NSMA_HUMAN
ID NSMA_HUMAN Reviewed; 423 AA.
AC O60906; Q5TED1; Q9BWR3;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 13-NOV-2007, sequence version 2.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Sphingomyelin phosphodiesterase 2 {ECO:0000305|PubMed:14741383};
DE EC=3.1.4.12 {ECO:0000269|PubMed:10608884, ECO:0000269|PubMed:14741383};
DE AltName: Full=Lyso-platelet-activating factor-phospholipase C {ECO:0000303|PubMed:10608884};
DE Short=Lyso-PAF-PLC {ECO:0000303|PubMed:10608884};
DE AltName: Full=Neutral sphingomyelinase {ECO:0000303|PubMed:9520418};
DE Short=N-SMase {ECO:0000303|PubMed:9520418};
DE Short=nSMase {ECO:0000303|PubMed:9520418};
DE Short=nSMase1 {ECO:0000303|PubMed:14741383};
GN Name=SMPD2 {ECO:0000312|HGNC:HGNC:11121};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS LEU-3 AND SER-265.
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 GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-265.
RC TISSUE=Brain;
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 [4]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP PATHWAY.
RX PubMed=10608884; DOI=10.1074/jbc.274.53.38131;
RA Sawai H., Domae N., Nagan N., Hannun Y.A.;
RT "Function of the cloned putative neutral sphingomyelinase as lyso-platelet
RT activating factor-phospholipase C.";
RL J. Biol. Chem. 274:38131-38139(1999).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY.
RX PubMed=14741383; DOI=10.1016/s0014-5793(03)01523-0;
RA Miura Y., Gotoh E., Nara F., Nishijima M., Hanada K.;
RT "Hydrolysis of sphingosylphosphocholine by neutral sphingomyelinases.";
RL FEBS Lett. 557:288-292(2004).
CC -!- FUNCTION: Catalyzes, at least in vitro, the hydrolysis of sphingomyelin
CC to form ceramide and phosphocholine (PubMed:10608884). Also hydrolyzes
CC 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine (lyso-platelet-activating
CC factor) in vivo (PubMed:10608884). Also acts on 1-acyl-2-lyso-sn-
CC glycero-3-phosphocholine (lyso-PC) and sphingosylphosphocholine
CC (PubMed:10608884, PubMed:14741383). {ECO:0000269|PubMed:10608884,
CC ECO:0000269|PubMed:14741383}.
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:10608884, ECO:0000269|PubMed:14741383};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19254;
CC Evidence={ECO:0000305|PubMed:10608884};
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:0000269|PubMed:14741383};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45301;
CC Evidence={ECO:0000305|PubMed:14741383};
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:0000269|PubMed:10608884, ECO:0000269|PubMed:14741383};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39924;
CC Evidence={ECO:0000305|PubMed:14741383};
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:0000269|PubMed:10608884};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36088;
CC Evidence={ECO:0000305|PubMed:10608884};
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:0000269|PubMed:14741383};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41120;
CC Evidence={ECO:0000305|PubMed:14741383};
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:0000269|PubMed:14741383};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45297;
CC Evidence={ECO:0000305|PubMed:14741383};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10608884};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=26.2 uM for sphingomyelin (at pH 7.4 and 37 degrees Celsius in the
CC presence of 0.05% Triton X-100) {ECO:0000269|PubMed:10608884};
CC KM=26.9 uM for 1-O-octadecyl-sn-glycero-3-phosphocholine (at pH 7.4
CC and 37 degrees Celsius) {ECO:0000269|PubMed:10608884};
CC KM=27.1 uM for 1-O-hexadecyl-sn-glycero-3-phosphocholine (at pH 7.4
CC and 37 degrees Celsius) {ECO:0000269|PubMed:10608884};
CC Vmax=367 nmol/h/mg enzyme with sphingomyelin as substrate (at pH 7.5
CC and 37 degrees Celsius in presence of 0.1% Triton X-100)
CC {ECO:0000269|PubMed:14741383};
CC Vmax=434 nmol/h/mg enzyme with sphingosylphosphocholine as substrate
CC (at pH 7.5 and 37 degrees Celsius) {ECO:0000269|PubMed:14741383};
CC Vmax=349 nmol/h/mg enzyme with 1-O-octadecyl-sn-glycero-3-
CC phosphocholine as substrate (at pH 7.5 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:14741383};
CC Vmax=611 nmol/h/mg enzyme with 1-hexadecanoyl-sn-glycero-3-
CC phosphocholine as substrate (at pH 7.5 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:14741383};
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC {ECO:0000269|PubMed:10608884, ECO:0000269|PubMed:14741383}.
