id: P27544
gene_symbol: CERS1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Ceramide synthase 1 (CERS1; also LASS1, UOG1), a multi-pass endoplasmic reticulum
  membrane enzyme that catalyzes the N-acylation step of de novo ceramide biosynthesis.
  It transfers an acyl group from acyl-CoA onto the amino group of a sphingoid base
  (sphinganine in the de novo pathway, sphingosine in the salvage pathway) to form
  dihydroceramide/ceramide. Among the six mammalian ceramide synthases, CERS1 is highly
  selective for stearoyl-CoA (C18:0-CoA) and therefore produces predominantly
  C18-(dihydro)ceramide; the resulting dihydroceramide is desaturated by DEGS1 to ceramide.
  CERS1 is enriched in brain (neurons, cerebellar Purkinje cells) and skeletal muscle,
  where its C18-ceramide output contributes to neuronal function and, in muscle, to
  glucose metabolism and insulin sensitivity. Loss-of-function variants cause autosomal
  recessive progressive myoclonic epilepsy type 8 (EPM8), reflecting the requirement of
  C18-ceramide for neuronal survival.
alternative_products:
- name: '1'
  id: P27544-1
- name: '2'
  id: P27544-2
  sequence_note: VSP_003049
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that CERS1 acts in the endoplasmic reticulum. This is
      consistent with all experimental evidence for CerS enzymes acting at the ER membrane.
    action: ACCEPT
    reason: >-
      CERS1 is an ER membrane enzyme; the ER localization is well supported experimentally
      (H183Q variant expressed and localized properly to the ER) and by UniProt. IBA at
      the organelle level is appropriate, though ER membrane (GO:0005789) is the more precise
      compartment.
    supported_by:
    - reference_id: PMID:24782409
      supporting_text: >-
        CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the
        biosynthesis of C18-ceramides.
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that CERS1 is involved in ceramide biosynthesis. This is
      the core biological process for this gene and its orthologs across eukaryotes.
    action: ACCEPT
    reason: >-
      Ceramide biosynthesis is the defining, experimentally established role of CERS1. IBA
      correctly captures the conserved family function.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of
        ceramide synthases (CerS), each of which displays a high specificity towards acyl
        CoAs of different chain lengths
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) inference of the ceramide-synthase molecular function
      (sphingosine/sphingoid-base N-acyltransferase). This is the core catalytic activity.
    action: ACCEPT
    reason: >-
      The sphingoid-base N-acyltransferase (ceramide synthase) activity is the core molecular
      function of CERS1, established biochemically and conserved across the CerS/LAG1 family.
    supported_by:
    - reference_id: PMID:12869556
      supporting_text: >-
        several human LAG1 homologues can rescue the viability of lag1delta lac1delta yeast
        cells and restore acyl-CoA-dependent ceramide and sphingolipid
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Automated (ARBA/UniProt SubCell SL-0097) assignment to the ER membrane, the precise
      compartment where CERS1 resides as a multi-pass membrane protein.
    action: ACCEPT
    reason: >-
      Correct and appropriately specific; matches the experimentally determined ER membrane
      localization in UniProt.
    supported_by:
    - reference_id: file:human/CERS1/CERS1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro2GO (TLC domain, IPR006634) mapping to the generic term membrane. CERS1 is a
      multi-pass membrane protein, but this is far less informative than the ER membrane
      annotation also present.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not wrong, but membrane is uninformatively general given the more specific,
      experimentally supported endoplasmic reticulum membrane (GO:0005789) annotation.
    supported_by:
    - reference_id: file:human/CERS1/CERS1-uniprot.txt
      supporting_text: 'Multi-pass membrane protein'
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Automated (ARBA + ortholog P27545) assignment to ceramide biosynthetic process, the
      core BP for CERS1.
    action: ACCEPT
    reason: >-
      Redundant with the experimental and IBA ceramide biosynthetic process annotations and
      correct.
    supported_by:
    - reference_id: PMID:24782409
      supporting_text: >-
        CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the
        biosynthesis of C18-ceramides.
