id: Q06136
gene_symbol: KDSR
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: KDSR (3-ketodihydrosphingosine reductase; also known as FVT-1 and SDR35C1)
  is an NADPH-dependent short-chain dehydrogenase/reductase that catalyses the second
  step of de novo sphingolipid biosynthesis, the reduction of 3-ketodihydrosphingosine
  (3-ketosphinganine / 3-oxosphinganine) to dihydrosphingosine (sphinganine). This
  step follows the serine palmitoyltransferase (SPT)-catalysed condensation of L-serine
  and palmitoyl-CoA and precedes N-acylation by the ceramide synthases, feeding the
  downstream production of ceramide and complex sphingolipids. It is the principal
  KDS reductase in mammalian cells and is essential for flux through this pathway.
  The enzyme is a multi-pass endoplasmic reticulum membrane protein whose large catalytic
  domain, carrying the NADPH-binding site and active-site residues, faces the cytosolic
  side of the ER membrane. Loss-of-function mutations cause erythrokeratodermia variabilis
  et progressiva 4 (a recessive skin/keratinization disorder) and a spectrum of keratinization
  disorders that can be accompanied by thrombocytopenia due to impaired proplatelet
  formation.
alternative_products:
- name: '1'
  id: Q06136-1
- name: '2'
  id: Q06136-2
  sequence_note: VSP_056641
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) inference that KDSR is active in the ER membrane. This
      is strongly supported by direct experimental evidence in human and mouse.
    action: ACCEPT
    reason: KDSR is an integral ER membrane protein with its catalytic domain on the
      cytosolic face of the ER; the IBA localization is correct and at an appropriate
      level of specificity.
    supported_by:
    - reference_id: PMID:15328338
      supporting_text: hFVT-1 is localized at the endoplasmic reticulum
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) inference that KDSR is involved in sphingolipid biosynthesis.
      This is the core biological process of the gene.
    action: ACCEPT
    reason: KDSR catalyses the second, obligatory step of de novo sphingolipid biosynthesis;
      this is directly supported by experimental and mutation data in addition to
      the phylogenetic inference.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: the second step of de novo sphingolipid biosynthesis
    - reference_id: PMID:19141869
      supporting_text: FVT1 is the principal 3-ketosphinganine reductase in mammalian
        cells
- term:
    id: GO:0006666
    label: 3-keto-sphinganine metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) inference that KDSR participates in 3-keto-sphinganine
      metabolism. KDSR consumes 3-keto-sphinganine (3-ketodihydrosphingosine), its
      direct substrate.
    action: ACCEPT
    reason: 3-keto-sphinganine (3-oxosphinganine) is the direct substrate of KDSR;
      this is a precise, correct BP for the enzyme's substrate metabolism, complementing
      the broader sphingolipid biosynthetic process term.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: Reaction=sphinganine + NADP(+) = 3-oxosphinganine + NADPH +
        H(+)
- term:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) inference of 3-dehydrosphinganine reductase (KDS reductase)
      activity. This is the defining molecular function of KDSR.
    action: ACCEPT
    reason: This IBA annotation captures the core molecular function of KDSR and is
      concordant with direct enzymatic characterization of the purified human protein.
    supported_by:
    - reference_id: PMID:15328338
      supporting_text: exhibited NADPH-dependent KDS reductase activity
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of ER membrane localization from the UniProt Subcellular
      Location mapping, consistent with experimental evidence.
    action: ACCEPT
    reason: The ER membrane localization is experimentally established; this IEA is
      accurate.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0006666
    label: 3-keto-sphinganine metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO electronic annotation to 3-keto-sphinganine metabolic process
      based on the KDSR-like family signature (IPR045022).
    action: ACCEPT
    reason: The InterPro family assignment correctly maps to the substrate-metabolism
      BP; consistent with the enzyme's characterized reaction.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: Reaction=sphinganine + NADP(+) = 3-oxosphinganine + NADPH +
        H(+)
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation (combined IEA methods / ARBA) to sphingolipid biosynthetic
      process, the core BP of KDSR.
