ID   SAMD8_HUMAN             Reviewed;         415 AA.
AC   Q96LT4; Q5JSC5; Q5JSC8; Q66K52;
DT   01-MAR-2004, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2004, sequence version 2.
DT   24-JAN-2024, entry version 168.
DE   RecName: Full=Sphingomyelin synthase-related protein 1 {ECO:0000305};
DE            Short=SMSr;
DE            EC=2.7.8.- {ECO:0000269|PubMed:19506037};
DE   AltName: Full=Ceramide phosphoethanolamine synthase;
DE            Short=CPE synthase;
DE   AltName: Full=Sterile alpha motif domain-containing protein 8;
DE            Short=SAM domain-containing protein 8;
GN   Name=SAMD8 {ECO:0000312|HGNC:HGNC:26320};
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 {ECO:0000312|EMBL:BAB71586.1};
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Huitema K.;
RL   Submitted (FEB-2003) to UniProtKB.
RN   [2] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Cerebellum {ECO:0000312|EMBL:BAB71586.1};
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15164054; DOI=10.1038/nature02462;
RA   Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA   Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA   Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA   Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA   Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA   Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA   Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA   Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA   Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA   Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA   Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA   Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA   McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA   Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA   Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA   Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA   Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA   Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA   Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA   Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA   Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 10.";
RL   Nature 429:375-381(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Lung;
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   [6]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 198-359 (ISOFORM 1).
RA   Ebert L., Heil O., Hennig S., Neubert P., Partsch E., Peters M.,
RA   Radelof U., Schneider D., Korn B.;
RL   Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN   [7] {ECO:0000305}
RP   IDENTIFICATION.
RX   PubMed=14685263; DOI=10.1038/sj.emboj.7600034;
RA   Huitema K., Van Den Dikkenberg J., Brouwers J.F.H.M., Holthuis J.C.;
RT   "Identification of a family of animal sphingomyelin synthases.";
RL   EMBO J. 23:33-44(2004).
RN   [8]
RP   SUBSTRATE SPECIFICITY, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF
RP   ASP-348, IDENTIFICATION BY MASS SPECTROMETRY, AND CATALYTIC ACTIVITY.
RX   PubMed=19506037; DOI=10.1083/jcb.200903152;
RA   Vacaru A.M., Tafesse F.G., Ternes P., Kondylis V., Hermansson M.,
RA   Brouwers J.F., Somerharju P., Rabouille C., Holthuis J.C.;
RT   "Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis
RT   in the ER.";
RL   J. Cell Biol. 185:1013-1027(2009).
CC   -!- FUNCTION: Sphingomyelin synthases synthesize sphingolipids through
CC       transfer of a phosphatidyl head group on to the primary hydroxyl of
CC       ceramide. SAMD8 is an endoplasmic reticulum (ER) transferase that has
CC       no sphingomyelin synthase activity but can convert
CC       phosphatidylethanolamine (PE) and ceramide to ceramide
CC       phosphoethanolamine (CPE) albeit with low product yield. Appears to
CC       operate as a ceramide sensor to control ceramide homeostasis in the
CC       endoplasmic reticulum rather than a converter of ceramides. Seems to be
CC       critical for the integrity of the early secretory pathway.
CC       {ECO:0000269|PubMed:19506037}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + N-
CC         hexadecanoylsphinganine = a 1,2-diacyl-sn-glycerol + N-hexadecanoyl-
CC         sphinganine-1-phosphoethanolamine; Xref=Rhea:RHEA:42128,
CC         ChEBI:CHEBI:17815, ChEBI:CHEBI:64612, ChEBI:CHEBI:67042,
CC         ChEBI:CHEBI:78654; Evidence={ECO:0000269|PubMed:19506037};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42129;
CC         Evidence={ECO:0000305|PubMed:19506037};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + N-
CC         hexadecanoyl-(4R)-hydroxysphinganine = a 1,2-diacyl-sn-glycerol + N-
CC         hexadecanoyl-(4R)-hydroxysphinganine-1-phosphoethanolamine;
CC         Xref=Rhea:RHEA:42144, ChEBI:CHEBI:17815, ChEBI:CHEBI:64612,
CC         ChEBI:CHEBI:65107, ChEBI:CHEBI:78656;
CC         Evidence={ECO:0000269|PubMed:19506037};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42145;
CC         Evidence={ECO:0000305|PubMed:19506037};
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:19506037}; Multi-pass membrane protein
CC       {ECO:0000269|PubMed:19506037}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q96LT4-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q96LT4-2; Sequence=VSP_038403, VSP_038404;
CC   -!- DOMAIN: The SAM domain is required to retain SMAD8 in the endoplasmic
CC       reticulum.
