id: Q8IU89
gene_symbol: CERS3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CERS3 (ceramide synthase 3; formerly LASS3) is an endoplasmic reticulum membrane
  enzyme that catalyzes the N-acylation step of de novo ceramide biosynthesis: transfer
  of a fatty acyl group from acyl-CoA onto the amino group of a sphingoid base
  (dihydrosphingosine/sphinganine in the de novo pathway, sphingosine in the
  salvage pathway) to form dihydroceramide/ceramide (sphingosine
  N-acyltransferase, EC 2.3.1.24). Among the six mammalian ceramide synthases it
  is distinguished by its selectivity for very-long- and ultra-long-chain acyl-CoAs
  (chain length greater than C22, up to C26 and longer). CERS3 produces the
  ultra-long-chain ceramides, including omega-hydroxy species and acylceramides,
  that form the extracellular lipid lamellae and cornified lipid envelope of the
  epidermis and are essential for the skin permeability barrier. It is expressed most
  prominently in the epidermis (at the interface between the stratum granulosum and
  stratum corneum) and in testis. It is a multi-pass ER membrane protein whose
  catalytic activity resides in a TLC (TRAM-LAG1-CLN8) domain; it also carries a
  degenerate homeobox-like region that has lost DNA-binding residues and is not
  functional. Loss-of-function variants cause autosomal recessive congenital
  ichthyosis 9 (ARCI9), a keratinization/skin-barrier disorder.
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 CERS3 is active in the endoplasmic
      reticulum. Correct: CERS3 is an ER membrane enzyme. The more precise
      curated location is ER membrane (GO:0005789); this ER term is accurate but
      less specific.
    action: ACCEPT
    reason: >-
      CERS3 and the whole LAG1/LASS/CerS family are ER-resident enzymes, and
      UniProt records ER membrane as the subcellular location. The IBA is
      consistent with the experimental/curated localization.
    supported_by:
    - reference_id: Reactome:R-HSA-428185
      supporting_text: >-
        Ceramide synthase enzymes (CerS, LASS) associated with the endoplasmic
        reticulum membrane catalyze the reaction of a sphingoid and a long-chain
        fatty acyl CoA such as stearyl-CoA to form a dihydroceramide and CoASH
- 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 CERS3 is involved in ceramide
      biosynthesis. This is a core function of CERS3, independently supported by
      direct experimental evidence.
    action: ACCEPT
    reason: >-
      CERS3 catalyzes the committed N-acylation step of de novo ceramide
      synthesis; ceramide biosynthetic process is a core biological process.
    supported_by:
    - reference_id: PMID:23754960
      supporting_text: >-
        CERS3 generates epidermis-specific ceramides by N-acylating
        dihydrosphingosine with acyl-CoAs ranging from long to very long
        aliphatic chains
- 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 sphingosine N-acyltransferase (ceramide
      synthase) activity. This is the core molecular function of CERS3.
    action: ACCEPT
    reason: >-
      This is the exact core catalytic activity of CERS3 (transfer of an acyl
      chain from acyl-CoA onto a sphingoid base).
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Automated InterPro2GO annotation triggered by the homeodomain-like signature
      (IPR001356) that CERS3 shares with the LAG1/LASS/CerS family. CERS3 does
      not bind DNA: its homeobox-like region is degenerate and lacks the residues
      required for DNA binding, and the protein is an ER membrane enzyme.
    action: REMOVE
    reason: >-
      This is a demonstrably wrong electronic (IEA) inference. UniProt explicitly
      cautions that the predicted homeobox domain is degenerated and lacks
      DNA-binding residues, and that ER localization argues against homeobox
      function. The catalytic activity resides in the TLC domain.
    supported_by:
    - reference_id: file:human/CERS3/CERS3-uniprot.txt
      supporting_text: >-
        Contains a predicted homeobox domain which is degenerated, lacking
        residues important for DNA-binding.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Automated (ARBA/UniProtKB-SubCell) annotation to ER membrane. This is the
      precise, correct subcellular location of CERS3.
    action: ACCEPT
    reason: >-
      CERS3 is a multi-pass ER membrane protein; ER membrane is the accurate
      curated location and the site of its catalytic activity.
    supported_by:
    - reference_id: file:human/CERS3/CERS3-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: >-
      Automated InterPro2GO annotation to the generic 'membrane' term. Correct in
      substance (CERS3 is an integral membrane protein) but far less informative
      than the ER membrane annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'membrane' is a high-level, uninformative location. The specific ER
      membrane term (GO:0005789) is already present and should be preferred.
    supported_by:
    - reference_id: file:human/CERS3/CERS3-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- 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/InterPro) annotation to ceramide biosynthetic
      process, redundant with the experimental and IBA annotations. Correct core
      process.
