id: Q96G23
gene_symbol: CERS2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CERS2 (ceramide synthase 2; formerly LASS2/LAG1 longevity assurance homolog 2)
  is a multi-pass endoplasmic reticulum membrane enzyme of the sphingosine
  N-acyltransferase (Lag1/Lac1, TLC-domain) family. It catalyzes the N-acylation
  step of ceramide biosynthesis, transferring a fatty acyl chain from acyl-CoA
  onto the amino group of a sphingoid base (sphinganine in the de novo pathway,
  sphingosine in the salvage pathway) to form (dihydro)ceramide. Its defining
  feature is high selectivity for very-long-chain (VLC) acyl-CoAs (C22-C24, up to
  C26), so it produces very-long-chain ceramides. CERS2 is the most highly and
  most broadly expressed of the six mammalian ceramide synthases, with prominent
  expression in liver, kidney and brain, and its very-long-chain ceramides are
  important precursors for the myelin sphingolipids galactosylceramide and
  sulfatide. Acyl-chain selectivity is conferred by a short loop within the
  TLC (TRAM-LAG1-CLN8) domain, and the enzyme is regulated by C-terminal
  phosphorylation and by inhibition from sphingosine 1-phosphate.
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 CERS2 is active in the endoplasmic
      reticulum. This is well supported: CERS2 is an ER-resident, multi-pass
      membrane ceramide synthase, and the ER is the site of de novo ceramide
      synthesis.
    action: ACCEPT
    reason: >-
      Consistent with experimental localization of CERS2 to the ER membrane and
      with the ER being the site of de novo ceramide biosynthesis. The more
      specific ER membrane term (GO:0005789) is captured in the core functions.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- 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 CERS2 is involved in ceramide
      biosynthesis. This is the core biological process of the gene.
    action: ACCEPT
    reason: >-
      CERS2 catalyzes the N-acylation step of ceramide biosynthesis, producing
      very-long-chain (dihydro)ceramides. Strongly supported by direct enzymatic
      characterization and consistent across the CerS family phylogeny.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: "ceramide is synthesized by N-acylation of a sphingoid long-chain base"
    - reference_id: PMID:18165233
      supporting_text: "rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis."
- 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 CERS2.
    action: ACCEPT
    reason: >-
      This is the exact GO term GO uses for ceramide synthase activity and it is
      directly supported by biochemical assays of human CERS2 as well as being
      consistent across the CerS family. Retained as a core function.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: "each of which displays a high"
    - reference_id: PMID:18165233
      supporting_text: "has the broadest tissue distribution."
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Electronic (InterPro2GO) annotation of DNA binding, transferred from the
      homeodomain-like signature (IPR001356) matching the CERS2 N-terminal
      Homeobox-like region. CERS2 does not bind DNA.
    action: REMOVE
    reason: >-
      This is a spurious InterPro homeodomain-signature transfer. UniProt states
      explicitly that the predicted Homeobox domain lacks residues needed for
      DNA binding and, given ER-membrane localization, does not constitute a
      canonical homeobox domain. CERS2 is an ER-membrane ceramide synthase with
      no DNA-binding role, so this IEA mapping is incorrect.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-uniprot.txt
      supporting_text: "The predicted Homeobox domain (Homeobox-like region) lacks"
- 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) annotation of ER membrane localization.
      This is the correct, specific compartment for CERS2.
    action: ACCEPT
    reason: >-
      Matches the experimentally determined subcellular location; CERS2 is a
      multi-pass ER membrane protein. Retained as a core cellular-component
      function.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-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: >-
      Generic membrane localization from InterPro (TLC-domain signature).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not incorrect but uninformatively general. The specific ER membrane
      localization (GO:0005789) is well established and is the appropriate term,
      making the bare "membrane" annotation an over-annotation.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-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/orthology) annotation to ceramide biosynthetic process,
      the core BP of CERS2.
    action: ACCEPT
    reason: >-
      Duplicates the well-supported core biological process; CERS2 catalyzes the
      N-acylation step of ceramide biosynthesis.
    supported_by:
    - reference_id: PMID:18165233
      supporting_text: "rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis."
