id: O15121
gene_symbol: DEGS1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DEGS1 (dihydroceramide desaturase 1 / sphingolipid delta(4)-desaturase DES1) is the
  endoplasmic reticulum enzyme that catalyzes the final step of de novo ceramide
  biosynthesis. It introduces a 4,5-trans double bond into dihydroceramide
  (an N-acylsphinganine) to convert it into ceramide (an N-acylsphing-4-enine), thereby
  turning the saturated dihydroceramide produced by the ceramide synthases into bioactive
  ceramide, the central hub of sphingolipid metabolism. The reaction (EC 1.14.19.17) is
  oxygen-dependent and iron-dependent. DEGS1 is a member of the fatty acid desaturase type 1
  (DEGS) family with three conserved histidine-box motifs coordinating a di-iron center, and
  it receives reducing equivalents from cytochrome b5 / NAD(P)H via a free-radical mechanism.
  It is a multi-pass membrane protein acting on the cytoplasmic (cytosolic) face of the ER
  membrane; a myristoylation-dependent pool can also localize to mitochondria. DEGS1 also
  displays a distinct retinol (vitamin A) isomerase activity in retinal Muller glial cells.
  Loss-of-function variants cause hypomyelinating leukodystrophy 18 (HLD18), a severe
  autosomal recessive neurological disorder with accumulation of dihydroceramides and
  dihydro-sphingolipids and demyelination of the central and peripheral nervous systems.
existing_annotations:
- term:
    id: GO:0042284
    label: sphingolipid delta-4 desaturase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assertion of the core molecular function. DEGS1/DES1 is the
      dihydroceramide (sphingolipid Delta4) desaturase, matching the exact GOA/UniProt
      catalytic activity (EC 1.14.19.17). This is the correct, well-supported core MF.
    action: ACCEPT
    reason: >-
      Directly supported by experimental characterization of the human enzyme and by disease
      genetics; the IBA is at the right level of specificity for the family.
    supported_by:
    - reference_id: PMID:11937514
      supporting_text: >-
        identification of the enzyme sphingolipid Delta4-desaturase (dihydroceramide
        desaturase) from Homo sapiens
    - reference_id: PMID:30620337
      supporting_text: >-
        This enzyme catalyzes the insertion of a Δ4,5- trans double bond into dihydroceramide
        (DhCer) to convert it to ceramide (Cer), in the final step of the de novo Cer
        biosynthesis pathway
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assertion that DEGS1 acts in ceramide biosynthesis. Correct: the
      delta-4 desaturase step converts dihydroceramide to ceramide as the last committed
      step of de novo ceramide synthesis.
    action: ACCEPT
    reason: >-
      Core biological process; consistent with experimental and disease evidence.
    supported_by:
    - reference_id: PMID:30620338
      supporting_text: DEGS1, which catalyzes the last step in the ceramide synthesis pathway
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Root-level catalytic activity from an ARBA machine-learning model. Not wrong, but far
      too general given that the specific desaturase MF (GO:0042284) is annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative parent term subsumed by the specific sphingolipid delta-4 desaturase
      activity; retained only as an electronic generalization.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      ER membrane localization inferred electronically from the UniProt subcellular-location
      vocabulary. This matches the experimentally established primary site of DEGS1.
    action: ACCEPT
    reason: >-
      ER membrane is the functional localization, corroborated by multiple experimental
      studies.
    supported_by:
    - reference_id: file:human/DEGS1/DEGS1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Generic lipid metabolic process from InterPro2GO. Correct but very broad; the specific
      ceramide/sphingolipid biosynthetic process terms are the informative annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-level parent subsumed by more specific accepted BP terms (ceramide/sphingolipid
      biosynthetic process).
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      Generic membrane localization from InterPro2GO. DEGS1 is indeed a multi-pass membrane
      protein, but this root term is uninformative relative to ER membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Subsumed by the specific endoplasmic reticulum membrane localization.