    action: ACCEPT
    reason: >-
      Ceramide biosynthesis is the core process CERS3 participates in.
    supported_by:
    - reference_id: PMID:23754960
      supporting_text: >-
        CERS3 generates epidermis-specific ceramides by N-acylating
        dihydrosphingosine with acyl-CoAs ranging from long to very long
        aliphatic chains
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (ARBA/InterPro/RHEA/EC 2.3.1.24) annotation of the core ceramide
      synthase activity, redundant with the experimental, ISS, IBA and TAS
      annotations.
    action: ACCEPT
    reason: >-
      Correctly captures the core catalytic function via EC 2.3.1.24 / RHEA
      mapping.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from a genome-scale binary interactome (HuRI, Y2H)
      screen, one of five partners reported (here UniProtKB:Q8N138 / ORMDL3).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare 'protein binding' is uninformative and is not
      retained as a core function. Experimental IPI is not removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        we present a human 'all-by-all' reference interactome map of human binary
        protein interactions, or 'HuRI'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from the HuRI binary interactome screen (partner
      UniProtKB:Q96FB2). Uninformative molecular function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' is not retained as a core function. Experimental IPI
      is not removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        we present a human 'all-by-all' reference interactome map of human binary
        protein interactions, or 'HuRI'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from the HuRI binary interactome screen (partner
      UniProtKB:Q99519 / NEU1). Uninformative molecular function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' is not retained as a core function. Experimental IPI
      is not removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        we present a human 'all-by-all' reference interactome map of human binary
        protein interactions, or 'HuRI'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from the HuRI binary interactome screen (partner
      UniProtKB:Q9H0N5 / PCBD2). Uninformative molecular function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' is not retained as a core function. Experimental IPI
      is not removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        we present a human 'all-by-all' reference interactome map of human binary
        protein interactions, or 'HuRI'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from the HuRI binary interactome screen (partner
      UniProtKB:Q9NUM3 / SLC39A9). Uninformative molecular function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' is not retained as a core function. Experimental IPI
      is not removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        we present a human 'all-by-all' reference interactome map of human binary
        protein interactions, or 'HuRI'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Automated ortholog transfer (Ensembl Compara, from mouse Cers3 Q1A3B0) of
      ER localization. Correct but less precise than ER membrane.
    action: ACCEPT
    reason: >-
      CERS3 is ER-localized; consistent with all other localization evidence.
    supported_by:
    - reference_id: file:human/CERS3/CERS3-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- term:
    id: GO:0008544
    label: epidermis development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Automated ortholog transfer (from mouse Cers3) of a role in epidermis
      development. CERS3-made ultra-long-chain ceramides are essential for the
      epidermal permeability barrier, a genuine physiological role downstream of
      the core molecular activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Epidermis development is a real, well-supported downstream role of
      CERS3-produced ULC-ceramides, but the core function is the ceramide synthase
      activity.
    supported_by:
    - reference_id: PMID:22038835
      supporting_text: >-
        are key components of extracellular lipid lamellae
- term:
    id: GO:0070268
    label: cornification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Automated ortholog transfer (from mouse Cers3) of a role in cornification.
      Loss of CERS3 produces deficient cornification; a downstream barrier
      outcome rather than the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      CERS3-derived ULC-ceramides contribute to the cornified lipid envelope;
      retain as a non-core downstream role.
    supported_by:
    - reference_id: PMID:22038835
      supporting_text: >-
        deficient cornification are hallmarks of mutant skin
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1660661
  qualifier: involved_in
  review:
    summary: >-
      Reactome (TAS) placement of CERS3 in sphingolipid de novo biosynthesis.
      Correct but broader than the specific ceramide biosynthetic process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Ceramide biosynthesis is part of sphingolipid biosynthesis; this parent
      term is accurate but less specific than GO:0046513.
    supported_by:
    - reference_id: Reactome:R-HSA-1660661
      supporting_text: >-
        Glycosphingolipid biosynthesis is based on salvage of sphingolipids and
        de novo sphingolipid synthesis.
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      Automated UniPathway (UPA00222) mapping. Correct but the broadest process
      term for CERS3; the specific biosynthetic branch is captured by GO:0046513.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but very general; ceramide biosynthetic process is the more
      informative term for CERS3.
    supported_by:
    - reference_id: file:human/CERS3/CERS3-uniprot.txt
      supporting_text: >-
        PATHWAY: 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 (TAS) annotation of the core ceramide synthase / sphingosine
      N-acyltransferase activity, redundant with the experimental and IBA
      annotations.
    action: ACCEPT
    reason: >-
      Correctly captures the core catalytic activity of CERS3.
