ACER1_MOUSE
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 03-AUG-2022, entry version 125.
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; Q8R4X1; -.
DR PRIDE; Q8R4X1; -.
DR ProteomicsDB; 285537; -.
DR Antibodypedia; 49939; 144 antibodies from 24 providers.
DR DNASU; 171168; -.
DR Ensembl; ENSMUST00000056113; ENSMUSP00000062037; ENSMUSG00000045019.
DR GeneID; 171168; -.
DR KEGG; mmu:171168; -.
DR UCSC; uc008ddl.1; mouse.
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; WTLAVAY; -.
DR OrthoDB; 969354at2759; -.
DR PhylomeDB; Q8R4X1; -.
DR TreeFam; TF313019; -.
DR BRENDA; 3.5.1.23; 3474.
DR Reactome; R-MMU-1660661; Sphingolipid de novo biosynthesis.
DR UniPathway; UPA00222; -.
DR BioGRID-ORCS; 171168; 2 hits in 75 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 tissues.
DR Genevisible; Q8R4X1; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0033561; P:regulation of water loss via skin; IMP:UniProtKB.
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; PTHR46139; 1.
DR Pfam; PF05875; Ceramidase; 1.
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