CC -!- INTERACTION:
CC O60906; P53367: ARFIP1; NbExp=3; IntAct=EBI-12828299, EBI-2808808;
CC O60906; O00622: CCN1; NbExp=3; IntAct=EBI-12828299, EBI-1237454;
CC O60906; Q8NI60: COQ8A; NbExp=3; IntAct=EBI-12828299, EBI-745535;
CC O60906; Q05329: GAD2; NbExp=3; IntAct=EBI-12828299, EBI-9304251;
CC O60906; Q9ULP0-2: NDRG4; NbExp=3; IntAct=EBI-12828299, EBI-11978907;
CC O60906; Q96AL5: PBX3; NbExp=3; IntAct=EBI-12828299, EBI-741171;
CC O60906; O15173: PGRMC2; NbExp=3; IntAct=EBI-12828299, EBI-1050125;
CC O60906; Q9UKF7-2: PITPNC1; NbExp=3; IntAct=EBI-12828299, EBI-14223623;
CC O60906; Q9Y371: SH3GLB1; NbExp=3; IntAct=EBI-12828299, EBI-2623095;
CC O60906; Q14973: SLC10A1; NbExp=3; IntAct=EBI-12828299, EBI-3923031;
CC O60906; Q9UHI5: SLC7A8; NbExp=3; IntAct=EBI-12828299, EBI-13292283;
CC O60906; P49675: STAR; NbExp=3; IntAct=EBI-12828299, EBI-722932;
CC O60906; Q9NUH8: TMEM14B; NbExp=3; IntAct=EBI-12828299, EBI-8638294;
CC O60906; Q9NRX6: TMEM167B; NbExp=3; IntAct=EBI-12828299, EBI-17684533;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O70572};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- SIMILARITY: Belongs to the neutral sphingomyelinase family.
CC {ECO:0000305}.
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DR EMBL; AJ222801; CAA10995.1; -; mRNA.
DR EMBL; AL109947; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000038; AAH00038.1; -; mRNA.
DR CCDS; CCDS5075.1; -.
DR RefSeq; NP_003071.2; NM_003080.2.
DR AlphaFoldDB; O60906; -.
DR BioGRID; 112494; 84.
DR IntAct; O60906; 43.
DR MINT; O60906; -.
DR STRING; 9606.ENSP00000258052; -.
DR BindingDB; O60906; -.
DR ChEMBL; CHEMBL4712; -.
DR SwissLipids; SLP:000000174; -.
DR iPTMnet; O60906; -.
DR PhosphoSitePlus; O60906; -.
DR BioMuta; SMPD2; -.
DR EPD; O60906; -.
DR jPOST; O60906; -.
DR MassIVE; O60906; -.
DR MaxQB; O60906; -.
DR PaxDb; O60906; -.
DR PeptideAtlas; O60906; -.
DR PRIDE; O60906; -.
DR ProteomicsDB; 49663; -.
DR Antibodypedia; 19179; 215 antibodies from 30 providers.
DR DNASU; 6610; -.
DR Ensembl; ENST00000258052.8; ENSP00000258052.3; ENSG00000135587.9.
DR GeneID; 6610; -.