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Sphingolipid biosynthetic process from InterPro2GO. Correct: ceramide made by DEGS1 is
      the precursor of all downstream sphingolipids. A valid, appropriately specific BP.
    action: ACCEPT
    reason: >-
      Consistent with the enzyme's role at the hub of de novo sphingolipid synthesis.
    supported_by:
    - reference_id: PMID:30620337
      supporting_text: >-
        This enzyme catalyzes the insertion of a Δ4,5- trans double bond into dihydroceramide
        (DhCer) to convert it to ceramide (Cer), in the final step of the de novo Cer
        biosynthesis pathway
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Mitochondrial membrane localization from the UniProt subcellular-location vocabulary.
      A myristoylation-dependent pool of DEGS1 is genuinely targeted to mitochondria, but
      this is a secondary, non-core localization relative to the ER.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally observed but secondary; myristoylation retargets part of the enzyme to
      mitochondria, raising ceramide/apoptosis. Not the primary functional site.
    supported_by:
    - reference_id: PMID:19647031
      supporting_text: >-
        DES1 myristoylation targets part of the recombinant protein to the mitochondria in
        COS-7 cells
    - reference_id: file:human/DEGS1/DEGS1-uniprot.txt
      supporting_text: Mitochondrion membrane
- term:
    id: GO:0042284
    label: sphingolipid delta-4 desaturase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      The core desaturase MF assigned electronically via combined IEA methods (InterPro,
      Rhea:46544, EC 1.14.19.17). Correct and matches the experimentally verified activity.
    action: ACCEPT
    reason: >-
      Duplicate electronic support for the well-established core molecular function.
    supported_by:
    - reference_id: file:human/DEGS1/DEGS1-uniprot.txt
      supporting_text: Reaction=an N-acylsphinganine + 2 Fe(II)-[cytochrome b5] + O2 + 2 H(+)
- term:
    id: GO:0050251
    label: retinol isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      Retinol isomerase activity from Rhea mapping (RHEA:19141, all-trans-retinol =
      11-cis-retinol). DEGS1 has a genuine, experimentally demonstrated retinol isomerase
      (vitamin A isomerase) activity in retinal Muller cells, distinct from its core
      dihydroceramide desaturase role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real moonlighting activity but tissue-restricted and secondary to de novo ceramide
      synthesis; keep as non-core.
    supported_by:
    - reference_id: PMID:23143414
      supporting_text: >-
        retinol-isomerase activity is a unique feature of DES1, and not a general property of
        membrane desaturases or diiron-binding proteins
- 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 high-throughput binary interactome (interaction with
      ARLN, Q8WVX3-2). Uninformative as a molecular function and not a curated biological
      partnership.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a systematic two-hybrid screen conveys no functional
      information for DEGS1; per curation policy, mark as over-annotated rather than remove.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        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 high-throughput binary interactome (second reported
      interactor, SEMA4G, Q9NTN9-2). Uninformative as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a systematic two-hybrid screen conveys no functional
      information for DEGS1; per curation policy, mark as over-annotated rather than remove.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        a human 'all-by-all' reference interactome map of human binary protein interactions,
        or 'HuRI'
- 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 assertion that DEGS1 acts in
      sphingolipid biosynthesis. Correct and consistent with the accepted BP.
    action: ACCEPT
    reason: >-
      Authoritative pathway annotation of the de novo sphingolipid biosynthesis role.
    supported_by:
    - reference_id: Reactome:R-HSA-428259
      supporting_text: catalyzes the desaturation of dihydroceramide to form ceramide
- term:
    id: GO:0042284
    label: sphingolipid delta-4 desaturase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-428259
  qualifier: enables
  review:
    summary: >-
      Reactome traceable assertion of the core desaturase reaction (DEGS1 dehydrogenates
      dihydroceramide). Correct core molecular function.
    action: ACCEPT
    reason: >-
      Matches the experimentally established dihydroceramide desaturase activity.
    supported_by:
    - reference_id: Reactome:R-HSA-428259
      supporting_text: catalyzes the desaturation of dihydroceramide to form ceramide
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1317856
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IDA) annotation to ceramide biosynthetic process. The cited 1992 study
      characterized the cytosolic-facing ER de novo sphingolipid-synthesis enzymes in mouse
      liver, establishing the pathway context; the experimental curator (UOS_MCB) read the
      full text. The core process assignment is correct.
    action: ACCEPT
    reason: >-
      Ceramide biosynthesis is the central role of DEGS1; defer to the experimental curator
      and accept.
    supported_by:
    - reference_id: PMID:1317856
      supporting_text: >-
        Serine palmitoyltransferase, 3-dehydrosphinganine reductase and sphinganine
        N-acyltransferase are responsible for the first steps in sphingolipid biosynthesis
- term:
    id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:1317856
  qualifier: is_active_in
  review:
    summary: >-
      Experimental (IDA) is_active_in the cytoplasmic (cytosolic) side of the ER membrane.
