340 350 360 ALVRKFLGPV PVYPAVGNHE STPVNSFPPP FIEGNHSSRW LYEAMAKAWE PWLPAEALRT 370 380 390 400 410 420 LRYLSSVETQ EGKRKVHIIG HIPPGHCLKS WSWNYYRIVA RYENTLAAQF FGHTHVDEFE 430 440 450 460 470 480 VFYDEETLSR PLAVAFLAPS ATTYIGLNPG YRVYQIDGNY SGSSHVVLDH ETYILNLTQA 490 500 510 520 530 540 NIPGAIPHWQ LLYRARETYG LPNTLPTAWH NLVYRMRGDM QLFQTFWFLY HKGHPPSEPC 550 560 570 580 GTPCRLATLC AQLSARADSP ALCRHLMPDG SLPEAQSLWP RPLFC
	Isoform 3 (ASM-3). Checksum: 093B405E0C0AE061	FASTA	573	63,511
	10 20 30 40 50 60 MPRYGASLRQ SCPRSGREQG QDGTAGAPGL LWMGLVLALA LALALALSDS RVLWAPAEAH 70 80 90 100 110 120 PLSPQGHPAR LHRIVPRLRD VFGWGNLTCP ICKGLFTAIN LGLKKEPNVA RVGSVAIKLC 130 140 150 160 170 180 NLLKIAPPAV CQSIVHLFED DMVEVWRRSV LSPSEACGLL LGSTCGHWDI FSSWNISLPT 190 200 210 220 230 240 VPKPPPKPPS PPAPGAPVSR ILFLTDLHWD HDYLEGTDPD CADPLCCRRG SGLPPASRPG 250 260 270 280 290 300 AGYWGEYSKC DLPLRTLESL LSGLGPAGPF DMVYWTGDIP AHDVWHQTRQ DQLRALTTVT 310 320 330 340 350 360 ALVRKFLGPV PVYPAVGNHE STPVNSFPPP FIEGNHSSRW LYEAMAKAWE PWLPAEALRT 370 380 390 400 410 420 LRKVHIIGHI PPGHCLKSWS WNYYRIVARY ENTLAAQFFG HTHVDEFEVF YDEETLSRPL 430 440 450 460 470 480 AVAFLAPSAT TYIGLNPGYR VYQIDGNYSG SSHVVLDHET YILNLTQANI PGAIPHWQLL 490 500 510 520 530 540 YRARETYGLP NTLPTAWHNL VYRMRGDMQL FQTFWFLYHK GHPPSEPCGT PCRLATLCAQ 550 560 570 LSARADSPAL CRHLMPDGSL PEAQSLWPRP LFC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs." Schuchman E.H., Suchi M., Takahashi T., Sandhoff K., Desnick R.J. J. Biol. Chem. 266:8531-8539(1991) [PubMed: 1840600] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE SPLICING, VARIANTS ILE-322 AND ARG-506.
[2]	"Molecular cloning of the acid sphingomyelinase of the mouse and the organization and complete nucleotide sequence of the gene." Newrzella D., Stoffel W. Biol. Chem. Hoppe-Seyler 373:1233-1238(1992) [PubMed: 1292508] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ARG-506.
[3]	"Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase (SMPD1)." Schuchman E.H., Levran O., Pereira L.V., Desnick R.J. Genomics 12:197-205(1992) [PubMed: 1740330] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ALA-36.
[4]	"Cloning of a human acid sphingomyelinase cDNA with a new mutation that renders the enzyme inactive." Ida H., Rennert O.M., Eto Y., Chan W.Y. J. Biochem. 114:15-20(1993) [PubMed: 8407868] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ARG-157.
[5]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed: 16554811] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"Isolation of cDNA clones encoding human acid sphingomyelinase: occurrence of alternatively processed transcripts." Quintern L.E., Schuchman E.H., Levran O., Suchi M., Ferlinz K., Reinke H., Sandhoff K., Desnick R.J. EMBO J. 8:2469-2473(1989) [PubMed: 2555181] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 128-629, PARTIAL PROTEIN SEQUENCE, ALTERNATIVE SPLICING, VARIANTS ILE-322 AND ARG-506. Tissue: Fibroblast.
[7]	"Functional characterization of the N-glycosylation sites of human acid sphingomyelinase by site-directed mutagenesis." Ferlinz K., Hurwitz R., Moczall H., Lansmann S., Schuchman E.H., Sandhoff K. Eur. J. Biochem. 243:511-517(1997) [PubMed: 9030779] [Abstract] Cited for: GLYCOSYLATION AT ASN-86; ASN-175; ASN-335; ASN-395 AND ASN-520.
[8]	"Human acid sphingomyelinase." Lansmann S., Schuette C.G., Bartelsen O., Hoernschemeyer J., Linke T., Weisgerber J., Sandhoff K. Eur. J. Biochem. 270:1076-1088(2003) [PubMed: 12631268] [Abstract] Cited for: DISULFIDE BONDS.
[9]	"Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A." Ferlinz K., Hurwitz R., Sandhoff K. Biochem. Biophys. Res. Commun. 179:1187-1191(1991) [PubMed: 1718266] [Abstract] Cited for: VARIANT NPA SER-577.
[10]	"Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients." Levran O., Desnick R.J., Schuchman E.H. Proc. Natl. Acad. Sci. U.S.A. 88:3748-3752(1991) [PubMed: 2023926] [Abstract] Cited for: VARIANT NPA LEU-496.
[11]	"Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients." Levran O., Desnick R.J., Schuchman E.H. J. Clin. Invest. 88:806-810(1991) [PubMed: 1885770] [Abstract] Cited for: VARIANT NPB ARG-608 DEL.
[12]	"Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients." Levran O., Desnick R.J., Schuchman E.H. Blood 80:2081-2087(1992) [PubMed: 1391960] [Abstract] Cited for: VARIANT NPA PRO-302.