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated assignment (ARBA + ortholog P27545 + RHEA:23768/36691 + EC:2.3.1.24) of the
      core ceramide-synthase catalytic activity.
    action: ACCEPT
    reason: >-
      Correct core molecular function; consistent with the RHEA/EC cross-references in
      UniProt and the experimental IDA annotations.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of
        ceramide synthases (CerS)
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl ortholog-based (mouse P27545) transfer of ER localization.
    action: ACCEPT
    reason: >-
      Correct; CERS1 is an ER protein. Redundant with the experimental ER annotations.
    supported_by:
    - reference_id: PMID:12105227
      supporting_text: 'UOG1 was localized to the endoplasmic reticulum'
- term:
    id: GO:0010614
    label: negative regulation of cardiac muscle hypertrophy
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog-projected phenotype (from rat A6KA58) linking CERS1/C18-ceramide to
      suppression of cardiac muscle hypertrophy. This is a downstream physiological/phenotypic
      consequence in a specific tissue, not the enzyme's core molecular role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible tissue-specific downstream effect of altered ceramide levels, transferred from
      a rodent ortholog. Retain as non-core rather than remove, since it is an
      experimentally-anchored ortholog transfer; it does not represent the core sphingolipid
      biosynthetic function.
- term:
    id: GO:0016747
    label: acyltransferase activity, transferring groups other than amino-acyl groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl ortholog-based (mouse P27545) transfer of the parent acyltransferase activity.
      This is a broad ancestor of the specific sphingosine N-acyltransferase activity
      (GO:0050291) already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct but too general; the specific ceramide-synthase activity (GO:0050291) captures
      the same function more informatively.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of
        ceramide synthases (CerS)
- term:
    id: GO:0046325
    label: negative regulation of D-glucose import across plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog-projected (mouse P27545) role of CERS1/C18-ceramide in suppressing
      glucose uptake, consistent with UniProt's By-similarity description of a skeletal-muscle
      role in whole-body glucose metabolism. Downstream physiological effect, not core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported at the ortholog/By-similarity level as a metabolic consequence of C18-ceramide
      production; retain as a non-core downstream process rather than the core biosynthetic
      function.
    supported_by:
    - reference_id: file:human/CERS1/CERS1-uniprot.txt
      supporting_text: >-
        suppressing the uptake of glucose in multiple
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1660661
  qualifier: involved_in
  review:
    summary: >-
      Reactome (Sphingolipid de novo biosynthesis) traceable assignment of CERS1 to
      sphingolipid biosynthesis, the pathway parent of ceramide biosynthesis.
    action: ACCEPT
    reason: >-
      Correct; CERS1 performs the N-acylation step within de novo sphingolipid biosynthesis.
    supported_by:
    - reference_id: PMID:12869556
      supporting_text: >-
        several human LAG1 homologues can rescue the viability of lag1delta lac1delta yeast
        cells and restore acyl-CoA-dependent ceramide and sphingolipid
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:17977534
  qualifier: enables
  review:
    summary: >-
      Direct biochemical assay characterizing the kinetics of mammalian ceramide synthases,
      including CerS1, toward sphinganine, confirming the sphingoid-base N-acyltransferase
      (ceramide synthase) activity.
    action: ACCEPT
    reason: >-
      Core molecular function directly measured; CerS1 N-acylates sphingoid bases using
      acyl-CoA. This is one of the defining experimental annotations.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: 'K(m) values towards sphinganine'
- term:
    id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:24782409
  qualifier: is_active_in
  review:
    summary: >-
      Assignment of CERS1 activity to the cytoplasmic (cytosolic) face of the ER membrane.