      The de novo sphingolipid-synthesis enzymes, including the ceramide-forming activities,
      face the cytosolic side of the ER; Reactome likewise places DEGS1 on the cytosolic ER
      face. This is the most specific and informative CC annotation.
    action: ACCEPT
    reason: >-
      Correct topology of the active enzyme on the cytosolic face of the ER membrane.
    supported_by:
    - reference_id: PMID:1317856
      supporting_text: >-
        they face the cytosolic side of the ER, so that substrates have free access to their
        active sites
    - reference_id: Reactome:R-HSA-428259
      supporting_text: enzyme associated with the cytosolic face of the endoplasmic reticulum
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence IDA to mitochondrion. Consistent with the myristoylation-
      dependent mitochondrial pool of DEGS1, but secondary to the ER.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine but non-core localization; the functional de novo ceramide-synthesis role is at
      the ER.
    supported_by:
    - reference_id: PMID:19647031
      supporting_text: >-
        native dihydroceramide Delta4-desaturase activity was found in both the endoplasmic
        reticulum and mitochondria in rat hepatocytes
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:19647031
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of DEGS1/DES1 to the ER membrane. This is the primary
      functional site of the enzyme.
    action: ACCEPT
    reason: >-
      ER membrane is the core localization; native desaturase activity is found in the ER.
    supported_by:
    - reference_id: PMID:19647031
      supporting_text: >-
        native dihydroceramide Delta4-desaturase activity was found in both the endoplasmic
        reticulum and mitochondria in rat hepatocytes
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:30620338
  qualifier: located_in
  review:
    summary: >-
      Experimental ER membrane localization from the HLD18 disease-gene study. Confirms the
      core ER localization of DEGS1.
    action: ACCEPT
    reason: >-
      Primary functional localization; DEGS1 catalyzes the last ceramide-synthesis step in
      the ER de novo pathway.
    supported_by:
    - reference_id: PMID:30620338
      supporting_text: DEGS1, which catalyzes the last step in the ceramide synthesis pathway
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:9188692
  qualifier: located_in
  review:
    summary: >-
      Original cloning study (MLD gene) localized the protein to the endoplasmic reticulum.
      Core localization, experimentally established.
    action: ACCEPT
    reason: >-
      Foundational experimental evidence for ER localization of DEGS1/MLD.
    supported_by:
    - reference_id: PMID:9188692
      supporting_text: MLD is widely expressed in human tissues and is localized to the endoplasmic reticulum
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: EXP
  original_reference_id: PMID:19647031
  qualifier: located_in
  review:
    summary: >-
      Experimental mitochondrial-membrane localization driven by N-myristoylation of DEGS1.
      Real but secondary; a myristoylation-dependent pool is targeted to mitochondria.
    action: KEEP_AS_NON_CORE
    reason: >-
      Non-core; the primary de novo ceramide-synthesis function occurs at the ER.
    supported_by:
    - reference_id: PMID:19647031
      supporting_text: >-
        DES1 myristoylation targets part of the recombinant protein to the mitochondria in
        COS-7 cells
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: EXP
  original_reference_id: PMID:30620338
  qualifier: located_in
  review:
    summary: >-
      Experimental mitochondrial-membrane localization reported alongside ER in the HLD18
      study. Secondary localization; keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Non-core relative to the ER, where the core catalytic function occurs.
    supported_by:
    - reference_id: PMID:19647031
      supporting_text: >-
        native dihydroceramide Delta4-desaturase activity was found in both the endoplasmic
        reticulum and mitochondria in rat hepatocytes
- term:
    id: GO:0042284
    label: sphingolipid delta-4 desaturase activity
  evidence_type: EXP
  original_reference_id: PMID:11937514
  qualifier: enables
  review:
    summary: >-
      Experimental characterization of the human sphingolipid Delta4-desaturase
      (dihydroceramide desaturase) by heterologous expression. This is the primary
      experimental basis for the core molecular function and UniProt's EC 1.14.19.17.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for the core catalytic activity of DEGS1.
