ID   ACER1_MOUSE             Reviewed;         273 AA.
AC   Q8R4X1; A1L3S2;
DT   25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2002, sequence version 1.
DT   27-MAR-2024, entry version 134.
DE   RecName: Full=Alkaline ceramidase 1 {ECO:0000305};
DE            Short=AlkCDase 1;
DE            Short=Alkaline CDase 1;
DE            Short=maCER1;
DE            EC=3.5.1.- {ECO:0000250|UniProtKB:Q8TDN7};
DE            EC=3.5.1.23 {ECO:0000269|PubMed:12783875, ECO:0000269|PubMed:27126290, ECO:0000269|PubMed:29056331};
DE   AltName: Full=Acylsphingosine deacylase 3;
DE   AltName: Full=N-acylsphingosine amidohydrolase 3;
GN   Name=Acer1 {ECO:0000312|MGI:MGI:2181962}; Synonyms=Asah3;
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, SUBSTRATE
RP   SPECIFICITY, PATHWAY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES,
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=12783875; DOI=10.1074/jbc.m303875200;
RA   Mao C., Xu R., Szulc Z.M., Bielawski J., Becker K.P., Bielawska A.,
RA   Galadari S.H., Hu W., Obeid L.M.;
RT   "Cloning and characterization of a mouse endoplasmic reticulum alkaline
RT   ceramidase: an enzyme that preferentially regulates metabolism of very long
RT   chain ceramides.";
RL   J. Biol. Chem. 278:31184-31191(2003).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Skin, and Tongue;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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, PATHWAY, TISSUE SPECIFICITY, AND DISRUPTION
RP   PHENOTYPE.
RX   PubMed=27126290; DOI=10.1002/path.4737;
RA   Liakath-Ali K., Vancollie V.E., Lelliott C.J., Speak A.O., Lafont D.,
RA   Protheroe H.J., Ingvorsen C., Galli A., Green A., Gleeson D., Ryder E.,
RA   Glover L., Vizcay-Barrena G., Karp N.A., Arends M.J., Brenn T., Spiegel S.,
RA   Adams D.J., Watt F.M., van der Weyden L.;
RT   "Alkaline ceramidase 1 is essential for mammalian skin homeostasis and
RT   regulating whole-body energy expenditure.";
RL   J. Pathol. 239:374-383(2016).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX   PubMed=29056331; DOI=10.1016/j.stemcr.2017.09.015;
RA   Lin C.L., Xu R., Yi J.K., Li F., Chen J., Jones E.C., Slutsky J.B.,
RA   Huang L., Rigas B., Cao J., Zhong X., Snider A.J., Obeid L.M., Hannun Y.A.,
RA   Mao C.;
RT   "Alkaline Ceramidase 1 Protects Mice from Premature Hair Loss by
RT   Maintaining the Homeostasis of Hair Follicle Stem Cells.";
RL   Stem Cell Reports 9:1488-1500(2017).
CC   -!- FUNCTION: Endoplasmic reticulum ceramidase that catalyzes the
CC       hydrolysis of ceramides into sphingosine and free fatty acids at
CC       alkaline pH (PubMed:12783875). Ceramides, sphingosine, and its
CC       phosphorylated form sphingosine-1-phosphate are bioactive lipids that
CC       mediate cellular signaling pathways regulating several biological
CC       processes including cell proliferation, apoptosis and differentiation
CC       (PubMed:12783875). Exhibits a strong substrate specificity towards the
CC       natural stereoisomer of ceramides with D-erythro-sphingosine as a
CC       backbone and has a higher activity towards very long-chain unsaturated
CC       fatty acids like the C24:1-ceramide (PubMed:12783875). May also
CC       hydrolyze dihydroceramides to produce dihydrosphingosine (By
CC       similarity). ACER1 is a skin-specific ceramidase that regulates the
CC       levels of ceramides, sphingosine and sphingosine-1-phosphate in the
CC       epidermis, mediates the calcium-induced differentiation of epidermal
CC       keratinocytes and more generally plays an important role in skin
CC       homeostasis (PubMed:27126290, PubMed:29056331).