      Topology studies of the CerS/Lass family place the conserved Lag1 motif with the
      C-terminal (catalytic) region facing the cytosolic side of the ER membrane.
    action: ACCEPT
    reason: >-
      Consistent with the ER membrane localization and with membrane-topology data for the
      family (C-terminus cytosolic). Retain as a refinement of the ER membrane annotation.
    supported_by:
    - reference_id: PMID:15823095
      supporting_text: >-
        the C-terminus of Lass6 faces the cytosolic side of the membrane
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway (UPA00222) mapping to the broad sphingolipid metabolic process. Correct but
      general; CERS1 specifically performs a biosynthetic step.
    action: ACCEPT
    reason: >-
      Correct parent process. The more specific sphingolipid/ceramide biosynthetic process
      annotations are also present; UniProt records the PATHWAY sphingolipid metabolism.
    supported_by:
    - reference_id: file:human/CERS1/CERS1-uniprot.txt
      supporting_text: 'Lipid metabolism; sphingolipid metabolism'
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-428185
  qualifier: enables
  review:
    summary: >-
      Reactome (Ceramide synthases transfer acyl-CoA onto sphingoid) traceable assignment of
      the core ceramide-synthase catalytic activity.
    action: ACCEPT
    reason: >-
      Correct core molecular function, redundant with the experimental and IBA annotations.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of
        ceramide synthases (CerS)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:24782409
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of CERS1 to the ER membrane (the EPM8-associated H183Q variant
      was shown to be expressed and localized properly to the ER).
    action: ACCEPT
    reason: >-
      Core, experimentally supported subcellular localization at the correct compartment.
    supported_by:
    - reference_id: PMID:24782409
      supporting_text: >-
        CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the
        biosynthesis of C18-ceramides.
- term:
    id: GO:0006686
    label: sphingomyelin biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:29632068
  qualifier: involved_in
  review:
    summary: >-
      Experimental annotation linking CERS1 to sphingomyelin biosynthesis. As the ceramide
      synthase producing C18-ceramide, CERS1 supplies the ceramide backbone that is
      downstream converted to sphingomyelin; the cited study dissected acyl-chain specificity
      determinants of the CerS family.
    action: KEEP_AS_NON_CORE
    reason: >-
      CERS1 contributes the ceramide precursor for sphingomyelin, but sphingomyelin synthesis
      per se is a downstream pathway carried out by sphingomyelin synthases. This is an
      experimental (IDA) curator annotation whose full text I cannot fully verify from the
      cached abstract; per policy I defer to the curator and retain it as a non-core
      contributory process rather than removing it.
    supported_by:
    - reference_id: PMID:29632068
      supporting_text: 'family of six ceramide synthases (CerS)'
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:36170811
  qualifier: involved_in
  review:
    summary: >-
      Experimental annotation placing CERS1 in ceramide biosynthesis in the context of a study
      of de novo sphingolipid biosynthesis and its detoxification requirement in cancer cells.
    action: ACCEPT
    reason: >-
      Ceramide biosynthesis is the core process for CERS1. This is an experimental (IDA)
      annotation by the curator; although the cached full text foregrounds KDSR/SPT in the de
      novo pathway, the pathway measured includes ceramide species and CERS1 is a canonical
      de novo ceramide synthase, so I accept and defer to the curator per policy.
    supported_by:
    - reference_id: file:human/CERS1/CERS1-uniprot.txt
      supporting_text: >-
        N-acylates
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:22922758
  qualifier: involved_in
  review:
    summary: >-
      Experimental demonstration that CerS1 expression generates endogenous C18-ceramide (and
      a catalytically dead H183A mutant does not), directly evidencing ceramide biosynthesis.
    action: ACCEPT
    reason: >-
      Directly supports the core ceramide biosynthetic function: induction of wild-type CerS1
      selectively increased C18-ceramide, while the His183Ala catalytic mutant did not.