    supported_by:
    - reference_id: PMID:11937514
      supporting_text: >-
        identification of the enzyme sphingolipid Delta4-desaturase (dihydroceramide
        desaturase) from Homo sapiens
- term:
    id: GO:0042284
    label: sphingolipid delta-4 desaturase activity
  evidence_type: IMP
  original_reference_id: PMID:30620338
  qualifier: enables
  review:
    summary: >-
      IMP evidence: the HLD18 A280V patient variant reduces DEGS1 enzymatic activity by ~80%,
      with accumulation of dihydro-sphingolipid substrate, directly demonstrating the
      sphingolipid delta-4 desaturase activity of the gene product.
    action: ACCEPT
    reason: >-
      Loss-of-function/mutant evidence supports the core desaturase MF.
    supported_by:
    - reference_id: PMID:30620338
      supporting_text: >-
        The enzymatic activity in patient fibroblasts was reduced by 80% compared with
        wild-type cells
    - reference_id: PMID:30620338
      supporting_text: >-
        The blood sphingolipid profile in the patient showed a significant increase in dihydro
        sphingolipid species
- term:
    id: GO:0006686
    label: sphingomyelin biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:24209621
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IDA) annotation to sphingomyelin biosynthetic process. Ceramide produced
      by DEGS1 is the precursor of sphingomyelin, so DEGS1 feeds this downstream process. The
      experimental curator (UOS_MCB) read the full text; this is a downstream, non-core BP.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream complex-sphingolipid process dependent on DEGS1-derived ceramide; secondary
      to the core ceramide-synthesis function.
    supported_by:
    - reference_id: PMID:24209621
      supporting_text: >-
        OSBP-mediated back transfer of PI(4)P might coordinate the transfer of other lipid
        species at the ER-Golgi interface
- term:
    id: GO:0006688
    label: glycosphingolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:34080016
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IDA) annotation to glycosphingolipid biosynthetic process. Glucosyl- and
      galactosyl-ceramides are built from ceramide, the product of DEGS1, so DEGS1 feeds
      glycosphingolipid synthesis. Downstream, non-core role.
    action: KEEP_AS_NON_CORE
    reason: >-
      DEGS1 supplies ceramide for downstream glycosphingolipid synthesis; secondary to the
      core desaturase function.
    supported_by:
    - reference_id: PMID:34080016
      supporting_text: GlcCer is a founder molecule for synthesis of hundreds of glycosphingolipids (GSLs)
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:16120614
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IDA) annotation to ceramide biosynthetic process. The cited study of the
      Serinc protein family placed DEGS1 among the ER sphingolipid-biosynthetic enzymes; the
      experimental curator read the full text. Correct core BP.
    action: ACCEPT
    reason: >-
      Core biological process of DEGS1; ceramide biosynthesis via delta-4 desaturation.
    supported_by:
    - reference_id: PMID:16120614
      supporting_text: >-
        A Serinc protein forms an intracellular complex with key enzymes involved in serine
        and sphingolipid biosyntheses
- term:
    id: GO:0098554
    label: cytoplasmic side of endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:16120614
  qualifier: is_active_in
  review:
    summary: >-
      Experimental (IDA) is_active_in the cytoplasmic side of the ER membrane, consistent
      with the cytosolic orientation of the de novo sphingolipid-synthesis machinery and with
      Reactome's placement of DEGS1 on the cytosolic ER face.
    action: ACCEPT
    reason: >-
      Correct, specific active-site topology of DEGS1 at the cytosolic face of the ER.
