ACER1

Summary

ACER1 (alkaline ceramidase 1, HGNC:18356) is a protein-coding gene on chromosome 19p13.3, encoding Alkaline ceramidase 1 (Q8TDN7). Endoplasmic reticulum ceramidase that catalyzes the hydrolysis of ceramides into sphingosine and free fatty acids at alkaline pH.

Ceramides are synthesized during epidermal differentiation and accumulate within the interstices of the stratum corneum, where they represent critical components of the epidermal permeability barrier. Excess cellular ceramide can trigger antimitogenic signals and induce apoptosis, and the ceramide metabolites sphingosine and sphingosine-1-phosphate (S1P) are important bioregulatory molecules. Ceramide hydrolysis in the nucleated cell layers regulates keratinocyte proliferation and apoptosis in response to external stress. Ceramide hydrolysis also occurs at the stratum corneum, releasing free sphingoid base that functions as an endogenous antimicrobial agent. ACER1 is highly expressed in epidermis and catalyzes the hydrolysis of very long chain ceramides to generate sphingosine (Houben et al., 2006 [PubMed 16477081]; Sun et al., 2008 [PubMed 17713573]).

Source: NCBI Gene 125981 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 60 total — 3 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_133492

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18356
Approved symbol	ACER1
Name	alkaline ceramidase 1
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167769
Ensembl biotype	protein_coding
OMIM	613491
Entrez	125981

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000301452

RefSeq mRNA: 1 — MANE Select: NM_133492 NM_133492

CCDS: CCDS12161

Canonical transcript exons

ENST00000301452 — 6 exons

Exon	Start	End
ENSE00001116785	6312385	6312499
ENSE00001116786	6312149	6312290
ENSE00001160535	6307153	6307290
ENSE00001160540	6309697	6309834
ENSE00001160559	6306142	6306882
ENSE00001312002	6333459	6333612

Expression profiles

Bgee: expression breadth broad, 97 present calls, max score 93.72.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0945 / max 54.2817, expressed in 18 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178615	0.0584	15
178616	0.0361	11

Top tissues by expression

214 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	93.72	gold quality
skin of abdomen	UBERON:0001416	93.24	gold quality
zone of skin	UBERON:0000014	92.02	gold quality
lower esophagus mucosa	UBERON:0035834	89.37	gold quality
upper leg skin	UBERON:0004262	81.54	gold quality
mammalian vulva	UBERON:0000997	81.00	gold quality
penis	UBERON:0000989	72.51	gold quality
nipple	UBERON:0002030	72.24	gold quality
esophagus mucosa	UBERON:0002469	71.83	gold quality
esophagus squamous epithelium	UBERON:0006920	65.65	silver quality
gingival epithelium	UBERON:0001949	64.27	gold quality
oral cavity	UBERON:0000167	62.63	gold quality
sperm	CL:0000019	60.36	gold quality
vagina	UBERON:0000996	59.56	gold quality
vena cava	UBERON:0004087	59.11	silver quality
lateral globus pallidus	UBERON:0002476	58.84	gold quality
lateral nuclear group of thalamus	UBERON:0002736	58.10	gold quality
saphenous vein	UBERON:0007318	57.96	gold quality
substantia nigra pars reticulata	UBERON:0001966	57.91	gold quality
skin of hip	UBERON:0001554	57.74	silver quality
pharyngeal mucosa	UBERON:0000355	57.46	gold quality
myocardium	UBERON:0002349	57.40	gold quality
trachea	UBERON:0003126	57.35	gold quality
endothelial cell	CL:0000115	57.23	gold quality
esophagus	UBERON:0001043	57.10	gold quality
subthalamic nucleus	UBERON:0001906	56.97	gold quality
tongue	UBERON:0001723	56.88	gold quality
substantia nigra pars compacta	UBERON:0001965	56.88	gold quality
pericardium	UBERON:0002407	56.88	gold quality
inferior vagus X ganglion	UBERON:0005363	56.83	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting ACER1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-7154-3P	97.65	65.02	985
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-4462	95.10	66.27	172
HSA-MIR-3914	94.91	65.77	643

Literature-anchored findings (GeneRIF, showing 2)