    supported_by:
    - reference_id: PMID:22922758
      supporting_text: >-
        C(18)-ceramide generation by ceramide synthase 1 (CerS1) expression mediates
- term:
    id: GO:1901526
    label: positive regulation of mitophagy
  evidence_type: IDA
  original_reference_id: PMID:22922758
  qualifier: involved_in
  review:
    summary: >-
      CerS1-generated C18-ceramide anchors LC3B-II autophagolysosomes to the mitochondrial
      outer membrane, driving lethal mitophagy; a catalytically inactive CerS1 mutant fails to
      do so. This is a signaling/effector consequence of C18-ceramide, downstream of the
      enzyme's biosynthetic role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Well-supported but represents a downstream, context-specific (tumor-suppressive
      mitophagy) signaling role of the C18-ceramide product rather than the core biosynthetic
      function of the enzyme.
    supported_by:
    - reference_id: PMID:22922758
      supporting_text: >-
        CerS1/C18-ceramide was necessary and sufficient for induction of lethal mitophagy
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:24782409
  qualifier: located_in
  review:
    summary: >-
      Experimental ER localization of CERS1 (EPM8 study).
    action: ACCEPT
    reason: >-
      Correct core localization; the ER membrane annotation from the same study is more
      precise.
    supported_by:
    - reference_id: PMID:24782409
      supporting_text: >-
        CerS1, a transmembrane protein of the endoplasmic reticulum (ER)
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:24782409
  qualifier: involved_in
  review:
    summary: >-
      Experimental evidence that CERS1 catalyzes C18-ceramide biosynthesis; the EPM8 mutation
      decreases C18-ceramide levels.
    action: ACCEPT
    reason: >-
      Core biological process, directly evidenced by loss of C18-ceramide with the
      pathogenic variant.
    supported_by:
    - reference_id: PMID:24782409
      supporting_text: 'We demonstrated that the mutation decreases C18-ceramide levels.'
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:24782409
  qualifier: enables
  review:
    summary: >-
      Experimental characterization of CERS1 as a ceramide synthase; the EPM8 H183Q variant
      shows impaired ceramide synthase activity.
    action: ACCEPT
    reason: >-
      Core molecular function; the catalytic activity is directly implicated by the
      activity-impairing pathogenic variant.
    supported_by:
    - reference_id: PMID:24782409
      supporting_text: >-
        CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the
        biosynthesis of C18-ceramides.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:17699106
  qualifier: located_in
  review:
    summary: >-
      CERS1 (LASS1) localizes to the ER under basal conditions; cisplatin induces a specific
      ER-to-Golgi translocation.
    action: ACCEPT
    reason: >-
      Correct basal ER localization, consistent with all other evidence.
    supported_by:
    - reference_id: PMID:17699106
      supporting_text: >-
        translocation of LASS1/CerS1, but not LASS4/CerS4 or
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:19800881
  qualifier: located_in
  review:
    summary: >-
      CerS1 resides in the ER under basal conditions and translocates to the Golgi upon
      diverse stresses (UV, DTT, chemotherapeutics).
    action: ACCEPT
    reason: >-
      Correct basal ER localization.
    supported_by:
    - reference_id: PMID:19800881
      supporting_text: 'CerS1 translocates from the endoplasmic reticulum'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:12869556
  qualifier: located_in
  review:
    summary: >-
      Traceable assignment of CERS1 to membrane (a broad term). CERS1 is a multi-pass ER
      membrane protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct but uninformatively general relative to the ER membrane (GO:0005789) annotation.
    supported_by:
    - reference_id: file:human/CERS1/CERS1-uniprot.txt
      supporting_text: 'Multi-pass membrane protein'
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12869556
  qualifier: involved_in
  review:
    summary: >-
      Human LAG1 homologues (including CERS1) rescue yeast lacking acyl-CoA-dependent ceramide
      synthase and restore ceramide/sphingolipid biosynthesis.
    action: ACCEPT
    reason: >-
      Core biological process, directly demonstrated by functional complementation in yeast.
    supported_by:
    - reference_id: PMID:12869556
      supporting_text: >-
        restore acyl-CoA-dependent ceramide and sphingolipid
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:15823095
  qualifier: involved_in
  review:
    summary: >-
      Overexpression of Lass1 (CERS1) preferentially increases C18:0-ceramide, demonstrating
      its role in ceramide biosynthesis with C18 acyl-chain specificity.