    supported_by:
    - reference_id: PMID:16120614
      supporting_text: co-localizes with lipid biosynthetic enzymes in endoplasmic reticulum membranes
    - reference_id: Reactome:R-HSA-428259
      supporting_text: enzyme associated with the cytosolic face of the endoplasmic reticulum
- term:
    id: GO:0050251
    label: retinol isomerase activity
  evidence_type: IDA
  original_reference_id: PMID:23143414
  qualifier: enables
  review:
    summary: >-
      Experimental (IDA) demonstration that DES1 is a retinol (vitamin A) isomerase
      (isomerase-2) in retinal Muller cells: purified DES1 has robust retinol-isomerase
      activity, it coimmunoprecipitates with CRALBP, and the activity is unique to DES1 among
      membrane desaturases. Genuine moonlighting activity, distinct from the core ceramide
      role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Well-supported second enzymatic activity but tissue-restricted (retina) and distinct
      from the primary de novo ceramide-synthesis function; keep as non-core.
    supported_by:
    - reference_id: PMID:23143414
      supporting_text: >-
        retinol-isomerase activity is a unique feature of DES1, and not a general property of
        membrane desaturases or diiron-binding proteins
    - reference_id: PMID:23143414
      supporting_text: coimmunoprecipitates with cellular retinaldehyde binding protein (CRALBP)
- term:
    id: GO:0042284
    label: sphingolipid delta-4 desaturase activity
  evidence_type: IMP
  original_reference_id: PMID:30620337
  qualifier: enables
  review:
    summary: >-
      IMP evidence from the leukodystrophy study: loss of DEGS1 function (patient variants)
      abolishes the delta-4 desaturase step, with accumulation of dihydroceramide. Supports
      the core molecular function.
    action: ACCEPT
    reason: >-
      Disease-variant/loss-of-function evidence confirms the core desaturase activity.
    supported_by:
    - reference_id: PMID:30620337
      supporting_text: >-
        This enzyme catalyzes the insertion of a Δ4,5- trans double bond into dihydroceramide
        (DhCer) to convert it to ceramide (Cer), in the final step of the de novo Cer
        biosynthesis pathway
- term:
    id: GO:0043217
    label: myelin maintenance
  evidence_type: IMP
  original_reference_id: PMID:30620337
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to myelin maintenance based on DEGS1-loss causing hypomyelinating
      leukodystrophy (HLD18). The dihydroceramide/ceramide imbalance disrupts myelin
      development and maintenance. This is a physiological consequence of the enzyme's
      lipid-metabolic role rather than a direct molecular function, but is experimentally
      supported.
    action: KEEP_AS_NON_CORE
    reason: >-
      Tissue-level physiological role downstream of the core ceramide-synthesis function;
      important for disease but not the core molecular activity.
    supported_by:
    - reference_id: PMID:30620337
      supporting_text: suggesting a critical role of DEGS1 in myelin development and maintenance
- term:
    id: GO:0043217
    label: myelin maintenance
  evidence_type: IMP
  original_reference_id: PMID:30620338
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to myelin maintenance from the second HLD18 study, where DEGS1
      dysfunction causes hypomyelination and degeneration of the nervous system. Same
      downstream physiological role as above.
    action: KEEP_AS_NON_CORE
    reason: >-
      Non-core physiological/disease role secondary to the core lipid-desaturase function.
    supported_by:
    - reference_id: PMID:30620338
      supporting_text: >-
        DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and
        degeneration of both the central and peripheral nervous systems
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: >-
      Plasma membrane localization from a Reactome neutrophil-degranulation pathway (specific
      granule exocytosis). This reflects bulk granule/membrane proteomics, not a functional
      DEGS1 site; DEGS1 acts at the ER, not the plasma membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-annotation from a granule-membrane proteomics pathway; inconsistent with the
      established ER localization and function of DEGS1.
    supported_by:
    - reference_id: Reactome:R-HSA-6799350
      supporting_text: >-
        Secondary (specific) granules are peroxidase-negative and rich in antimicrobial
        substances
- term:
    id: GO:0035579
    label: specific granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: >-
      Specific granule membrane localization from the same neutrophil-degranulation pathway.