DR KEGG; hsa:6610; -.
DR MANE-Select; ENST00000258052.8; ENSP00000258052.3; NM_003080.3; NP_003071.2.
DR UCSC; uc003pti.4; human.
DR CTD; 6610; -.
DR DisGeNET; 6610; -.
DR GeneCards; SMPD2; -.
DR HGNC; HGNC:11121; SMPD2.
DR HPA; ENSG00000135587; Tissue enhanced (testis).
DR MIM; 603498; gene.
DR neXtProt; NX_O60906; -.
DR OpenTargets; ENSG00000135587; -.
DR PharmGKB; PA35970; -.
DR VEuPathDB; HostDB:ENSG00000135587; -.
DR eggNOG; KOG3873; Eukaryota.
DR GeneTree; ENSGT00390000009166; -.
DR HOGENOM; CLU_034001_4_0_1; -.
DR InParanoid; O60906; -.
DR OMA; IEVNCQV; -.
DR OrthoDB; 589366at2759; -.
DR PhylomeDB; O60906; -.
DR TreeFam; TF313899; -.
DR BRENDA; 3.1.4.12; 2681.
DR PathwayCommons; O60906; -.
DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism.
DR Reactome; R-HSA-193681; Ceramide signalling.
DR Reactome; R-HSA-5626978; TNFR1-mediated ceramide production.
DR SignaLink; O60906; -.
DR UniPathway; UPA00222; -.
DR BioGRID-ORCS; 6610; 13 hits in 1079 CRISPR screens.
DR GeneWiki; SMPD2; -.
DR GenomeRNAi; 6610; -.
DR Pharos; O60906; Tchem.
DR PRO; PR:O60906; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; O60906; protein.
DR Bgee; ENSG00000135587; Expressed in right uterine tube and 116 other tissues.
DR ExpressionAtlas; O60906; baseline and differential.
DR Genevisible; O60906; HS.
DR GO; GO:0005901; C:caveola; IBA:GO_Central.
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; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
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; IDA:UniProtKB.
DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0046513; P:ceramide biosynthetic process; IBA:GO_Central.
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..423
FT /note="Sphingomyelin phosphodiesterase 2"
FT /id="PRO_0000075686"
FT TRANSMEM 330..350
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 354..374
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 400..423
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
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"
FT VARIANT 3
FT /note="P -> L (in dbSNP:rs1048197)"
FT /evidence="ECO:0000269|PubMed:9520418"
FT /id="VAR_050305"
FT VARIANT 223
FT /note="V -> I (in dbSNP:rs9386806)"
FT /id="VAR_050306"
FT VARIANT 265
FT /note="R -> S (in dbSNP:rs1476387)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:9520418"
FT /id="VAR_024181"
SQ SEQUENCE 423 AA; 47646 MW; 3C1514CE21560501 CRC64;
MKPNFSLRLR IFNLNCWGIP YLSKHRADRM RRLGDFLNQE SFDLALLEEV WSEQDFQYLR
QKLSPTYPAA HHFRSGIIGS GLCVFSKHPI QELTQHIYTL NGYPYMIHHG DWFSGKAVGL
LVLHLSGMVL NAYVTHLHAE YNRQKDIYLA HRVAQAWELA QFIHHTSKKA DVVLLCGDLN
MHPEDLGCCL LKEWTGLHDA YLETRDFKGS EEGNTMVPKN CYVSQQELKP FPFGVRIDYV
LYKAVSGFYI SCKSFETTTG FDPHRGTPLS DHEALMATLF VRHSPPQQNP SSTHGPAERS
PLMCVLKEAW TELGLGMAQA RWWATFASYV IGLGLLLLAL LCVLAAGGGA GEAAILLWTP
SVGLVLWAGA FYLFHVQEVN GLYRAQAELQ HVLGRAREAQ DLGPEPQPAL LLGQQEGDRT
KEQ