• regulates the signaling system mediated by sphingolipids (PMID:11915342)
• upregulation of haCER1 and AC mediates the Ca2+(o)-induced growth arrest and differentiation of keratinocytes by generating sphingosine and its phosphate (PMID:17713573)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	acer1	ENSDARG00000010347
mus_musculus	Acer1	ENSMUSG00000045019
rattus_norvegicus	Acer1	ENSRNOG00000047368
caenorhabditis_elegans		WBGENE00020947

Paralogs (2): ACER3 (ENSG00000078124), ACER2 (ENSG00000177076)

Protein

Protein identifiers

Alkaline ceramidase 1 — Q8TDN7 (reviewed: Q8TDN7)

Alternative names: Acylsphingosine deacylase 3, N-acylsphingosine amidohydrolase 3

All UniProt accessions (1): Q8TDN7

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum ceramidase that catalyzes the hydrolysis of ceramides into sphingosine and free fatty acids at alkaline pH. Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation. Exhibits a strong substrate specificity towards the natural stereoisomer of ceramides with D-erythro-sphingosine as a backbone and has a higher activity towards very long-chain unsaturated fatty acids like the C24:1-ceramide. May also hydrolyze dihydroceramides to produce dihydrosphingosine. ACER1 is a skin-specific ceramidase that regulates the levels of ceramides, sphingosine and sphingosine-1-phosphate in the epidermis, mediates the calcium-induced differentiation of epidermal keratinocytes and more generally plays an important role in skin homeostasis.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Mainly expressed in epidermis.

Activity regulation. Inhibited by sphingosine. Activity is Ca(2+)-dependent.

Induction. Up-regulated by Ca(2+). Down-regulated by epidermal growth factor/EGF.

Pathway. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the alkaline ceramidase family.

RefSeq proteins (1): NP_597999* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008901	ACER	Family

Pfam: PF05875

Enzyme classification (BRENDA):

• EC 3.5.1.23 — ceramidase (BRENDA: 26 organisms, 303 substrates, 355 inhibitors, 64 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

43 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-LAUROYLSPHINGOSINE	0.149–0.4132	5
D-ERYTHRO-C12-4-NITROBENZO-2-OXA-1,3-DIAZOLE-CER	0.0393–0.0601	3
N-[12-[(7-NITRO-2-1,3-BENZOXADIAZOL-4-YL)AMINE]D	0.0155–0.066	3
(2R,3Z)-2-([(2E)-1-HYDROXY-12-[(7-NITRO-2,1,3-BE	0.087–0.19	2
N-[(2S,3R,4E)-1,3-DIHYDROXY-14-[(7-NITRO-2,1,3-B	0.193–0.204	2
N-[(2S,3R,4E)-1,3-DIHYDROXYNONADEC-4-EN-2-YL]-12	0.085–0.11	2
N-[(2S,3R,4E)-13-[[9-(ETHYLAMINO)-5-OXO-5H-BENZO	0.036–0.082	2
N-[(2S,3R,4E)-7-[[9-(DIETHYLAMINO)-5-OXO-5H-BENZ	0.1418–0.1818	2
(13E)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1	0.033	1
(15E)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1	0.04	1
(2R)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1-	0.042	1
(2S)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1-	0.021	1
(4E,2S,3R)-2-N-(10-PYRENEDECANOYL)-1,3,17-TRIHYD	0.0005	1
(9E)-N-[(2S,3R,4E)-1,3-DIHYDROXY-7-[(2-OXO-2H-1-	0.139	1
2,4-DIDEOXY-2-(HEXADECANOYLAMINO)-5-O-(2-OXO-2H-	0.016	1

Catalyzed reactions (Rhea), 5 shown:

• an N-acylsphing-4-enine + H2O = sphing-4-enine + a fatty acid (RHEA:20856)
• an N-acylsphinganine + H2O = sphinganine + a fatty acid (RHEA:33551)
• N-(15Z-tetracosenoyl)-sphing-4-enine + H2O = (15Z)-tetracosenoate + sphing-4-enine (RHEA:41267)
• N-tetracosanoyl-sphing-4-enine + H2O = tetracosanoate + sphing-4-enine (RHEA:41283)
• N-(9Z-octadecenoyl)-sphing-4-enine + H2O = sphing-4-enine + (9Z)-octadecenoate (RHEA:41299)

UniProt features (24 total): topological domain 8, binding site 8, transmembrane region 7, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDN7-F1	93.54	0.88

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 13; 14; 16; 18; 27; 77; 206; 210