[13]	"Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease." Takahashi T., Desnick R.J., Takada G., Schuchman E.H. Hum. Mutat. 1:70-71(1992) [PubMed: 1301192] [Abstract] Cited for: VARIANT NPB ARG-436.
[14]	"Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease. Molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms." Takahashi T., Suchi M., Desnick R.J., Takada G., Schuchman E.H. J. Biol. Chem. 267:12552-12558(1992) [PubMed: 1618760] [Abstract] Cited for: VARIANT NPA ILE-382, VARIANTS NPB ARG-242 AND SER-383.
[15]	"A family with visceral course of Niemann-Pick disease, macular halo syndrome and low sphingomyelin degradation rate." Sperl W., Bart G., Vanier M.T., Christomanou H., Baldissera I., Steichensdorf E., Paschke E. J. Inherit. Metab. Dis. 17:93-103(1994) [PubMed: 8051942] [Abstract] Cited for: VARIANT NPB GLY-391.
[16]	"Two new mutations in the acid sphingomyelinase gene causing type A Niemann-pick disease: N389T and R441X." Schuchman E.H. Hum. Mutat. 6:352-354(1995) [PubMed: 8680412] [Abstract] Cited for: VARIANT NPA THR-389.
[17]	"Identification and expression of a missense mutation (Y446C) in the acid sphingomyelinase gene from a Japanese patient with type A Niemann-Pick disease." Takahashi T., Suchi M., Sato W., Ten S.B., Sakuragawa N., Desnick R.J., Schuchman E.H., Takada G. Tohoku J. Exp. Med. 177:117-123(1995) [PubMed: 8693491] [Abstract] Cited for: VARIANT NPA CYS-446.
[18]	"Identification of three novel mutations in the acid sphingomyelinase gene of Japanese patients with Niemann-Pick disease type A and B." Ida H., Rennert O.M., Maekawa K., Eto Y. Hum. Mutat. 7:65-67(1996) [PubMed: 8664904] [Abstract] Cited for: VARIANT NPA GLN-246.
[19]	"The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations." Simonaro C.M., Desnick R.J., McGovern M.M., Wasserstein M.P., Schuchman E.H. Am. J. Hum. Genet. 71:1413-1419(2002) [PubMed: 12369017] [Abstract] Cited for: VARIANT NPB TYR-421.
[20]	"Seven novel Acid sphingomyelinase gene mutations in Niemann-Pick type A and B patients." Sikora J., Pavlu-Pereira H., Elleder M., Roelofs H., Wevers R.A. Ann. Hum. Genet. 67:63-70(2003) [PubMed: 12556236] [Abstract] Cited for: VARIANTS NPA ARG-248; TYR-319; SER-463; LEU-475 AND HIS-537, VARIANTS NPB SER-371 AND ARG-608 DEL.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	M59916 mRNA. Translation: AAA58377.1. M59917 Genomic DNA. Translation: AAA58378.1. X63600 Genomic DNA. Translation: CAA45145.1. M81780 Genomic DNA. Translation: AAA75008.1. M81780 Genomic DNA. Translation: AAA75009.1. X59960 mRNA. Translation: CAA42584.1. AC068733 Genomic DNA. No translation available. X52678 mRNA. Translation: CAA36901.1. X52679 mRNA. Translation: CAA36902.1.
IPI	IPI00218784. IPI00218785. IPI00296461.
PIR	S06958. A39825. S27009.
RefSeq	NP_000534.3.
UniGene	Hs.498173
3D structure databases
ModBase	Search...
PTM databases
PhosphoSite	P17405.
Proteomic databases
PRIDE	P17405.
Genome annotation databases
Ensembl	ENSG00000166311. Homo sapiens. [Contig view]
GeneID	6609.
KEGG	hsa:6609.
Organism-specific databases
GeneCards	GC11P006368.
HGNC	HGNC:11120. SMPD1.
HPA	HPA001823.
MIM	257200. phenotype. 607608. gene. 607616. phenotype.
Orphanet	645. Niemann-Pick disease. 77292. Niemann-Pick disease, type A. 77293. Niemann-Pick disease, type B.
PharmGKB	PA35969.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	P17405.
Enzyme and pathway databases
BRENDA	3.1.4.12. 247.
Pathway_Interaction_DB	ceramidepathway. Ceramide signaling pathway. il2_pi3kpathway. IL2 signaling events mediated by PI3K. tnfpathway. TNF receptor signaling pathway. trail_pathway. TRAIL signaling pathway.
Gene expression databases
ArrayExpress	P17405.
Bgee	P17405.
CleanEx	HS_SMPD1.
GermOnline	ENSG00000166311. Homo sapiens.
Family and domain databases
InterPro	IPR004843. M-pesterase. IPR008139. SaposinB. IPR011160. Sphingomy_PDE. [Graphical view]
Pfam	PF00149. Metallophos. 1 hit. [Graphical view]
PIRSF	PIRSF000948. Sphingomy_PDE. 1 hit.
SMART	SM00741. SapB. 1 hit. [Graphical view]
PROSITE	PS50015. SAP_B. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB01151. Desipramine.
NextBio	25729.
SOURCE	Search...

Entry information

Entry name

ASM_HUMAN

Accession

Primary (citable) accession number: P17405
Secondary accession number(s): P17406 , Q13811, Q16837, Q16841

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1990
Last sequence update:	March 3, 2009
Last modified:	June 16, 2009
This is version 113 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)