NSMA_MOUSE
ID NSMA_MOUSE Reviewed; 419 AA.
AC O70572;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1998, sequence version 1.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Sphingomyelin phosphodiesterase 2 {ECO:0000305|PubMed:9520418};
DE EC=3.1.4.12 {ECO:0000269|PubMed:15764706, ECO:0000269|PubMed:9520418};
DE AltName: Full=Lyso-platelet-activating factor-phospholipase C;
DE Short=Lyso-PAF-PLC;
DE AltName: Full=Neutral sphingomyelinase {ECO:0000303|PubMed:9520418};
DE Short=N-SMase {ECO:0000303|PubMed:9520418};
DE Short=nSMase {ECO:0000303|PubMed:9520418};
GN Name=Smpd2 {ECO:0000312|MGI:MGI:1278330};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, COFACTOR,
RP ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY, ALTERNATIVE
RP SPLICING, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=9520418; DOI=10.1073/pnas.95.7.3638;
RA Tomiuk S., Hofmann K., Nix M., Zumbansen M., Stoffel W.;
RT "Cloned mammalian neutral sphingomyelinase: functions in sphingolipid
RT signaling?";
RL Proc. Natl. Acad. Sci. U.S.A. 95:3638-3643(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Salivary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND DISRUPTION PHENOTYPE.
RX PubMed=15764706; DOI=10.1073/pnas.0406380102;
RA Stoffel W., Jenke B., Bloeck B., Zumbansen M., Koebke J.;
RT "Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and
RT development.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:4554-4559(2005).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Heart, Kidney, Liver, Lung, and Pancreas;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Catalyzes, at least in vitro, the hydrolysis of sphingomyelin
CC to form ceramide and phosphocholine (PubMed:9520418). Also hydrolyzes
CC 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine (lyso-platelet-activating
CC factor) in vivo (By similarity). Also acts on 1-acyl-2-lyso-sn-glycero-
CC 3-phosphocholine (lyso-PC) and sphingosylphosphocholine (By
CC similarity). {ECO:0000250|UniProtKB:O60906,
CC ECO:0000269|PubMed:9520418}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingomyelin + H2O = an N-acylsphing-4-enine + H(+) +
CC phosphocholine; Xref=Rhea:RHEA:19253, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17636, ChEBI:CHEBI:52639,
CC ChEBI:CHEBI:295975; EC=3.1.4.12;
CC Evidence={ECO:0000269|PubMed:15764706, ECO:0000269|PubMed:9520418};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19254;
CC Evidence={ECO:0000305|PubMed:15764706};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-(acyl)-sphingosylphosphocholine + H2O = an N-acyl-
CC sphingoid base + H(+) + phosphocholine; Xref=Rhea:RHEA:45300,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:64583,
CC ChEBI:CHEBI:83273, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45301;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-O-octadecyl-sn-glycero-3-phosphocholine + H2O = 1-O-
CC octadecyl-sn-glycerol + H(+) + phosphocholine; Xref=Rhea:RHEA:39923,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:74001,
CC ChEBI:CHEBI:75216, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39924;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1-
CC hexadecanoyl-sn-glycerol + H(+) + phosphocholine;
CC Xref=Rhea:RHEA:41119, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:72998, ChEBI:CHEBI:75542, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41120;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingosylphosphocholine + H2O = a sphingoid base + H(+) +
CC phosphocholine; Xref=Rhea:RHEA:45296, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:84410, ChEBI:CHEBI:85171,
CC ChEBI:CHEBI:295975; Evidence={ECO:0000250|UniProtKB:O60906};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45297;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-O-hexadecyl-sn-glycero-3-phosphocholine + H2O = 1-O-
CC hexadecyl-sn-glycerol + H(+) + phosphocholine; Xref=Rhea:RHEA:36087,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:34115,
CC ChEBI:CHEBI:64496, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36088;
CC Evidence={ECO:0000250|UniProtKB:O60906};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:9520418};
CC -!- ACTIVITY REGULATION: Activated by arachidonic acid.
CC {ECO:0000269|PubMed:15764706, ECO:0000269|PubMed:9520418}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=15 uM for sphingomyelin (at pH 7.4 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:9520418};
CC Vmax=10 umol/h/mg enzyme with sphingomyelin as substrate (at pH 7.4
CC and 37 degrees Celsius) {ECO:0000269|PubMed:9520418};
CC pH dependence:
CC Optimum pH is 6.5-7.5. {ECO:0000269|PubMed:9520418};
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC {ECO:0000269|PubMed:9520418}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9520418};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Although widely expressed in all tissues examined,
CC except the spleen, high enzymatic activity occurs only in the brain.
CC {ECO:0000269|PubMed:9520418}.
CC -!- DISRUPTION PHENOTYPE: Mice lacking Smpd2 and Smpd3 are completely
CC devoid of neutral SMase activity but do not developed sphingomyelin
CC storage abnormalities. {ECO:0000269|PubMed:15764706}.