CC       {ECO:0000250|UniProtKB:Q8TDN7, ECO:0000269|PubMed:12783875,
CC       ECO:0000269|PubMed:27126290, ECO:0000269|PubMed:29056331,
CC       ECO:0000303|PubMed:12783875}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=an N-acylsphing-4-enine + H2O = a fatty acid + sphing-4-enine;
CC         Xref=Rhea:RHEA:20856, ChEBI:CHEBI:15377, ChEBI:CHEBI:28868,
CC         ChEBI:CHEBI:52639, ChEBI:CHEBI:57756; EC=3.5.1.23;
CC         Evidence={ECO:0000269|PubMed:12783875, ECO:0000269|PubMed:27126290};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20857;
CC         Evidence={ECO:0000269|PubMed:27126290};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H2O + N-tetracosanoyl-sphing-4-enine = sphing-4-enine +
CC         tetracosanoate; Xref=Rhea:RHEA:41283, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:31014, ChEBI:CHEBI:57756, ChEBI:CHEBI:72965;
CC         Evidence={ECO:0000250|UniProtKB:Q8TDN7};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41284;
CC         Evidence={ECO:0000250|UniProtKB:Q8TDN7};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=an N-acylsphinganine + H2O = a fatty acid + sphinganine;
CC         Xref=Rhea:RHEA:33551, ChEBI:CHEBI:15377, ChEBI:CHEBI:28868,
CC         ChEBI:CHEBI:31488, ChEBI:CHEBI:57817;
CC         Evidence={ECO:0000250|UniProtKB:Q8TDN7};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33552;
CC         Evidence={ECO:0000250|UniProtKB:Q8TDN7};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H2O + N-(9Z-octadecenoyl)-sphing-4-enine = (9Z)-octadecenoate
CC         + sphing-4-enine; Xref=Rhea:RHEA:41299, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:57756, ChEBI:CHEBI:77996;
CC         Evidence={ECO:0000269|PubMed:29056331};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41300;
CC         Evidence={ECO:0000250|UniProtKB:Q8TDN7};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H2O + N-(15Z-tetracosenoyl)-sphing-4-enine = (15Z)-
CC         tetracosenoate + sphing-4-enine; Xref=Rhea:RHEA:41267,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:32392, ChEBI:CHEBI:57756,
CC         ChEBI:CHEBI:74450; Evidence={ECO:0000269|PubMed:29056331};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41268;
CC         Evidence={ECO:0000250|UniProtKB:Q8TDN7};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000250|UniProtKB:Q9NUN7};
CC   -!- ACTIVITY REGULATION: Inhibited by sphingosine (PubMed:12783875).
CC       Inhibited by Mn(2+), Zn(2+), and Cu(2+) in a dose-dependent manner
CC       (PubMed:12783875). Slightly activated by Ca(2+) in a dose-dependent
CC       manner (PubMed:12783875). {ECO:0000269|PubMed:12783875}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       pH dependence:
CC         Optimum pH is 8.0. {ECO:0000269|PubMed:12783875};
CC   -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC       {ECO:0000269|PubMed:12783875, ECO:0000269|PubMed:27126290}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:12783875}; Multi-pass membrane protein
CC       {ECO:0000255}.
CC   -!- TISSUE SPECIFICITY: Highly expressed in skin. Weakly or not expressed
CC       in other tissues (PubMed:12783875). Expressed by granular layer of
CC       interfollicular epidermis, sebaceous glands and infundibulum
CC       (PubMed:29056331). {ECO:0000269|PubMed:12783875,
CC       ECO:0000269|PubMed:29056331}.
CC   -!- DISRUPTION PHENOTYPE: Homozygous knockout mice are viable and fertile,
CC       with a normal lifespan but display several postnatal skin phenotypes
CC       (PubMed:27126290, PubMed:29056331). It includes an increase in total
CC       ceramide levels in the dorsal skin, tail epidermis and dermis
CC       (PubMed:27126290, PubMed:29056331). This is associated with hair shafts
CC       and sebaceous glands abnormalities, cyclic alopecia, a progressive loss
CC       of hair follicle stem cells, hyperproliferation, inflammation and
CC       abnormal differentiation of the epidermis and results in increased
CC       transepidermal water loss and reduction of fat content during aging
CC       (PubMed:27126290, PubMed:29056331). {ECO:0000269|PubMed:27126290,
CC       ECO:0000269|PubMed:29056331}.
CC   -!- SIMILARITY: Belongs to the alkaline ceramidase family. {ECO:0000305}.
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DR   EMBL; AF347023; AAL83821.1; -; mRNA.
DR   EMBL; AK028901; BAC26186.1; -; mRNA.
DR   EMBL; AK075884; BAC36029.1; -; mRNA.
DR   EMBL; BC130254; AAI30255.1; -; mRNA.
DR   CCDS; CCDS28919.1; -.
DR   RefSeq; NP_783858.1; NM_175731.4.
DR   AlphaFoldDB; Q8R4X1; -.
DR   SMR; Q8R4X1; -.
DR   STRING; 10090.ENSMUSP00000062037; -.
DR   SwissLipids; SLP:000000676; -.
DR   PaxDb; 10090-ENSMUSP00000062037; -.
DR   ProteomicsDB; 285537; -.