CC   -!- SIMILARITY: Belongs to the sphingomyelin synthase family.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH80593.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AK057811; BAB71586.1; -; mRNA.
DR   EMBL; AL392111; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471083; EAW54566.1; -; Genomic_DNA.
DR   EMBL; CH471083; EAW54567.1; -; Genomic_DNA.
DR   EMBL; BC080593; AAH80593.1; ALT_INIT; mRNA.
DR   EMBL; BX280496; -; NOT_ANNOTATED_CDS; mRNA.
DR   CCDS; CCDS53543.1; -. [Q96LT4-1]
DR   CCDS; CCDS7347.1; -. [Q96LT4-2]
DR   RefSeq; NP_001167627.1; NM_001174156.1. [Q96LT4-1]
DR   RefSeq; NP_653261.1; NM_144660.2. [Q96LT4-2]
DR   RefSeq; XP_005269598.1; XM_005269541.4. [Q96LT4-1]
DR   RefSeq; XP_011537613.1; XM_011539311.1.
DR   RefSeq; XP_011537614.1; XM_011539312.2. [Q96LT4-1]
DR   RefSeq; XP_016871228.1; XM_017015739.1.
DR   AlphaFoldDB; Q96LT4; -.
DR   SMR; Q96LT4; -.
DR   BioGRID; 126778; 8.
DR   IntAct; Q96LT4; 4.
DR   STRING; 9606.ENSP00000500411; -.
DR   SwissLipids; SLP:000000704; -.
DR   iPTMnet; Q96LT4; -.
DR   PhosphoSitePlus; Q96LT4; -.
DR   SwissPalm; Q96LT4; -.
DR   BioMuta; SAMD8; -.
DR   DMDM; 44888529; -.
DR   EPD; Q96LT4; -.
DR   jPOST; Q96LT4; -.
DR   MassIVE; Q96LT4; -.
DR   MaxQB; Q96LT4; -.
DR   PaxDb; 9606-ENSP00000438042; -.
DR   PeptideAtlas; Q96LT4; -.
DR   ProteomicsDB; 77245; -. [Q96LT4-1]
DR   ProteomicsDB; 77246; -. [Q96LT4-2]
DR   Antibodypedia; 29663; 128 antibodies from 23 providers.
DR   DNASU; 142891; -.
DR   Ensembl; ENST00000372687.4; ENSP00000361772.3; ENSG00000156671.15. [Q96LT4-2]
DR   Ensembl; ENST00000542569.6; ENSP00000438042.1; ENSG00000156671.15. [Q96LT4-1]
DR   Ensembl; ENST00000671800.1; ENSP00000500411.1; ENSG00000156671.15. [Q96LT4-1]
DR   GeneID; 142891; -.
DR   KEGG; hsa:142891; -.
DR   MANE-Select; ENST00000542569.6; ENSP00000438042.1; NM_001174156.2; NP_001167627.1.
DR   UCSC; uc001jwx.2; human. [Q96LT4-1]
DR   AGR; HGNC:26320; -.
DR   CTD; 142891; -.
DR   DisGeNET; 142891; -.
DR   GeneCards; SAMD8; -.
DR   HGNC; HGNC:26320; SAMD8.
DR   HPA; ENSG00000156671; Low tissue specificity.
DR   MIM; 611575; gene.
DR   neXtProt; NX_Q96LT4; -.
DR   OpenTargets; ENSG00000156671; -.
DR   PharmGKB; PA134868247; -.
DR   VEuPathDB; HostDB:ENSG00000156671; -.
DR   eggNOG; KOG3058; Eukaryota.
DR   GeneTree; ENSGT00940000155540; -.
DR   HOGENOM; CLU_027104_1_1_1; -.
DR   InParanoid; Q96LT4; -.
DR   OrthoDB; 1343173at2759; -.
DR   PhylomeDB; Q96LT4; -.
DR   TreeFam; TF314547; -.
DR   PathwayCommons; Q96LT4; -.
DR   Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR   SignaLink; Q96LT4; -.