CC -!- SIMILARITY: Belongs to the neutral sphingomyelinase family.
CC {ECO:0000305}.
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DR EMBL; AJ222800; CAA10994.1; -; mRNA.
DR EMBL; BC010978; AAH10978.1; -; mRNA.
DR CCDS; CCDS23805.1; -.
DR RefSeq; NP_033239.1; NM_009213.2.
DR AlphaFoldDB; O70572; -.
DR SMR; O70572; -.
DR BioGRID; 203346; 1.
DR STRING; 10090.ENSMUSP00000019965; -.
DR iPTMnet; O70572; -.
DR PhosphoSitePlus; O70572; -.
DR EPD; O70572; -.
DR jPOST; O70572; -.
DR MaxQB; O70572; -.
DR PaxDb; O70572; -.
DR PeptideAtlas; O70572; -.
DR PRIDE; O70572; -.
DR ProteomicsDB; 295531; -.
DR Antibodypedia; 19179; 215 antibodies from 30 providers.
DR DNASU; 20598; -.
DR Ensembl; ENSMUST00000019965; ENSMUSP00000019965; ENSMUSG00000019822.
DR GeneID; 20598; -.
DR KEGG; mmu:20598; -.
DR UCSC; uc007exs.1; mouse.
DR CTD; 6610; -.
DR MGI; MGI:1278330; Smpd2.
DR VEuPathDB; HostDB:ENSMUSG00000019822; -.
DR eggNOG; KOG3873; Eukaryota.
DR GeneTree; ENSGT00390000009166; -.
DR HOGENOM; CLU_034001_4_0_1; -.
DR InParanoid; O70572; -.
DR OMA; IEVNCQV; -.
DR OrthoDB; 589366at2759; -.
DR PhylomeDB; O70572; -.
DR TreeFam; TF313899; -.
DR Reactome; R-MMU-1660662; Glycosphingolipid metabolism.
DR Reactome; R-MMU-5626978; TNFR1-mediated ceramide production.
DR UniPathway; UPA00222; -.
DR BioGRID-ORCS; 20598; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Smpd2; mouse.
DR PRO; PR:O70572; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; O70572; protein.
DR Bgee; ENSMUSG00000019822; Expressed in right kidney and 263 other tissues.
DR ExpressionAtlas; O70572; baseline and differential.
DR Genevisible; O70572; MM.
DR GO; GO:0005901; C:caveola; ISO:MGI.
DR GO; GO:0071944; C:cell periphery; IBA:GO_Central.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004620; F:phospholipase activity; IBA:GO_Central.
DR GO; GO:0008081; F:phosphoric diester hydrolase activity; ISO:MGI.
DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0046513; P:ceramide biosynthetic process; ISO:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:0009612; P:response to mechanical stimulus; ISO:MGI.
DR GO; GO:0030149; P:sphingolipid catabolic process; IBA:GO_Central.
DR GO; GO:0006685; P:sphingomyelin catabolic process; IDA:UniProtKB.
DR GO; GO:0006684; P:sphingomyelin metabolic process; IBA:GO_Central.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR InterPro; IPR038772; SMPD2-like.
DR PANTHER; PTHR12393; PTHR12393; 1.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR SUPFAM; SSF56219; SSF56219; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Hydrolase; Lipid metabolism; Magnesium; Membrane;
KW Metal-binding; Reference proteome; Sphingolipid metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..419
FT /note="Sphingomyelin phosphodiesterase 2"
FT /id="PRO_0000075687"
FT TRANSMEM 326..346
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 354..374
FT /note="Helical"
FT /evidence="ECO:0000255"
FT ACT_SITE 272
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT BINDING 49
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT SITE 180
FT /note="Important for substrate recognition"
FT /evidence="ECO:0000250"
SQ SEQUENCE 419 AA; 47467 MW; 5812FC630A69C356 CRC64;
MKLNFSLRLR VFNLNCWDIP YLSKHRADRM KRLGDFLNLE NFDLALLEEV WSEQDFQYLR
QRLSLTYPDA HYFRSGMIGS GLCVFSKHPI QEIFQHVYSL NGYPYMFHHG DWFCGKSVGL
LVLRLSGLVL NAYVTHLHAE YSRQKDIYFA HRVAQAWELA QFIHHTSKNA DVVLLCGDLN
MHPKDLGCCL LKEWTGLHDA FVETEDFKGS DDGCTMVPKN CYVSQQDLGP FPSGIRIDYV
LYKAVSEFHV CCETLKTTTG CDPHSDKPFS DHEALMATLY VKHSPPQEDP CTACGPLERS
DLISVLREAR TELGLGIAKA RWWAAFSGYV IVWGLSLLVL LCVLAAGEEA REVAIILCIP
SVGLVLVAGA VYLFHKQEAK GLCRAQAEML HVLTRETETQ DRGSEPHLAY CLQQEGDRA