      Reflects granule-membrane proteomics rather than a functional DEGS1 location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-annotation; not the functional site of the ER-resident desaturase.
    supported_by:
    - reference_id: Reactome:R-HSA-6799350
      supporting_text: >-
        Secondary (specific) granules are peroxidase-negative and rich in antimicrobial
        substances
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-428259
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion of ER membrane localization for the DEGS1 desaturation
      reaction. Correct core localization.
    action: ACCEPT
    reason: >-
      Consistent with the ER as the functional site of DEGS1.
    supported_by:
    - reference_id: Reactome:R-HSA-428259
      supporting_text: enzyme associated with the cytosolic face of the endoplasmic reticulum
- term:
    id: GO:0009055
    label: electron transfer activity
  evidence_type: TAS
  original_reference_id: PMID:9188692
  qualifier: enables
  review:
    summary: >-
      Electron transfer activity assigned from the desaturase family context. DEGS1 receives
      electrons from cytochrome b5 to drive desaturation, but it is the terminal desaturase
      acceptor, not an electron-carrier; this activity is better captured by the desaturase MF
      and its di-iron/cytochrome-b5 coupling.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Mechanistically peripheral; DEGS1 is the desaturase, not an electron-transfer protein.
      The core MF (GO:0042284) captures the redox chemistry.
    supported_by:
    - reference_id: PMID:23143414
      supporting_text: >-
        DES1 is coupled to the cytochrome b5 electron-transport chain, and acts via a
        free-radical mechanism
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:9188692
  qualifier: located_in
  review:
    summary: >-
      ER localization (parent of ER membrane) from the original MLD cloning study. Correct
      but less specific than the ER membrane annotation.
    action: ACCEPT
    reason: >-
      Correct localization; a valid, if less specific, parent of endoplasmic reticulum
      membrane.
    supported_by:
    - reference_id: PMID:9188692
      supporting_text: MLD is widely expressed in human tissues and is localized to the endoplasmic reticulum
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:9188692
  qualifier: located_in
  review:
    summary: >-
      Plasma membrane localization traced to the 1997 MLD cloning paper, which localized the
      protein to the ER (and reported detergent-extractable membrane association), not the
      plasma membrane. This appears to be an over-annotation; DEGS1 is an ER/mitochondrial
      protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Inconsistent with the ER localization reported in the same paper and with all other
      evidence; likely an over-broad membrane call.
    supported_by:
    - reference_id: PMID:9188692
      supporting_text: MLD is widely expressed in human tissues and is localized to the endoplasmic reticulum
- term:
    id: GO:0006636
    label: unsaturated fatty acid biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:9188692
  qualifier: involved_in
  review:
    summary: >-
      Annotation to unsaturated fatty acid biosynthesis, dating from when DEGS1 was known
      only as a membrane fatty acid desaturase family member. DEGS1 desaturates the
      sphingoid base of dihydroceramide, not free fatty acids; the ceramide/sphingolipid
      biosynthetic process terms are the accurate BPs.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Misleading generalization from family membership; the true substrate is dihydroceramide,
      not a fatty acid, so this BP mischaracterizes the reaction.
    supported_by:
    - reference_id: PMID:9188692
      supporting_text: We have cloned a new member of the human membrane fatty acid (lipid) desaturase gene family, MLD
    - reference_id: PMID:23143414
      supporting_text: DES1 introduces a 4,5-trans-double bond in dihydroceramide as the final step in ceramide synthesis
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:9188692
  qualifier: located_in
  review:
    summary: >-
      Generic membrane localization from the original cloning study, which showed DEGS1/MLD
      is a multi-pass membrane protein. Correct but subsumed by the specific ER membrane
      annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Root-level term superseded by endoplasmic reticulum membrane.
    supported_by:
    - reference_id: PMID:9188692
      supporting_text: MLD is widely expressed in human tissues and is localized to the endoplasmic reticulum
core_functions:
- description: >-
    Catalyzes the final step of de novo ceramide biosynthesis: introduces a 4,5-trans double
    bond into dihydroceramide (an N-acylsphinganine) to form ceramide (an N-acylsphing-4-enine),
    an O2- and iron/cytochrome b5-dependent reaction (EC 1.14.19.17) at the cytosolic face of
    the ER membrane.