    action: ACCEPT
    reason: >-
      Core biological process, directly evidenced by the ceramide species produced upon
      overexpression.
    supported_by:
    - reference_id: PMID:15823095
      supporting_text: 'increased C18:0-ceramide levels preferentially'
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:18541923
  qualifier: involved_in
  review:
    summary: >-
      In vitro CerS assays confirmed CerS1 can also utilize 2-hydroxy-stearoyl-CoA, producing
      2-hydroxy-C18-ceramide, extending its ceramide biosynthetic role to 2-hydroxy species.
    action: ACCEPT
    reason: >-
      Supports ceramide biosynthesis (including 2-hydroxy-ceramide) with retained C18
      chain-length specificity; consistent with the core biosynthetic function.
    supported_by:
    - reference_id: PMID:18541923
      supporting_text: 'CerS1 to utilize 2-hydroxy-stearoyl-CoA as a substrate'
- term:
    id: GO:0071466
    label: cellular response to xenobiotic stimulus
  evidence_type: IDA
  original_reference_id: PMID:19800881
  qualifier: involved_in
  review:
    summary: >-
      Diverse stresses, including drugs/xenobiotics, trigger a specific proteasome-dependent
      ER-to-Golgi translocation of CerS1. This is a stress-response behavior of the protein,
      not its core biosynthetic function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported response of CERS1 to xenobiotic/drug stress via regulated
      translocation, but a peripheral regulatory behavior rather than the core function.
    supported_by:
    - reference_id: PMID:19800881
      supporting_text: >-
        wide variety of stresses result in the specific translocation of CerS1
- term:
    id: GO:0071492
    label: cellular response to UV-A
  evidence_type: IDA
  original_reference_id: PMID:19800881
  qualifier: involved_in
  review:
    summary: >-
      UV light induces the specific ER-to-Golgi translocation and proteolytic processing of
      CerS1, evidencing a UV stress response.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real, experimentally supported stress-response behavior, but peripheral to the core
      ceramide-biosynthetic role.
    supported_by:
    - reference_id: PMID:19800881
      supporting_text: >-
        UV-light (which causes pyrimidine dimer formation) or DTT
- term:
    id: GO:0072721
    label: cellular response to dithiothreitol
  evidence_type: IDA
  original_reference_id: PMID:19800881
  qualifier: involved_in
  review:
    summary: >-
      DTT (an ER-stress/UPR inducer) triggers the specific CerS1 ER-to-Golgi translocation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported stress response, but peripheral to the core biosynthetic
      function.
    supported_by:
    - reference_id: PMID:19800881
      supporting_text: >-
        UV-light (which causes pyrimidine dimer formation) or DTT
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12105227
  qualifier: involved_in
  review:
    summary: >-
      UOG1 (CERS1) expression regulates C18-(dihydro)ceramide synthesis and channels product
      into neutral glycosphingolipids, evidencing a role in sphingolipid biosynthesis.
    action: ACCEPT
    reason: >-
      Core biological process (sphingolipid/ceramide biosynthesis), directly demonstrated by
      the increase in C18 sphingolipids and elevated CerS activity with stearoyl-CoA.
    supported_by:
    - reference_id: PMID:12105227
      supporting_text: 'impacts neutral glycosphingolipid synthesis'
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12105227
  qualifier: involved_in
  review:
    summary: >-
      UOG1 (CERS1) expression regulates synthesis of C18-(dihydro)ceramide (N-stearoyl-
      sphinganine), directly evidencing its role in ceramide biosynthesis with C18
      specificity.
    action: ACCEPT
    reason: >-
      Core biological process; the same study directly shows elevated ceramide synthase
      activity with stearoyl-CoA and increased C18-ceramide upon UOG1 expression.