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9845614	Sphingolipid catabolism
R-HSA-1430728	Metabolism
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 69 (showing top): GOBP_CERAMIDE_CATABOLIC_PROCESS, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_METAL_ION, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_SPHINGOID_METABOLIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_DIOL_METABOLIC_PROCESS, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_LIPID_METABOLIC_PROCESS

GO Biological Process (14): sphingolipid metabolic process (GO:0006665), epidermis development (GO:0008544), response to alkaline pH (GO:0010446), regulation of lipid metabolic process (GO:0019216), sphingolipid biosynthetic process (GO:0030148), sphingolipid catabolic process (GO:0030149), cell differentiation (GO:0030154), keratinocyte differentiation (GO:0030216), sphingosine biosynthetic process (GO:0046512), ceramide catabolic process (GO:0046514), sebaceous gland development (GO:0048733), cellular response to calcium ion (GO:0071277), lipid metabolic process (GO:0006629), ceramide metabolic process (GO:0006672)

GO Molecular Function (5): N-acylsphingosine amidohydrolase activity (GO:0017040), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sphingolipid metabolic process	3
lipid metabolic process	2
skin development	2
tissue development	1
response to pH	1
regulation of primary metabolic process	1
lipid biosynthetic process	1
lipid catabolic process	1
cellular developmental process	1
epidermal cell differentiation	1
sphingosine metabolic process	1
diol biosynthetic process	1
sphingoid biosynthetic process	1
ceramide metabolic process	1
sphingolipid catabolic process	1
gland development	1
response to calcium ion	1
cellular response to metal ion	1
primary metabolic process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
cation binding	1
binding	1
catalytic activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

642 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACER1	ASAH2	Q9NR71	855
ACER1	ASAH1	Q13510	827
ACER1	SPTLC1	O15269	772
ACER1	SPTLC2	O15270	710
ACER1	SPTLC3	Q9NUV7	700
ACER1	SMPD2	O60906	664
ACER1	CERK	Q8TCT0	655
ACER1	SPHK2	Q9NRA0	644
ACER1	SPHK1	Q9NYA1	638
ACER1	CERS4	Q9HA82	636
ACER1	CERS6	Q6ZMG9	634
ACER1	CERS3	Q8IU89	626
ACER1	UGCG	Q16739	625
ACER1	SGMS1	Q86VZ5	603
ACER1	ASAH2B	P0C7U1	577

IntAct

5 interactions, top by confidence:

A	B	Type	Score
MPP1	ACER1	psi-mi:“MI:0915”(physical association)	0.560
ACER1	UBA52	psi-mi:“MI:0915”(physical association)	0.400
MPP1	ACER1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): ACER1 (Two-hybrid), ACER1 (Proximity Label-MS), ACER1 (Affinity Capture-MS)

ESM2 similar proteins: A2A559, A2V7M9, A6H7B8, A6X919, A7YWP2, A8KBG2, A8WFS8, B2GV22, D4AD75, E1BYA3, F1Q8R9, O08888, O45145, O49639, P25625, P38298, P70245, Q0VFE3, Q15125, Q290J8, Q2ABP2, Q2ABP3, Q3SZ36, Q3TQR0, Q568I2, Q5M9A7, Q60490, Q60WT2, Q68EV0, Q6P0S3, Q753H5, Q7K0P4, Q801D8, Q801G2, Q8C2R7, Q8N4S7, Q8R4X1, Q8T8L8, Q8TDN7, Q91VH1

Diamond homologs: P38298, Q02896, Q568I2, Q5QJU3, Q8R4X1, Q8TDN7, Q8VD53, Q9D099, Q9NUN7, O45145, Q60WT2, Q9VIP7, Q6TMJ1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

60 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	49
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2684882	GRCh37/hg19 19p13.3-13.2(chr19:260912-7246777)x3	Pathogenic
564607	GRCh37/hg19 19p13.3-13.2(chr19:3120160-9732820)x3	Pathogenic
59085	GRCh38/hg38 19p13.3(chr19:4934885-6501642)x3	Pathogenic

SpliceAI

1117 predictions. Top by Δscore:

Variant	Effect	Δscore
19:6309695:A:AC	donor_gain	1.0000
19:6309695:AC:A	donor_loss	1.0000
19:6309695:ACTT:A	donor_gain	1.0000
19:6309696:C:CC	donor_gain	1.0000
19:6309696:CTT:C	donor_gain	1.0000
19:6309696:CTTC:C	donor_gain	1.0000
19:6309698:T:TA	donor_gain	1.0000
19:6312286:CAGGC:C	acceptor_gain	1.0000
19:6312291:C:CC	acceptor_gain	1.0000
19:6333455:TCACC:T	donor_loss	1.0000
19:6333456:CACCG:C	donor_loss	1.0000
19:6333457:A:AC	donor_gain	1.0000
19:6333457:AC:A	donor_gain	1.0000
19:6333458:C:CC	donor_gain	1.0000
19:6333458:CC:C	donor_gain	1.0000
19:6306846:CA:C	acceptor_gain	0.9900
19:6306851:C:CT	acceptor_gain	0.9900
19:6306878:CATGC:C	acceptor_gain	0.9900
19:6309688:TTCAC:T	donor_loss	0.9900
19:6309689:TCACT:T	donor_loss	0.9900
19:6309695:ACTTC:A	donor_gain	0.9900
19:6309696:CTTCC:C	donor_gain	0.9900
19:6309699:C:A	donor_gain	0.9900
19:6309704:ACT:A	donor_gain	0.9900
19:6309705:CTC:C	donor_gain	0.9900
19:6309707:C:CA	donor_gain	0.9900
19:6312189:T:TA	donor_gain	0.9900
19:6312287:AGGC:A	acceptor_gain	0.9900
19:6312288:GGC:G	acceptor_gain	0.9900
19:6312291:C:CG	acceptor_loss	0.9900

AlphaMissense

1762 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:6312219:A:G	W94R	0.996
19:6312219:A:T	W94R	0.996
19:6312236:T:G	D88A	0.996
19:6312236:T:A	D88V	0.995
19:6312237:C:G	D88H	0.993
19:6312271:G:C	F76L	0.993
19:6312271:G:T	F76L	0.993
19:6312273:A:G	F76L	0.993
19:6333508:C:G	C15S	0.993
19:6333509:A:T	C15S	0.993
19:6306867:G:C	S214R	0.992
19:6306867:G:T	S214R	0.992
19:6306869:T:G	S214R	0.992
19:6307158:G:C	S207R	0.992
19:6307158:G:T	S207R	0.992
19:6307160:T:G	S207R	0.992
19:6312235:G:C	D88E	0.992
19:6312235:G:T	D88E	0.992
19:6312256:G:C	S81R	0.992
19:6312256:G:T	S81R	0.992
19:6312258:T:G	S81R	0.992
19:6312270:G:C	H77D	0.992
19:6333462:G:C	N30K	0.992
19:6333462:G:T	N30K	0.992
19:6312249:C:G	G84R	0.991
19:6307220:A:G	W187R	0.990
19:6307220:A:T	W187R	0.990
19:6312236:T:C	D88G	0.990
19:6312491:A:C	N34K	0.990
19:6312491:A:T	N34K	0.990

dbSNP variants (sampled 300 via entrez): RS1000180285 (19:6353512 C>A), RS1000194419 (19:6349449 G>C,T), RS1000201033 (19:6342929 C>T), RS1000230624 (19:6311119 G>T), RS1000365049 (19:6321764 C>T), RS1000369090 (19:6315878 T>C), RS1000389766 (19:6351097 T>C), RS1000420085 (19:6306576 G>A,C), RS1000426021 (19:6311385 T>A), RS1000480485 (19:6359247 T>C), RS1000480610 (19:6319854 G>A,T), RS1000511237 (19:6320098 G>C,T), RS1000542687 (19:6335459 G>A), RS1000557198 (19:6342591 C>T), RS1000659115 (19:6315596 G>A)

Disease associations

OMIM: gene MIM:613491 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007637_20	Diffusing capacity of carbon monoxide	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009369	diffusing capacity of the lung for carbon monoxide

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3351194 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Alkaline ceramidases

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
sodium arsenate	decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
Arsenic	decreases expression, increases abundance	1
Methapyrilene	decreases methylation	1
Nickel	decreases expression	1
Aflatoxin B1	affects methylation, decreases methylation	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3381636	Binding	Inhibition of AlkCDase in microsomes of human HeLa cells using D-e-C18:1-Cer substrate up to 250 uM after 30 mins	Targeting (cellular) lysosomal acid ceramidase by B13: design, synthesis and evaluation of novel DMG-B13 ester prodrugs. — Bioorg Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.