  molecular_function:
    id: GO:0042284
    label: sphingolipid delta-4 desaturase activity
  directly_involved_in:
  - id: GO:0046513
    label: ceramide biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:11937514
    supporting_text: >-
      identification of the enzyme sphingolipid Delta4-desaturase (dihydroceramide desaturase)
      from Homo sapiens
  - reference_id: PMID:30620337
    supporting_text: >-
      This enzyme catalyzes the insertion of a Δ4,5- trans double bond into dihydroceramide
      (DhCer) to convert it to ceramide (Cer), in the final step of the de novo Cer
      biosynthesis pathway
  - reference_id: PMID:30620338
    supporting_text: DEGS1, which catalyzes the last step in the ceramide synthesis pathway
- description: >-
    Feeds ceramide into the broader de novo sphingolipid biosynthetic network, generating the
    ceramide precursor from which sphingomyelin, glucosyl/galactosyl-ceramides and downstream
    complex sphingolipids are built at the ER.
  molecular_function:
    id: GO:0042284
    label: sphingolipid delta-4 desaturase activity
  directly_involved_in:
  - id: GO:0030148
    label: sphingolipid biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: Reactome:R-HSA-428259
    supporting_text: catalyzes the desaturation of dihydroceramide to form ceramide
  - reference_id: PMID:30620337
    supporting_text: >-
      This enzyme catalyzes the insertion of a Δ4,5- trans double bond into dihydroceramide
      (DhCer) to convert it to ceramide (Cer), in the final step of the de novo Cer
      biosynthesis pathway
proposed_new_terms: []
suggested_questions:
- question: >-
    Is the retinol (vitamin A) isomerase activity of DES1 a physiologically significant second
    function outside the retina, and does it share the di-iron active site with the
    dihydroceramide desaturase reaction?
- question: >-
    What determines the partitioning of DEGS1 between the ER and mitochondria, and does the
    mitochondrial (myristoylated) pool have a distinct pro-apoptotic ceramide-signaling role in
    vivo?
suggested_experiments:
- description: >-
    Structure-function analysis of the three histidine boxes and di-iron center to define the
    catalytic residues required for dihydroceramide desaturation versus retinol isomerization.
- description: >-
    Lipidomic and myelination phenotyping of DEGS1 HLD18 patient variants in oligodendrocyte
    models to quantify the dihydroceramide/ceramide imbalance and test substrate-reduction
    (e.g. CerS-inhibitor) rescue.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
    mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11937514
  title: Identification and characterization of a sphingolipid delta 4-desaturase family.
  findings:
  - statement: >-
      Identified and biochemically characterized the human sphingolipid Delta4-desaturase
      (dihydroceramide desaturase), the enzyme underlying the core DEGS1 catalytic activity;
      basis for UniProt EC 1.14.19.17.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; primary characterization of the human dihydroceramide desaturase core
      function.
- id: PMID:1317856
  title: Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine
    reductase, and sphinganine N-acyltransferase in mouse liver.
  findings:
  - statement: >-
      Established that the de novo sphingolipid-synthesis enzymes reside in the ER and face
      its cytosolic side, providing the pathway and topology context used for DEGS1 ceramide
      biosynthesis and cytosolic-ER-face annotations.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache; about upstream ceramide-synthesis enzymes but establishes the
      cytosolic-ER-face topology of the pathway. Used by the experimental curator (UOS_MCB)
      for DEGS1 process and topology annotations; do not overrule.
- id: PMID:16120614
  title: Serinc, an activity-regulated protein family, incorporates serine into membrane lipid
    synthesis.
  findings:
  - statement: >-
      Places DEGS1 among the ER sphingolipid-biosynthetic enzymes acting on the cytosolic face;
      basis for experimental ceramide-biosynthesis and cytosolic-ER-face annotations.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only in cache; experimental curator read full text for the DEGS1 annotations.
- id: PMID:19647031
  title: 'N-Myristoylation targets dihydroceramide Delta4-desaturase 1 to mitochondria: partial
    involvement in the apoptotic effect of myristic acid.'
  findings:
  - statement: >-
      N-myristoylation of DES1 (Gly-2) targets a fraction of the enzyme to mitochondria and
      increases ceramide production and apoptosis; native desaturase activity occurs in both
      ER and mitochondria. Explains the secondary mitochondrial localization.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; explains the non-core mitochondrial pool of DEGS1.
- id: PMID:23143414
  title: Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina.
  findings:
  - statement: >-
      DES1 is a retinol (vitamin A) isomerase (isomerase-2) in retinal Muller cells, a
      distinct moonlighting activity; purified DES1 has robust activity and coimmunoprecipitates
      with CRALBP. Basis for the retinol isomerase activity annotation.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the secondary retinol isomerase activity.