    supported_by:
    - reference_id: PMID:12105227
      supporting_text: 'regulates N-stearoyl-sphinganine'
- term:
    id: GO:0036146
    label: cellular response to mycotoxin
  evidence_type: IDA
  original_reference_id: PMID:12105227
  qualifier: involved_in
  review:
    summary: >-
      UOG1 (CERS1) confers fumonisin B1 (a mycotoxin) resistance for cellular ceramide
      production, evidencing a cellular response to the mycotoxin.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported response to the mycotoxin fumonisin B1, but a peripheral
      phenotype linked to CERS1 activity rather than its core biosynthetic function.
    supported_by:
    - reference_id: PMID:12105227
      supporting_text: >-
        fumonisin B(1) resistance with respect to the ability of the cells to continue
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:17548428
  qualifier: involved_in
  review:
    summary: >-
      Generation of C18-ceramide via CerS1 expression (but not C16-ceramide via CerS5/CerS6)
      represses the hTERT promoter, evidencing CERS1-dependent C18-ceramide biosynthesis.
    action: ACCEPT
    reason: >-
      Supports the core ceramide biosynthetic function (specific production of C18-ceramide by
      CerS1). The hTERT repression itself is a downstream signaling consequence.
    supported_by:
    - reference_id: PMID:17548428
      supporting_text: 'generation of C18-ceramide via'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-428185
  qualifier: located_in
  review:
    summary: >-
      Reactome (Ceramide synthases transfer acyl-CoA onto sphingoid) traceable assignment of
      CERS1 to the ER membrane.
    action: ACCEPT
    reason: >-
      Correct and appropriately specific compartment.
    supported_by:
    - reference_id: file:human/CERS1/CERS1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator sequence-similarity transfer from mouse ortholog P27545 for the core ceramide
      biosynthetic process.
    action: ACCEPT
    reason: >-
      Correct core process, redundant with abundant experimental support.
    supported_by:
    - reference_id: PMID:15823095
      supporting_text: 'increased C18:0-ceramide levels preferentially'
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Curator sequence-similarity transfer from mouse ortholog P27545 for the core
      ceramide-synthase catalytic activity.
    action: ACCEPT
    reason: >-
      Correct core molecular function, redundant with experimental IDA support.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of
        ceramide synthases (CerS)
core_functions:
- description: >-
    Sphingoid-base N-acyltransferase (ceramide synthase) that N-acylates sphinganine (and
    sphingosine in the salvage pathway) using acyl-CoA, with high selectivity for
    stearoyl-CoA (C18:0-CoA), to produce C18-(dihydro)ceramide in de novo sphingolipid
    biosynthesis.
  molecular_function:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  directly_involved_in:
  - id: GO:0046513
    label: ceramide biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:17977534
    supporting_text: >-
      ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of
      ceramide synthases (CerS), each of which displays a high specificity towards acyl
      CoAs of different chain lengths
  - reference_id: PMID:15823095
    supporting_text: 'increased C18:0-ceramide levels preferentially'
  - reference_id: PMID:24782409
    supporting_text: >-
      CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the
      biosynthesis of C18-ceramides.
proposed_new_terms: []
suggested_questions:
- question: >-
    Beyond de novo biosynthesis, how is the balance between CERS1's biosynthetic (ER) role
    and its stress-induced ER-to-Golgi translocation regulated in neurons, and does the
    cleaved C-terminal fragment retain any function?
- question: >-
    Is the mitochondrial pool of CERS1-derived C18-ceramide produced at ER-mitochondria
    contact sites, and does CERS1 relocalize, or is only the lipid product trafficked?
suggested_experiments:
- description: >-
    Acyl-CoA chain-length profiling of purified human CERS1 across the full C14-C26 acyl-CoA
    panel with sphinganine and sphingosine acceptors to quantify the degree of C18 selectivity
    and any minor activities.