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (ARBA/RHEA/EC 2.3.1.24) annotation of sphingosine
      N-acyltransferase (ceramide synthase) activity, the core MF of CERS2.
    action: ACCEPT
    reason: >-
      Duplicates the experimentally supported core molecular function. The RHEA
      and EC cross-references correspond to the ceramide synthase reaction that
      CERS2 catalyzes.
    supported_by:
    - reference_id: PMID:18165233
      supporting_text: "has the broadest tissue distribution."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11543633
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from the LASS2 cloning study, which reported
      yeast two-hybrid and GST pull-down interactions with membrane-associated
      receptors/transporters (ATP6V0C, ASGR1, ASGR2, SLC22A1/OCT1).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is an uninformative molecular-function term that does not
      capture CERS2's catalytic role. The underlying interactions are real but the
      bare term should not be treated as a core function. Per curation policy the
      experimental IPI is retained (not removed).
    supported_by:
    - reference_id: PMID:11543633
      supporting_text: "glutathione S-transferase pull-down assays showed that the LASS2 protein"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20195357
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from a large-scale mRNA-display interacting-
      region resource for human transcription factors.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare, uninformative "protein binding" from a high-throughput interaction
      screen; does not describe CERS2's function. Retained (not removed) as an
      experimental IPI per policy but marked as over-annotated.
    supported_by:
    - reference_id: PMID:20195357
      supporting_text: "large-scale IR data set obtained using mRNA display"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from a yeast-two-hybrid human liver protein
      interaction network.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a proteome-scale Y2H map; does not
      inform CERS2 molecular function. Retained as an experimental IPI per policy.
    supported_by:
    - reference_id: PMID:21988832
      supporting_text: "human liver protein interaction network (HLPN)"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from the HuRI reference binary interactome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a systematic binary interactome map.
      Does not describe CERS2 function; retained as experimental IPI per policy.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: "A reference map of the human binary protein interactome"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32911434
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from a high-density NRF2 (NFE2L2) interactome
      screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a targeted NRF2 interactome; does not
      capture CERS2 molecular function. Retained as experimental IPI per policy.
    supported_by:
    - reference_id: PMID:32911434
      supporting_text: "high-density human NRF2 interactome"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from the BioPlex 3.0 affinity-purification
      mass-spectrometry interactome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a proteome-scale AP-MS network; does
      not describe CERS2 function. Retained as experimental IPI per policy.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: "affinity-purification mass spectrometry"
- term:
    id: GO:0010626
    label: negative regulation of Schwann cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Orthology-transferred (Ensembl Compara, from rat Q3T1K1) role in negatively
      regulating Schwann cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: >-
      A plausible downstream/tissue-specific consequence of altering
      very-long-chain sphingolipid (myelin) composition, transferred from rat
      orthology. It is peripheral to the core enzymatic function and should be
      kept as a non-core annotation.
- 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: >-
      Orthology-transferred (from mouse Q924Z4) general acyltransferase activity.
    action: MODIFY
    reason: >-
      Correct in essence (CERS2 transfers an acyl group) but too general; the
      specific ceramide-synthase activity term GO:0050291 (sphingosine
      N-acyltransferase activity) is the appropriate molecular function.
    proposed_replacement_terms:
    - id: GO:0050291
      label: sphingosine N-acyltransferase activity
- term:
    id: GO:0019216
    label: regulation of lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Orthology-transferred (from mouse Q924Z4) role in regulation of lipid
      metabolic process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad regulatory term. CERS2 shapes cellular sphingolipid (ceramide)
      composition, so it does influence lipid metabolism, but this general term is
      not the core molecular/biological function and is better kept as non-core.
- term:
    id: GO:0048681
    label: negative regulation of axon regeneration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Orthology-transferred (Ensembl Compara, from rat Q3T1K1) role in negatively
      regulating axon regeneration.
    action: KEEP_AS_NON_CORE
    reason: >-
      A peripheral, nervous-system-specific developmental role transferred from
      rat orthology, downstream of CERS2's effect on myelin sphingolipids. Kept as
      non-core.
- term:
    id: GO:1900148
    label: negative regulation of Schwann cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Orthology-transferred (Ensembl Compara, from rat Q3T1K1) role in negatively
      regulating Schwann cell migration.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peripheral nervous-system-specific role transferred from rat orthology,
      downstream of altered sphingolipid composition. Kept as non-core.