    supported_by:
    - reference_id: Reactome:R-HSA-428185
      supporting_text: >-
        Ceramide synthase enzymes (CerS, LASS) associated with the endoplasmic
        reticulum membrane catalyze the reaction of a sphingoid and a long-chain
        fatty acyl CoA such as stearyl-CoA to form a dihydroceramide and CoASH
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence (IDA) annotation to nucleoplasm. This conflicts with
      the well-established ER membrane localization of CERS3 and with the UniProt
      CAUTION that the protein is not nuclear. Likely nonspecific antibody signal.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      CERS3 is a multi-pass ER membrane enzyme, and UniProt explicitly states it
      localizes in the ER and not the nucleus; a nucleoplasmic location is not
      biologically supported. The experimental IDA is not removed.
    supported_by:
    - reference_id: file:human/CERS3/CERS3-uniprot.txt
      supporting_text: >-
        the protein localizes in the endoplasmic reticulum and not in the
        nucleus, which also argues against homeobox function
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Curator sequence-similarity (ISS, from mouse Cers3 Q1A3B0) annotation to ER
      membrane. This is the precise, correct location of CERS3.
    action: ACCEPT
    reason: >-
      ER membrane is the accurate curated location and the site of CERS3
      catalytic activity.
    supported_by:
    - reference_id: file:human/CERS3/CERS3-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- 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 (ISS, from mouse Cers3) annotation of the core
      ceramide synthase activity, redundant with the experimental, IBA, TAS and
      IEA annotations.
    action: ACCEPT
    reason: >-
      Correctly captures the core catalytic function of CERS3.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Curator sequence-similarity (ISS, from mouse Cers3) annotation to ER.
      Correct but less specific than ER membrane.
    action: ACCEPT
    reason: >-
      CERS3 is ER-resident; consistent with the more precise ER membrane
      annotation.
    supported_by:
    - reference_id: file:human/CERS3/CERS3-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- term:
    id: GO:0008544
    label: epidermis development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator sequence-similarity (ISS, from mouse Cers3) annotation to epidermis
      development, consistent with the essential role of CERS3-made ULC-ceramides
      in the skin barrier. A genuine downstream role, not the core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Epidermis development is a real physiological outcome of CERS3 activity but
      is downstream of its ceramide synthase function.
    supported_by:
    - reference_id: PMID:22038835
      supporting_text: >-
        are key components of extracellular lipid lamellae
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:17977534
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) annotation from biochemical characterization of
      mammalian ceramide synthases, including CERS3, N-acylating sphinganine to
      form (dihydro)ceramide. Core biological process.
    action: ACCEPT
    reason: >-
      Ceramide biosynthesis is the core process CERS3 participates in;
      established directly by enzyme assays measuring ceramide synthase activity
      and K(m) toward sphinganine.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        ceramide is synthesized by N-acylation of a sphingoid long-chain base
    - reference_id: PMID:17977534
      supporting_text: >-
        K(m) value of each CerS towards sphinganine
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:22038835
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) annotation showing CERS3 is required for
      synthesis of ultra-long-chain ceramides; CerS3 deficiency abolishes
      ULC-ceramides. Core biological process.
    action: ACCEPT
    reason: >-
      CERS3 is exclusively required for ultra-long-chain ceramide synthesis, a
      specialized part of ceramide biosynthesis; strong direct evidence.
    supported_by:
    - reference_id: PMID:22038835
      supporting_text: >-
        we identified human and mouse ceramide synthase 3 (CerS3), among
    - reference_id: PMID:22038835
      supporting_text: >-
        Deficiency of CerS3 in mice results in complete loss of
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:17977534
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) determination of ceramide synthase / sphingosine
      N-acyltransferase activity, including kinetic characterization (K(m) toward
      sphinganine). This is the core molecular function of CERS3.
    action: ACCEPT
    reason: >-
      Biochemical assays directly demonstrate the N-acyltransferase activity of
      CERS3, with each CerS showing chain-length-specific acyl-CoA preference.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: >-
        specificity towards acyl CoAs of different chain lengths
    - reference_id: PMID:17977534
      supporting_text: >-
        K(m) value of each CerS towards sphinganine
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:22038835
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) demonstration that CERS3 has ceramide synthase
      activity with selectivity for ultra-long-chain acyl-CoAs, required for
      ULC-ceramide synthesis. Core molecular function.
    action: ACCEPT
    reason: >-
      CERS3 is the ceramide synthase exclusively responsible for ULC-ceramide
      synthesis in vitro, establishing its N-acyltransferase activity with
      ultra-long-chain substrate selectivity.
    supported_by:
    - reference_id: PMID:22038835
      supporting_text: >-
        to be exclusively required for the ULC-Cer synthesis in vitro
- term:
    id: GO:0070268
    label: cornification
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator sequence-similarity (ISS, from mouse Cers3) annotation to
      cornification. CerS3 loss causes deficient cornification; a downstream
      barrier outcome rather than the core molecular activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      CERS3-derived ULC-ceramides contribute to the cornified lipid envelope;
      retain as a non-core downstream role.