    action: ACCEPT
    reason: Correct core biological process, redundant with better-supported experimental
      annotations to the same term.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: the second step of de novo sphingolipid biosynthesis
- term:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation of the reductase molecular function from InterPro/RHEA/EC
      mappings (EC 1.1.1.102, RHEA:22640).
    action: ACCEPT
    reason: Correctly assigns the defining molecular function via the enzyme's EC number
      and Rhea reaction; concordant with experimental data.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: EC=1.1.1.102
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare "protein binding" from a large-scale yeast two-hybrid interactome
      study, capturing interactions with KIF1B, HSPB1, TTR and WFS1. This term is
      uninformative about KDSR's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The GO:0005515 "protein binding" term conveys no specific functional information,
      and the underlying interactions are high-throughput Y2H hits from a neurodegeneration
      interactome screen with no established relevance to KDSR's enzymatic role. Per
      curation guidance, bare protein binding is retained but flagged as an over-annotation
      rather than removed.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: systematic yeast two-hybrid interaction screening
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1660661
  qualifier: involved_in
  review:
    summary: Reactome traceable annotation placing KDSR in de novo sphingolipid biosynthesis.
    action: ACCEPT
    reason: Reactome correctly assigns KDSR to the sphingolipid de novo biosynthesis
      pathway; this is the core BP.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: the second step of de novo sphingolipid biosynthesis
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-based electronic annotation to the broad sphingolipid metabolic
      process term.
    action: KEEP_AS_NON_CORE
    reason: Correct but less informative than the biosynthetic-process child term (GO:0030148),
      which is separately annotated with experimental support. Retained as a valid
      but general parent annotation.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: 'PATHWAY: Lipid metabolism; sphingolipid metabolism'
- term:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-428123
  qualifier: enables
  review:
    summary: Reactome traceable annotation of the KDS reductase molecular function
      (reaction "KDSR reduces 3-ketosphingoid").
    action: ACCEPT
    reason: Correctly captures the defining molecular function of KDSR.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: Reaction=sphinganine + NADP(+) = 3-oxosphinganine + NADPH +
        H(+)
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1317856
  qualifier: involved_in
  review:
    summary: Classic biochemical study localizing serine palmitoyltransferase, 3-dehydrosphinganine
      reductase and sphinganine N-acyltransferase to the cytosolic face of mouse liver
      ER. The reductase activity feeds the pathway that produces dihydroceramide/ceramide.
    action: KEEP_AS_NON_CORE
    reason: KDSR (3-dehydrosphinganine reductase) provides sphinganine, an obligatory
      precursor for ceramide synthesis, and this paper measures the reductase activity
      as part of the early ceramide-forming pathway. However, KDSR does not itself
      catalyse ceramide formation, so ceramide biosynthetic process is a pathway-level
      annotation kept as non-core rather than a direct catalytic function.
    supported_by:
    - reference_id: PMID:1317856
      supporting_text: are responsible for the first steps in sphingolipid
    - reference_id: PMID:1317856
      supporting_text: '3-oxosphinganine, sphinganine, and dihydroceramide'
- term:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  evidence_type: IDA
  original_reference_id: PMID:36170811
  qualifier: enables
  review:
    summary: Study establishing that KDSR reduces 3KDS to sphinganine and that KDSR
      loss causes toxic 3KDS accumulation. Supports the reductase molecular function.
    action: ACCEPT
    reason: Directly attributes the 3KDS-reducing (3-dehydrosphinganine reductase)
      activity to KDSR; this is the core molecular function.
    supported_by:
    - reference_id: PMID:36170811
      supporting_text: 3KDS is subsequently converted to sphinganine by 3KDS reductase
        (KDSR)
- term:
    id: GO:0006686
    label: sphingomyelin biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:36170811
  qualifier: involved_in
  review:
    summary: KDSR loss affects downstream sphingomyelin levels because sphingomyelin
      is a major downstream product of de novo sphingolipid biosynthesis; sphingomyelins
      were measured as downstream readouts of the KDSR-dependent pathway.