- 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) annotation placing CERS2 in sphingolipid de novo
      biosynthesis, the pathway superset of ceramide biosynthesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but more general than the specific ceramide biosynthetic process
      that CERS2 directly catalyzes. Kept as a valid but non-core (parent) BP
      annotation.
    supported_by:
    - reference_id: PMID:20937905
      supporting_text: "ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis."
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based (IEA) annotation to the general sphingolipid metabolic
      process.
    action: KEEP_AS_NON_CORE
    reason: >-
      A high-level parent of the specific ceramide biosynthetic process. Correct
      but too general to be a core function; kept as non-core.
- 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 sphingosine N-acyltransferase (ceramide
      synthase) activity, the core MF.
    action: ACCEPT
    reason: >-
      Correct core molecular function, consistent with biochemical
      characterization of CERS2.
    supported_by:
    - reference_id: PMID:18165233
      supporting_text: "has the broadest tissue distribution."
- term:
    id: GO:0010626
    label: negative regulation of Schwann cell proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator ISS transfer (from rat Q3T1K1) of negative regulation of Schwann
      cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicates the orthology-based Schwann-cell role; peripheral,
      nervous-system-specific and non-core.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct (HPA immunofluorescence) localization to the endoplasmic reticulum.
    action: ACCEPT
    reason: >-
      Consistent with the established ER-membrane localization of CERS2. The more
      specific ER membrane term is captured in core functions.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0031965
    label: nuclear membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct (HPA immunofluorescence) annotation to the nuclear membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      The nuclear membrane (outer nuclear envelope) is continuous with the ER, so
      a fraction of an ER-membrane enzyme can appear at the nuclear membrane. This
      is a minor/secondary localization, not the core ER-membrane site of activity;
      kept as non-core.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:18165233
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of CERS2 to the ER membrane, the core cellular
      component for its activity.
    action: ACCEPT
    reason: >-
      Directly supported experimental ER-membrane localization; this is the core
      compartment where CERS2 catalyzes ceramide synthesis.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:20937905
  qualifier: enables
  review:
    summary: >-
      Experimental annotation of ceramide synthase activity in the study linking
      ELOVL1-derived C24 acyl-CoAs to CERS2-dependent C24 sphingolipid synthesis.
    action: ACCEPT
    reason: >-
      CERS2 is characterized as the ceramide synthase essential for C24
      (very-long-chain) sphingolipid synthesis, directly supporting its
      sphingosine N-acyltransferase activity. Core molecular function.
    supported_by:
    - reference_id: PMID:20937905
      supporting_text: "ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis."
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:18165233
  qualifier: enables
  review:
    summary: >-
      Direct assay of CERS2 ceramide synthase activity with defined VLC acyl-CoA
      specificity.
    action: ACCEPT
    reason: >-
      Direct biochemical demonstration of sphingosine N-acyltransferase (ceramide
      synthase) activity for CERS2, with characteristic very-long-chain acyl-CoA
      specificity. Core molecular function.
    supported_by:
    - reference_id: PMID:18165233
      supporting_text: "rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis."
- term:
    id: GO:0006688
    label: glycosphingolipid biosynthetic process
  evidence_type: EXP
  original_reference_id: PMID:34080016
  qualifier: involved_in
  review:
    summary: >-
      Annotation to glycosphingolipid biosynthetic process, citing a general
      review of glucosylceramide and galactosylceramide.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      CERS2 synthesizes the very-long-chain ceramide backbone that is a precursor
      for glycosphingolipids such as galactosylceramide/sulfatide, but it does not
      itself catalyze the glycosylation step of glycosphingolipid biosynthesis.
      The cited reference is a general GlcCer/GalCer review that does not establish
      a direct CERS2 role in glycosphingolipid biosynthesis, so annotating CERS2 to
      this specific process is an over-annotation. Its role is upstream (ceramide
      biosynthesis).
    supported_by:
    - reference_id: PMID:34080016
      supporting_text: "The galactosylceramides are enriched in very-long-chain"
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:36170811
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation (UOS_MCB) to ceramide biosynthetic process citing a cancer
      de novo sphingolipid biosynthesis study.
    action: ACCEPT
    reason: >-
      Ceramide biosynthesis is unquestionably the correct process for CERS2 and is
      independently and strongly supported by other experimental annotations to
      this same term. The cited paper (Spears et al.) is a de novo sphingolipid
      biosynthesis study; its cached text foregrounds the upstream SPT/KDSR enzymes
      and does not mention CERS2, but per curation policy the experimental IDA is
      not overruled from incomplete cached evidence when the function is clearly
      correct. Accepted, deferring to the curator; see reference_review note on the
      unverifiable citation.