DR   BioGRID-ORCS; 142891; 9 hits in 1155 CRISPR screens.
DR   ChiTaRS; SAMD8; human.
DR   GenomeRNAi; 142891; -.
DR   Pharos; Q96LT4; Tbio.
DR   PRO; PR:Q96LT4; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; Q96LT4; Protein.
DR   Bgee; ENSG00000156671; Expressed in medial globus pallidus and 189 other cell types or tissues.
DR   ExpressionAtlas; Q96LT4; baseline and differential.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR   GO; GO:0047493; F:ceramide cholinephosphotransferase activity; IBA:GO_Central.
DR   GO; GO:0002950; F:ceramide phosphoethanolamine synthase activity; TAS:Reactome.
DR   GO; GO:0033188; F:sphingomyelin synthase activity; IBA:GO_Central.
DR   GO; GO:0046513; P:ceramide biosynthetic process; IDA:UniProtKB.
DR   GO; GO:1905373; P:ceramide phosphoethanolamine biosynthetic process; IEA:Ensembl.
DR   GO; GO:2000303; P:regulation of ceramide biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0030148; P:sphingolipid biosynthetic process; TAS:Reactome.
DR   GO; GO:0006686; P:sphingomyelin biosynthetic process; NAS:UniProtKB.
DR   CDD; cd09515; SAM_SGMS1-like; 1.
DR   Gene3D; 1.10.150.50; Transcription Factor, Ets-1; 1.
DR   InterPro; IPR001660; SAM.
DR   InterPro; IPR013761; SAM/pointed_sf.
DR   InterPro; IPR045221; Sphingomyelin_synth-like.
DR   InterPro; IPR025749; Sphingomyelin_synth-like_dom.
DR   PANTHER; PTHR21290:SF25; SPHINGOMYELIN SYNTHASE-RELATED PROTEIN 1; 1.
DR   PANTHER; PTHR21290; SPHINGOMYELIN SYNTHETASE; 1.
DR   Pfam; PF14360; PAP2_C; 1.
DR   Pfam; PF00536; SAM_1; 1.
DR   SMART; SM00454; SAM; 1.
DR   SUPFAM; SSF47769; SAM/Pointed domain; 1.
DR   PROSITE; PS50105; SAM_DOMAIN; 1.
DR   Genevisible; Q96LT4; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Endoplasmic reticulum; Lipid metabolism; Membrane;
KW   Reference proteome; Sphingolipid metabolism; Transferase; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..415
FT                   /note="Sphingomyelin synthase-related protein 1"
FT                   /id="PRO_0000221080"
FT   TRANSMEM        153..173
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        201..221
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        232..252
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        277..297
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        322..342
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        347..367
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        368..415
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          12..78
FT                   /note="SAM"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT   ACT_SITE        301
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        344
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        348
FT   VAR_SEQ         315..326
FT                   /note="YTPRSWNFLHTL -> CKYLFSASMRIR (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_038403"
FT   VAR_SEQ         327..415
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_038404"
FT   MUTAGEN         348
FT                   /note="D->E: Abolishes CPE synthase activity."
FT                   /evidence="ECO:0000269|PubMed:19506037"
SQ   SEQUENCE   415 AA;  48321 MW;  AAED366F56C9CDC9 CRC64;
     MAGPNQLCIR RWTTKHVAVW LKDEGFFEYV DILCNKHRLD GITLLTLTEY DLRSPPLEIK
     VLGDIKRLML SVRKLQKIHI DVLEEMGYNS DSPMGSMTPF ISALQSTDWL CNGELSHDCD
     GPITDLNSDQ YQYMNGKNKH SVRRLDPEYW KTILSCIYVF IVFGFTSFIM VIVHERVPDM
     QTYPPLPDIF LDSVPRIPWA FAMTEVCGMI LCYIWLLVLL LHKHRSILLR RLCSLMGTVF
     LLRCFTMFVT SLSVPGQHLQ CTGKIYGSVW EKLHRAFAIW SGFGMTLTGV HTCGDYMFSG
     HTVVLTMLNF FVTEYTPRSW NFLHTLSWVL NLFGIFFILA AHEHYSIDVF IAFYITTRLF
     LYYHTLANTR AYQQSRRARI WFPMFSFFEC NVNGTVPNEY CWPFSKPAIM KRLIG
//