    action: MARK_AS_OVER_ANNOTATED
    reason: KDSR contributes to sphingomyelin biosynthesis only indirectly, by supplying
      the sphinganine backbone upstream; it does not catalyse any sphingomyelin-forming
      step. In this study cancer cells could still salvage sphingomyelin, and total
      sphingomyelins did not necessarily decrease on KDSR knockout. This is a distal
      pathway-product annotation rather than a direct function.
    supported_by:
    - reference_id: PMID:36170811
      supporting_text: major downstream products of sphingolipid biosynthesis
- term:
    id: GO:0006688
    label: glycosphingolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:34080016
  qualifier: involved_in
  review:
    summary: Reference is a review of glucosylceramide and galactosylceramide biology.
      Glycosphingolipids are distal products of the de novo pathway that KDSR feeds,
      but the reference does not itself assay or even mention KDSR.
    action: MARK_AS_OVER_ANNOTATED
    reason: Glycosphingolipid biosynthesis is several enzymatic steps downstream of
      KDSR (sphinganine -> ceramide -> glucosyl/galactosylceramide -> complex GSL);
      KDSR catalyses none of these glycosylation steps. The cited review never mentions
      KDSR, so this is a pathway-level over-annotation, not a direct function.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: the second step of de novo sphingolipid biosynthesis
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:16120614
  qualifier: involved_in
  review:
    summary: Study of the Serinc protein family, which forms an intracellular complex
      with enzymes of serine and sphingolipid biosynthesis to incorporate serine into
      membrane lipids. The abstract does not directly assay KDSR in ceramide synthesis.
    action: KEEP_AS_NON_CORE
    reason: Ceramide biosynthesis is downstream of the sphinganine KDSR produces; KDSR
      is required for the pathway but does not catalyse a ceramide-forming step. Because
      only the abstract is available and the experimental (IDA) full text may implicate
      KDSR in the biosynthetic complex, the annotation is retained as a valid pathway-level,
      non-core assignment rather than removed.
    supported_by:
    - reference_id: PMID:16120614
      supporting_text: 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:19416851
  qualifier: is_active_in
  review:
    summary: Annotation that KDSR is active on the cytoplasmic side of the ER membrane.
      This is the most precise localization consistent with the enzyme's topology.
    action: ACCEPT
    reason: KDSR's large catalytic domain, bearing the active-site and NADPH-binding
      residues, faces the cytosol at the ER membrane; the cytoplasmic-side term is
      the most accurate CC and reflects where catalysis occurs.
    supported_by:
    - reference_id: PMID:15328338
      supporting_text: which contains putative active site residues, faces the cytosol
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: TOPO_DOM        26..270
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:15328338
  qualifier: located_in
  review:
    summary: Direct experimental (immunofluorescence) demonstration that human FVT-1/KDSR
      localizes to the endoplasmic reticulum.
    action: ACCEPT
    reason: Robust experimental support for ER membrane localization.
    supported_by:
    - reference_id: PMID:15328338
      supporting_text: hFVT-1 is localized at the endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:19141869
  qualifier: located_in
  review:
    summary: Experimental localization and topology study placing FVT1/KDSR at the
      ER membrane.
    action: ACCEPT
    reason: Confirms ER membrane localization by independent experimental methods.
    supported_by:
    - reference_id: PMID:19141869
      supporting_text: oriented to place
- term:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  evidence_type: EXP
  original_reference_id: PMID:15328338
  qualifier: enables
  review:
    summary: Purified recombinant human FVT-1/KDSR exhibits NADPH-dependent KDS reductase
      activity in vitro, and rescues KDS reductase-deficient yeast.
    action: ACCEPT
    reason: Direct enzymatic demonstration of the defining molecular function; core
      function.
    supported_by:
    - reference_id: PMID:15328338
      supporting_text: exhibited NADPH-dependent KDS reductase activity
- term:
    id: GO:0006666
    label: 3-keto-sphinganine metabolic process
  evidence_type: IMP
  original_reference_id: PMID:19141869
  qualifier: involved_in
  review:
    summary: Silencing/mutation of FVT1 alters 3-ketosphinganine reductase activity,
      implicating KDSR in 3-keto-sphinganine metabolism.