- term:
    id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:36170811
  qualifier: is_active_in
  review:
    summary: >-
      IDA annotation (UOS_MCB) placing CERS2 activity on the cytoplasmic side of
      the ER membrane, citing the same cancer de novo sphingolipid study.
    action: UNDECIDED
    reason: >-
      A cytosolic-facing active site is topologically consistent with the CERS2
      C-terminus being cytoplasmic (UniProt topology; C-terminal cytoplasmic
      phosphorylation), but the cited reference does not mention CERS2 in the
      cached full text and therefore cannot be verified as the source of this
      specific membrane-sidedness claim. Marked UNDECIDED rather than removed.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-uniprot.txt
      supporting_text: "TOPO_DOM        325..380"
- term:
    id: GO:0019216
    label: regulation of lipid metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator ISS transfer (from mouse Q924Z4) of regulation of lipid metabolic
      process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad regulatory term duplicating the Ensembl IEA. CERS2 influences cellular
      ceramide/sphingolipid composition but this general term is non-core.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:18165233
  qualifier: located_in
  review:
    summary: >-
      Direct experimental localization of CERS2 to the endoplasmic reticulum.
    action: ACCEPT
    reason: >-
      Consistent with the established ER-membrane localization of CERS2; the more
      specific ER membrane term is a core function.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:17977534
  qualifier: involved_in
  review:
    summary: >-
      Direct kinetic characterization of mammalian ceramide synthases including
      CERS2, supporting its role in ceramide biosynthesis.
    action: ACCEPT
    reason: >-
      CERS2 is directly assayed as a ceramide synthase acting by N-acylation of a
      sphingoid base; core biological process.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: "ceramide is synthesized by N-acylation of a sphingoid long-chain base"
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:18165233
  qualifier: involved_in
  review:
    summary: >-
      Direct characterization of CERS2 ceramide-synthesizing activity with VLC
      acyl-CoA specificity.
    action: ACCEPT
    reason: >-
      Directly supported core biological process; CERS2 makes very-long-chain
      ceramides.
    supported_by:
    - reference_id: PMID:18165233
      supporting_text: "rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis."
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:29632068
  qualifier: involved_in
  review:
    summary: >-
      Direct study mapping the acyl-chain specificity of ceramide synthases,
      showing CERS2 generates C22-C24 ceramides.
    action: ACCEPT
    reason: >-
      Directly demonstrates CERS2 ceramide-biosynthetic activity and its
      very-long-chain product specificity; core biological process.
    supported_by:
    - reference_id: PMID:29632068
      supporting_text: "containing 11 residues from CerS2 (which generates"
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:17977534
  qualifier: enables
  review:
    summary: >-
      Direct kinetic assay of CERS2 sphingosine N-acyltransferase (ceramide
      synthase) activity.
    action: ACCEPT
    reason: >-
      Direct biochemical support for the core molecular function.
    supported_by:
    - reference_id: PMID:17977534
      supporting_text: "each of which displays a high"
- term:
    id: GO:0050291
    label: sphingosine N-acyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:29632068
  qualifier: enables
  review:
    summary: >-
      Direct demonstration of CERS2 ceramide synthase activity and its C22-C24
      acyl-chain specificity.
    action: ACCEPT
    reason: >-
      Direct experimental support for the core molecular function, with the
      very-long-chain acyl-CoA specificity that distinguishes CERS2.
    supported_by:
    - reference_id: PMID:29632068
      supporting_text: "containing 11 residues from CerS2 (which generates"
- term:
    id: GO:0048681
    label: negative regulation of axon regeneration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator ISS transfer (from rat Q3T1K1) of negative regulation of axon
      regeneration.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicates the Ensembl IEA; peripheral nervous-system role, non-core.
- term:
    id: GO:1900148
    label: negative regulation of Schwann cell migration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator ISS transfer (from rat Q3T1K1) of negative regulation of Schwann
      cell migration.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicates the Ensembl IEA; peripheral nervous-system role, non-core.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic detection of CERS2 in an NK-cell membrane
      proteome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic membrane localization from a high-throughput membrane-proteome
      study; uninformative relative to the specific ER-membrane localization.