- description: >-
    Neuron-specific Cers1 knockout / EPM8-variant knock-in models with spatial lipidomics to
    map where C18-ceramide is required for Purkinje/neuronal survival.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/CERS1/CERS1-uniprot.txt
  title: UniProtKB entry P27544 (CERS1_HUMAN), ceramide synthase 1
  findings: []
- id: PMID:12105227
  title: Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog
    of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine
    (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian
    cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      First demonstration of C18 fatty-acid specificity of the human enzyme; shows ER
      localization and stearoyl-CoA (not palmitoyl-CoA) preference. Supports core MF/BP/CC.
- id: PMID:12869556
  title: Human homologues of LAG1 reconstitute Acyl-CoA-dependent ceramide synthesis
    in yeast.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Functional complementation of yeast lag1/lac1 by human LAG1 homologues restores
      acyl-CoA-dependent ceramide/sphingolipid synthesis. Supports core MF/BP.
- id: PMID:15823095
  title: Mammalian Lass6 and its related family members regulate synthesis of specific
    ceramides.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes CERS1(Lass1) C18-ceramide specificity and family membrane topology
      (N-terminus luminal, C-terminus cytosolic). Supports MF/BP and cytosolic-side CC.
- id: PMID:17548428
  title: Mechanisms of ceramide-mediated repression of the human telomerase reverse
    transcriptase promoter via deacetylation of Sp3 by histone deacetylase 1.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows CERS1-specific C18-ceramide generation drives hTERT repression; supports the
      biosynthetic function, with the transcriptional effect being downstream.
- id: PMID:17699106
  title: (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated
    with the activation of p38 mitogen-activated protein kinase and is abrogated by
    sphingosine kinase 1.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Basal ER localization plus cisplatin-induced ER-to-Golgi translocation of CerS1;
      supports ER localization and drug-stress behavior (non-core).
- id: PMID:17977534
  title: 'Kinetic characterization of mammalian ceramide synthases: determination
    of K(m) values towards sphinganine.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct biochemical (IDA) characterization of CerS enzymes including CerS1; supports
      the core sphingosine N-acyltransferase activity.
- id: PMID:18541923
  title: '2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis
    for the preference of FA chain length.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      In vitro shows CerS1 can use 2-hydroxy-stearoyl-CoA; extends ceramide biosynthetic
      role to 2-hydroxy-C18 species.
- id: PMID:19800881
  title: Stress-induced ER to Golgi translocation of ceramide synthase 1 is dependent
    on proteasomal processing.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text available; UV/DTT/drug stresses drive specific proteasome-dependent
      ER-to-Golgi translocation and cleavage of CerS1. Supports ER localization and the
      several stress-response BP annotations (non-core).
- id: PMID:22922758
  title: Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; wild-type CerS1 (but not H183A) generates C18-ceramide and drives
      lethal mitophagy. Supports core ceramide biosynthesis (via catalytic-dead control) and
      the mitophagy annotation (non-core).
- id: PMID:24782409
  title: Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      EPM8-defining study; CerS1 is an ER transmembrane protein catalyzing C18-ceramide
      biosynthesis, and the H183Q variant reduces C18-ceramide with impaired activity.
      Supports core MF/BP/CC and disease.
- id: PMID:29632068
  title: Eleven residues determine the acyl chain specificity of ceramide synthases.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Maps the acyl-chain-length specificity determinants of the CerS family (context for
      CERS1 C18 selectivity). Cited for a sphingomyelin-biosynthesis IDA that is a
      contributory/non-core process.
- id: PMID:36170811
  title: De novo sphingolipid biosynthesis necessitates detoxification in cancer cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Full text available but centered on KDSR/SPT in de novo sphingolipid biosynthesis; does
      not name CERS1. Cited for a ceramide-biosynthetic-process IDA — accepted deferring to
      the curator, since CERS1 is a canonical de novo ceramide synthase in this pathway.
- id: Reactome:R-HSA-1660661
  title: Sphingolipid de novo biosynthesis
  findings: []
- id: Reactome:R-HSA-428185
  title: Ceramide synthases transfer acyl-CoA onto sphingoid
  findings: []