    action: ACCEPT
    reason: Loss-of-function evidence supports KDSR's role in metabolizing its substrate
      3-keto-sphinganine.
    supported_by:
    - reference_id: PMID:19141869
      supporting_text: FVT1 is the principal 3-ketosphinganine reductase in mammalian
        cells
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:19141869
  qualifier: involved_in
  review:
    summary: Mutational/silencing evidence that FVT1/KDSR is required for long-chain
      base (sphingoid) synthesis, i.e. sphingolipid biosynthesis.
    action: ACCEPT
    reason: Core biological process supported by loss-of-function data.
    supported_by:
    - reference_id: PMID:19141869
      supporting_text: required for long-chain base synthesis in yeast and mammals
- term:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  evidence_type: IMP
  original_reference_id: PMID:19141869
  qualifier: enables
  review:
    summary: FVT1 silencing directly correlates with cellular KDS reductase activity,
      identifying KDSR as the principal enzyme carrying this activity.
    action: ACCEPT
    reason: Loss-of-function evidence for the defining molecular function; core function.
    supported_by:
    - reference_id: PMID:19141869
      supporting_text: a direct correlation between FVT1 levels and reductase activity
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity-based transfer of sphingolipid biosynthetic process
      from the yeast ortholog (TSC10, P38342).
    action: ACCEPT
    reason: Correct core BP; the ortholog-based inference agrees with direct experimental
      data in human.
    supported_by:
    - reference_id: PMID:19141869
      supporting_text: required for long-chain base synthesis in yeast and mammals
- term:
    id: GO:0070402
    label: NADPH binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity inference of NADPH binding, consistent with the Rossmann-fold
      NADPH-binding motif and the NADPH-dependent reductase mechanism.
    action: ACCEPT
    reason: KDSR is an NADPH-dependent reductase with a conserved N-terminal NADPH-binding
      (Rossmann) region; NADPH binding is a genuine molecular function supporting the
      catalytic activity.
    supported_by:
    - reference_id: PMID:15328338
      supporting_text: exhibited NADPH-dependent KDS reductase activity
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: /ligand="NADPH"
- term:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  evidence_type: IMP
  original_reference_id: PMID:28575652
  qualifier: enables
  review:
    summary: Disease-gene study showing biallelic KDSR mutations cause progressive
      symmetric erythrokeratoderma, with yeast complementation and immunohistochemistry
      demonstrating defective KDSR function.
    action: ACCEPT
    reason: Patient mutations that abolish/impair the reductase function, validated
      by yeast complementation, provide loss-of-function support for the enzymatic
      activity.
    supported_by:
    - reference_id: PMID:28575652
      supporting_text: demonstrated that the mutations cause defects in KDSR function
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput proteomics identification of KDSR in the membrane proteome
      of an NK-like cell line.
    action: KEEP_AS_NON_CORE
    reason: Correct but very general; KDSR is an integral membrane protein, and the
      more specific ER membrane / cytoplasmic side of ER membrane annotations are the
      informative localizations. Retained as a non-core, low-specificity localization.
    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-428123
  qualifier: located_in
  review:
    summary: Reactome traceable annotation of ER membrane localization.
    action: ACCEPT
    reason: Consistent with the experimentally established ER membrane localization.
    supported_by:
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:15364918
  qualifier: located_in
  review:
    summary: MGI-assigned IDA to endoplasmic reticulum. The cited reference (PMID:15364918)
      is a study of IP3R1 lateral diffusion in neurons and does not concern KDSR, so
      this appears to be a mis-attributed citation; however ER localization of KDSR
      is itself well established.
    action: ACCEPT
    reason: The endoplasmic reticulum localization is correct and independently supported
      by direct experimental evidence (PMID:15328338, PMID:19141869). The original
      reference appears to be a wrong-PMID citation (flagged in reference_review),
      but the annotation content is accurate and is retained on the basis of the other
      evidence.