      Over-annotation.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: "define the composition of the membrane"
- 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 of ER membrane localization.
    action: ACCEPT
    reason: >-
      Matches the experimentally established ER-membrane localization; core
      cellular component.
    supported_by:
    - reference_id: file:human/CERS2/CERS2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20937905
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from the study showing CERS2 interacts with
      the fatty-acid elongation machinery (ELOVL1, HSD17B12, TECR), coordinating
      C24 acyl-CoA production with its use for ceramide synthesis.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This interaction is functionally meaningful (physical coupling of CERS2 to
      the VLC fatty-acid elongase complex), but the bare "protein binding" term is
      uninformative and does not represent a core molecular function. Retained (not
      removed) as an experimental IPI; the functional relationship is captured in
      the description and core functions.
    supported_by:
    - reference_id: PMID:20937905
      supporting_text: "ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis."
core_functions:
- description: >-
    Ceramide synthase (sphingosine N-acyltransferase) that N-acylates a sphingoid
    base (sphinganine/sphingosine) using very-long-chain fatty acyl-CoA (C22-C24,
    up to C26) to form very-long-chain (dihydro)ceramide at the endoplasmic
    reticulum membrane.
  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:18165233
    supporting_text: "rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis."
  - reference_id: PMID:20937905
    supporting_text: "ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis."
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: file:human/CERS2/CERS2-uniprot.txt
  title: UniProtKB entry Q96G23 (CERS2_HUMAN)
  findings: []
- id: PMID:11543633
  title: Cloning, mapping, and characterization of a human homologue of the yeast
    longevity assurance gene LAG1.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Original LASS2/CERS2 cloning paper; establishes high liver/kidney expression
      and interactions with membrane-associated receptors/transporters. Predates
      the enzymatic (ceramide synthase) characterization.
- 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 kinetic characterization of the CerS family (incl. CERS2); establishes
      the N-acylation mechanism and sphinganine Km. Abstract-only in cache.
- id: PMID:18165233
  title: 'Characterization of ceramide synthase 2: tissue distribution, substrate
    specificity, and inhibition by sphingosine 1-phosphate.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive CERS2 characterization: broadest/highest expression among CerS,
      VLC (C20-C26) acyl-CoA specificity, ER-membrane localization, and S1P
      inhibition. Abstract-only in cache but directly on-target.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput NK-cell membrane proteome; source of the generic membrane
      (HDA) annotation, not informative for specific function.
- id: PMID:20195357
  title: A comprehensive resource of interacting protein regions for refining human
    transcription factor networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale mRNA-display interacting-region resource; source of a bare
      protein-binding IPI, not informative for CERS2 function.
- id: PMID:20937905
  title: ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes CERS2 as essential for C24 (very-long-chain) sphingolipid
      synthesis and its physical/functional coupling to the ELOVL1/HSD17B12/TECR
      elongase machinery.
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale liver Y2H network; source of a bare protein-binding IPI.
- id: PMID:29632068
  title: Eleven residues determine the acyl chain specificity of ceramide synthases.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Maps the TLC-domain loop determining acyl-chain specificity; confirms CERS2
      generates C22-C24 ceramides. Abstract-only in cache but on-target.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome; source of a bare protein-binding IPI.
- id: PMID:32911434
  title: A functionally defined high-density NRF2 interactome reveals new conditional
    regulators of ARE transactivation.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Targeted NRF2 interactome; source of a bare protein-binding IPI.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 3.0 AP-MS interactome; source of a bare protein-binding IPI.
- id: PMID:34080016
  title: Glucosylceramide and galactosylceramide, small glycosphingolipids with significant
    impact on health and disease.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      General GlcCer/GalCer review; does not mention CERS2. Cited for the
      glycosphingolipid biosynthetic process (EXP) annotation, which over-reaches
      CERS2's role (it supplies the VLC-ceramide precursor, not the glycosylation
      step).
- id: PMID:36170811
  title: De novo sphingolipid biosynthesis necessitates detoxification in cancer cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Cached full text is entirely about SPT/KDSR (first two de novo pathway
      enzymes) and never mentions CERS2 or ceramide synthase; cannot verify the
      CERS2-specific IDA annotations (GO:0046513, GO:0098554) sourced from it.
- 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: []