DR   Antibodypedia; 49939; 162 antibodies from 24 providers.
DR   DNASU; 171168; -.
DR   Ensembl; ENSMUST00000056113.5; ENSMUSP00000062037.5; ENSMUSG00000045019.5.
DR   GeneID; 171168; -.
DR   KEGG; mmu:171168; -.
DR   UCSC; uc008ddl.1; mouse.
DR   AGR; MGI:2181962; -.
DR   CTD; 125981; -.
DR   MGI; MGI:2181962; Acer1.
DR   VEuPathDB; HostDB:ENSMUSG00000045019; -.
DR   eggNOG; KOG2329; Eukaryota.
DR   GeneTree; ENSGT00730000110920; -.
DR   HOGENOM; CLU_088280_1_0_1; -.
DR   InParanoid; Q8R4X1; -.
DR   OMA; NYKHSEH; -.
DR   OrthoDB; 2910516at2759; -.
DR   PhylomeDB; Q8R4X1; -.
DR   TreeFam; TF313019; -.
DR   BRENDA; 3.5.1.23; 3474.
DR   Reactome; R-MMU-428157; Sphingolipid metabolism.
DR   UniPathway; UPA00222; -.
DR   BioGRID-ORCS; 171168; 2 hits in 80 CRISPR screens.
DR   ChiTaRS; Acer1; mouse.
DR   PRO; PR:Q8R4X1; -.
DR   Proteomes; UP000000589; Chromosome 17.
DR   RNAct; Q8R4X1; Protein.
DR   Bgee; ENSMUSG00000045019; Expressed in skin of external ear and 35 other cell types or tissues.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0102121; F:ceramidase activity; IEA:UniProtKB-EC.
DR   GO; GO:0071633; F:dihydroceramidase activity; ISS:UniProtKB.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0017040; F:N-acylsphingosine amidohydrolase activity; IDA:UniProtKB.
DR   GO; GO:0030154; P:cell differentiation; ISO:MGI.
DR   GO; GO:0071277; P:cellular response to calcium ion; ISO:MGI.
DR   GO; GO:0046514; P:ceramide catabolic process; IDA:MGI.
DR   GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl.
DR   GO; GO:0019216; P:regulation of lipid metabolic process; IDA:MGI.
DR   GO; GO:0010446; P:response to alkaline pH; ISO:MGI.
DR   GO; GO:0048733; P:sebaceous gland development; IMP:UniProtKB.
DR   GO; GO:0030148; P:sphingolipid biosynthetic process; ISO:MGI.
DR   GO; GO:0006665; P:sphingolipid metabolic process; IDA:MGI.
DR   GO; GO:0046512; P:sphingosine biosynthetic process; IMP:UniProtKB.
DR   InterPro; IPR008901; ACER.
DR   PANTHER; PTHR46139; ALKALINE CERAMIDASE; 1.
DR   PANTHER; PTHR46139:SF2; ALKALINE CERAMIDASE 1; 1.
DR   Pfam; PF05875; Ceramidase; 1.
DR   Genevisible; Q8R4X1; MM.
PE   1: Evidence at protein level;
KW   Calcium; Endoplasmic reticulum; Hydrolase; Lipid metabolism; Membrane;
KW   Metal-binding; Reference proteome; Sphingolipid metabolism; Transmembrane;
KW   Transmembrane helix; Zinc.
FT   CHAIN           1..273
FT                   /note="Alkaline ceramidase 1"
FT                   /id="PRO_0000247746"
FT   TOPO_DOM        1..36
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        37..57
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        58..72
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        73..93
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        94..114
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        115..126
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        127..147
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        148..149
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        150..167
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        168..177
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        178..198
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        199..215
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        216..236
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        237..273
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   BINDING         22
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT   BINDING         23
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT   BINDING         25
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT   BINDING         27
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT   BINDING         36
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT   BINDING         86
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT   BINDING         215
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT   BINDING         219
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NUN7"
SQ   SEQUENCE   273 AA;  32082 MW;  0B84D015D7870219 CRC64;
     MHVPGTRAKM SSIFAYQSSE VDWCESNFQH SELVAEFYNT FSNVFFLIFG PLMMFLMHPY
     AQKRTRCFYG VSVLFMLIGL FSMYFHMTLS FLGQLLDEIS ILWLLASGYS VWLPRCYFPK
     FVKGNRFYFS CLVTITTIIS TFLTFVKPTV NAYALNSIAI HILYIVRTEY KKIRDDDLRH
     LIAVSVVLWA AALTSWISDR VLCSFWQRIH FYYLHSIWHV LISITFPYGI VTMALVDAKY
     EMPDKTLKVH YWPRDSWVIG LPYVEIQEND KNC
//