    supported_by:
    - reference_id: PMID:15328338
      supporting_text: hFVT-1 is localized at the endoplasmic reticulum
- term:
    id: GO:0006666
    label: 3-keto-sphinganine metabolic process
  evidence_type: IDA
  original_reference_id: PMID:15364918
  qualifier: acts_upstream_of_or_within
  review:
    summary: MGI-assigned IDA linking KDSR to 3-keto-sphinganine metabolism. The cited
      reference is an IP3R1 diffusion study unrelated to KDSR, so the citation appears
      mis-attributed, but the underlying biology (KDSR metabolizes 3-keto-sphinganine)
      is correct.
    action: ACCEPT
    reason: KDSR reduces 3-keto-sphinganine (its substrate); the BP is correct and
      well supported by direct enzymology elsewhere. The original PMID is flagged as
      a likely wrong-identifier citation but does not affect the correctness of the
      annotation.
    supported_by:
    - reference_id: PMID:19141869
      supporting_text: FVT1 is the principal 3-ketosphinganine reductase in mammalian
        cells
- term:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  evidence_type: IDA
  original_reference_id: PMID:15364918
  qualifier: enables
  review:
    summary: MGI-assigned IDA to the reductase molecular function. The cited reference
      is an IP3R1 lateral-diffusion study unrelated to KDSR, so the citation is likely
      mis-attributed; nonetheless the reductase activity is the well-established core
      function of KDSR.
    action: ACCEPT
    reason: The 3-dehydrosphinganine reductase activity is the defining, extensively
      validated molecular function of KDSR. The original PMID appears to be a wrong-identifier
      citation (flagged in reference_review), but the annotation itself is correct
      and supported by direct enzymology (PMID:15328338, PMID:19141869).
    supported_by:
    - reference_id: PMID:15328338
      supporting_text: exhibited NADPH-dependent KDS reductase activity
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: PMID:8417785
  qualifier: located_in
  review:
    summary: Legacy annotation (ProtInc) derived from the 1993 FVT-1 cloning paper,
      which described FVT-1 as a "putatively secreted protein" based on sequence prediction
      before its function was known.
    action: REMOVE
    reason: This localization is contradicted by all subsequent experimental evidence
      KDSR is a multi-pass integral endoplasmic reticulum membrane protein with its
      catalytic domain facing the cytosol, not a secreted/extracellular protein. The
      extracellular assignment reflects an outdated sequence-based prediction of secretion
      that has been superseded, and is a demonstrably wrong legacy inference.
    supported_by:
    - reference_id: PMID:8417785
      supporting_text: codes for a putatively secreted protein of 36 Kd
    - reference_id: file:human/KDSR/KDSR-uniprot.txt
      supporting_text: Multi-pass
core_functions:
- description: NADPH-dependent 3-ketodihydrosphingosine (3-dehydrosphinganine) reductase
    that catalyses the second step of de novo sphingolipid biosynthesis, reducing
    3-ketodihydrosphingosine to dihydrosphingosine (sphinganine) at the cytosolic
    face of the ER membrane.
  molecular_function:
    id: GO:0047560
    label: 3-dehydrosphinganine reductase activity
  supported_by:
  - reference_id: PMID:15328338
    supporting_text: exhibited NADPH-dependent KDS reductase activity
  - reference_id: file:human/KDSR/KDSR-uniprot.txt
    supporting_text: 'Reaction=sphinganine + NADP(+) = 3-oxosphinganine + NADPH + H(+)'
  directly_involved_in:
  - id: GO:0030148
    label: sphingolipid biosynthetic process
  locations:
  - id: GO:0005789
    label: 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: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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1317856
  title: Subcellular localization and membrane topology of serine palmitoyltransferase,
    3-dehydrosphinganine reductase, and sphinganine N-acyltransferase in mouse liver.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary biochemical study localizing 3-dehydrosphinganine reductase
      (KDSR) activity to the cytosolic face of mouse liver ER; supports the reductase
      function and ER cytosolic-side topology.