- id: PMID:24209621
  title: A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the
    ER-Golgi tether OSBP.
  findings:
  - statement: >-
      ER-Golgi lipid-exchange context (OSBP cycle) relevant to downstream sphingolipid and
      sphingomyelin trafficking; cited for the DEGS1 sphingomyelin-biosynthesis annotation.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; about OSBP-mediated ER-Golgi lipid exchange, tangential to DEGS1; the
      sphingomyelin-biosynthesis annotation is downstream and non-core.
- id: PMID:30620337
  title: Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.
  findings:
  - statement: >-
      Biallelic DEGS1 loss-of-function causes hypomyelinating leukodystrophy (HLD18); DEGS1
      inserts the Δ4,5-trans double bond into dihydroceramide as the final step of de novo
      ceramide synthesis; critical for myelin development and maintenance.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; primary disease-gene and mechanism paper.
- id: PMID:30620338
  title: DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function
    in humans.
  findings:
  - statement: >-
      Homozygous DEGS1 p.Ala280Val causes a multisystem neurological disorder; the variant
      reduces enzyme activity by about 80% with accumulation of dihydro-sphingolipids; DEGS1
      catalyzes the last step of ceramide synthesis. IMP basis for the core MF and myelin
      annotations.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache but rich; independent HLD18 disease-gene paper confirming core
      function via loss-of-function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      High-throughput binary interactome (HuRI) reporting DEGS1 interactions (ARLN, SEMA4G);
      source of the uninformative bare protein-binding IPIs.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Systematic two-hybrid screen; interactions are not functionally interpreted for DEGS1
      (over-annotation of protein binding).
- id: PMID:34080016
  title: Glucosylceramide and galactosylceramide, small glycosphingolipids with significant
    impact on health and disease.
  findings:
  - statement: >-
      Review of glucosyl- and galactosyl-ceramide biology; glucosylceramide is the founder of
      hundreds of glycosphingolipids, all built from ceramide (the DEGS1 product). Context for
      the downstream glycosphingolipid-biosynthesis annotation.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review; supports the downstream (non-core) glycosphingolipid-biosynthesis role.
- id: PMID:9188692
  title: 'The product of the MLD gene is a member of the membrane fatty acid desaturase family:
    overexpression of MLD inhibits EGF receptor biosynthesis.'
  findings:
  - statement: >-
      Original cloning of the human MLD gene (DEGS1) as a membrane fatty acid desaturase family
      member localized to the ER and predicted to be multi-pass. Basis for early ER, membrane,
      and fatty-acid annotations.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; foundational cloning and localization paper. Its plasma-membrane and
      unsaturated-fatty-acid annotations are over-annotations superseded by later specific data.
- id: Reactome:R-HSA-1660661
  title: Sphingolipid de novo biosynthesis
  findings: []
- id: Reactome:R-HSA-428259
  title: DEGS1 dehydrogenates dihydroceramide
  findings:
  - statement: >-
      Reactome curated reaction in which DEGS1, at the cytosolic face of the ER, desaturates
      dihydroceramide to ceramide as part of an enzyme complex with cytochrome b5 (Fe2+)
      refreshed by NADH.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome curated reaction for the core DEGS1 activity and cytosolic ER localization.
- id: Reactome:R-HSA-6799350
  title: Exocytosis of specific granule membrane proteins
  findings:
  - statement: >-
      Neutrophil specific-granule exocytosis pathway; source of the plasma-membrane and
      specific-granule-membrane over-annotations for DEGS1 (bulk granule proteomics).
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Granule-membrane proteomics pathway; the resulting DEGS1 localizations are
      over-annotations, not functional sites.
- id: file:human/DEGS1/DEGS1-uniprot.txt
  title: UniProtKB entry O15121 (DEGS1_HUMAN)
  findings:
  - statement: >-
      UniProt records the core catalytic activity (EC 1.14.19.17; N-acylsphinganine plus O2
      plus Fe(II)-cytochrome b5 giving N-acylsphing-4-enine), ER and mitochondrion membrane
      localization, DEGS-subfamily membership, and causation of HLD18.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record for O15121; the source of the file supporting quotes.