    supported_by:
    - reference_id: PMID:22038835
      supporting_text: >-
        deficient cornification are hallmarks of mutant skin
- term:
    id: GO:0030216
    label: keratinocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:23754960
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype (IMP) annotation: CERS3 loss-of-function mutations in
      humans (ARCI9) disturb the epidermal sphingolipid profile and impair
      terminal keratinocyte differentiation. Genuine downstream physiological
      role.
    action: KEEP_AS_NON_CORE
    reason: >-
      CERS3-produced ceramides are required for proper terminal differentiation
      of keratinocytes; a real but downstream role, secondary to the core
      ceramide synthase activity.
    supported_by:
    - reference_id: PMID:23754960
      supporting_text: >-
        these observations suggest that mutated CERS3 affects the terminal
        differentiation process in human skin
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:23754960
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype (IMP) annotation: CERS3 loss-of-function reduces
      epidermis-specific very-long-chain ceramides, establishing CERS3's role in
      ceramide biosynthesis in human skin. Core biological process.
    action: ACCEPT
    reason: >-
      Patient keratinocytes carrying CERS3 mutations show a marked decrease in
      very-long-chain ceramides, directly demonstrating CERS3's involvement in
      ceramide biosynthesis.
    supported_by:
    - reference_id: PMID:23754960
      supporting_text: >-
        marked decrease of very long-chain (VLC) ceramides
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-428185
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation to ER membrane, the precise and correct
      subcellular location of CERS3 and site of its catalytic activity.
    action: ACCEPT
    reason: >-
      ER membrane is the accurate curated location; Reactome describes ceramide
      synthases as ER-membrane-associated enzymes.
    supported_by:
    - reference_id: Reactome:R-HSA-428185
      supporting_text: >-
        Ceramide synthase enzymes (CerS, LASS) associated with the endoplasmic
        reticulum membrane catalyze the reaction of a sphingoid and a long-chain
        fatty acyl CoA such as stearyl-CoA to form a dihydroceramide and CoASH
core_functions:
- description: >-
    Ceramide synthase (sphingosine N-acyltransferase) that catalyzes the
    N-acylation step of de novo ceramide biosynthesis at the ER membrane,
    transferring a very-long/ultra-long-chain fatty acyl group from acyl-CoA onto
    a sphingoid base (sphinganine) to form (dihydro)ceramide, producing the
    ultra-long-chain ceramides required for the epidermal permeability barrier.
  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
  - reference_id: PMID:22038835
    supporting_text: >-
      to be exclusively required for the ULC-Cer synthesis in vitro
  - reference_id: file:human/CERS3/CERS3-uniprot.txt
    supporting_text: >-
      SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  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: 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: >-
      Biochemical characterization of mammalian ceramide synthases including CERS3;
      supports the sphingosine N-acyltransferase activity and ceramide biosynthetic
      process annotations. Cached entry is abstract-only; the curator's IDA was made
      from the full text.
- id: PMID:22038835
  title: Loss of ceramide synthase 3 causes lethal skin barrier disruption.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies CERS3 as exclusively required for ultra-long-chain ceramide
      synthesis; CerS3-deficient mice lose ULC-ceramides and die of skin-barrier
      failure. Directly supports the core catalytic and biosynthetic annotations.
- id: PMID:23754960
  title: Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes CERS3 loss-of-function as the cause of ARCI9 and its role in
      producing epidermis-specific very-long-chain ceramides and in keratinocyte
      terminal differentiation. Full text available and PMC-verified.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Genome-scale Y2H (HuRI) interactome screen; source of five bare 'protein
      binding' IPIs for CERS3. Correctly cited but only supports uninformative
      protein-binding annotations, not a specific molecular function.
- 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: []
- id: file:human/CERS3/CERS3-uniprot.txt
  title: UniProtKB Q8IU89 (CERS3_HUMAN) record
  findings: []
suggested_questions:
- question: >-
    What are the specific in vivo acyl-chain-length preferences of human CERS3,
    and how do partner proteins such as ORMDL3, fatty acid elongases, and
    hydroxylases shape the ultra-long-chain acylceramide output in epidermis?
suggested_experiments:
- description: >-
    Reconstitute human CERS3 in a defined membrane system and measure activity
    across a panel of acyl-CoA chain lengths with sphinganine and sphingosine
    acceptors to quantify its ultra-long-chain selectivity.
- description: >-
    Test whether the CERS3-ORMDL3 interaction detected in HuRI modulates CERS3
    activity or sphingolipid flux in differentiating keratinocytes.