- id: PMID:15328338
  title: FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site
    that faces the cytosolic side of the endoplasmic reticulum membrane.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key paper identifying human FVT-1/KDSR as the mammalian KDS reductase;
      purified enzyme has NADPH-dependent activity, localizes to ER, catalytic domain
      faces cytosol.
- id: PMID:15364918
  title: Lateral diffusion of inositol 1,4,5-trisphosphate receptor type 1 is regulated
    by actin filaments and 4.1N in neuronal dendrites.
  findings: []
  reference_review:
    relevance: NONE
    correctness: WRONG_IDENTIFIER
    review_notes: This PMID is a study of IP3R1 lateral diffusion in neurons and does
      not concern KDSR, yet it is cited as the MGI IDA source for three KDSR annotations
      (ER localization, 3-keto-sphinganine metabolic process, and reductase activity).
      Appears to be a wrong-PMID/mis-attributed citation. The affected annotations
      are nonetheless biologically correct and are independently supported by PMID:15328338
      and PMID:19141869.
- id: PMID:16120614
  title: Serinc, an activity-regulated protein family, incorporates serine into membrane
    lipid synthesis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Study of the Serinc family that forms complexes with serine/sphingolipid
      biosynthetic enzymes; abstract only, does not directly assay KDSR in ceramide
      synthesis. Used to support a pathway-level ceramide biosynthesis annotation.
- id: PMID:19141869
  title: 'Tsc10p and FVT1: topologically distinct short-chain reductases required
    for long-chain base synthesis in yeast and mammals.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes FVT1/KDSR as the principal mammalian 3-ketosphinganine
      reductase required for long-chain base (sphingoid) synthesis; provides silencing,
      mutagenesis, localization and topology data.
- id: PMID:19416851
  title: Identification of small subunits of mammalian serine palmitoyltransferase
    that confer distinct acyl-CoA substrate specificities.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Abstract focuses on SPT small subunits; cited as the IDA source for
      KDSR being active on the cytoplasmic side of the ER membrane. Only the abstract
      is available; the cytosolic-face topology of KDSR is independently well established.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput membrane proteomics; supports only the general "membrane"
      localization of KDSR.
- id: PMID:28575652
  title: Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Disease-gene identification; biallelic KDSR mutations cause progressive
      symmetric erythrokeratoderma, with yeast complementation showing loss of KDSR
      function.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale yeast two-hybrid interactome; source of four uninformative
      protein-binding interactions for KDSR (KIF1B, HSPB1, TTR, WFS1). No established
      functional relevance to KDSR's enzymatic role.
- 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: Review of glucosyl-/galactosylceramide biology; does not mention
      or assay KDSR. Cited for a glycosphingolipid biosynthesis annotation that is
      several enzymatic steps downstream of KDSR - a pathway-level over-annotation.
- id: PMID:36170811
  title: De novo sphingolipid biosynthesis necessitates detoxification in cancer cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; shows KDSR reduces 3KDS to sphinganine and that
      KDSR loss causes toxic 3KDS accumulation, ER dysfunction and proteotoxic stress,
      highlighting KDSR as a cancer therapy target.
- id: PMID:8417785
  title: FVT-1, a novel human transcription unit affected by variant translocation
    t(2;18)(p11;q21) of follicular lymphoma.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original FVT-1 cloning paper describing the follicular-lymphoma translocation
      and predicting a "putatively secreted protein"; the secretion prediction (basis
      of the extracellular-region annotation) was later superseded by ER membrane topology.
- id: Reactome:R-HSA-1660661
  title: Sphingolipid de novo biosynthesis
  findings: []
- id: Reactome:R-HSA-428123
  title: KDSR reduces 3-ketosphingoid
  findings: []
- id: file:human/KDSR/KDSR-uniprot.txt
  title: UniProtKB entry Q06136 (KDSR_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: UniProt record for human KDSR; source of catalytic activity (EC 1.1.1.102,
      RHEA:22640), ER membrane multi-pass topology, NADPH-binding sites, and disease
      associations.