id: O15270
gene_symbol: SPTLC2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SPTLC2 (serine palmitoyltransferase long chain base subunit 2; EC 2.3.1.50) is the
  pyridoxal-5'-phosphate (PLP)-binding catalytic subunit of serine palmitoyltransferase
  (SPT). Together with SPTLC1 it forms the catalytic heterodimeric core of the SPT complex,
  which additionally contains a small activating subunit (SPTSSA or SPTSSB, which set acyl-CoA
  substrate preference) and negative regulators (ORMDL1/2/3). SPT catalyzes the first,
  committed, and rate-limiting step of de novo sphingolipid biosynthesis: the PLP-dependent
  condensation of L-serine with palmitoyl-CoA (and other long-chain acyl-CoAs) to form
  3-ketodihydrosphingosine (3-oxosphinganine), the precursor of all sphingoid bases and
  downstream sphingolipids (ceramides, sphingomyelin, glycosphingolipids). The catalytic
  lysine (Lys379) forms a Schiff base with the PLP cofactor. SPTLC2 is a single-pass
  endoplasmic reticulum membrane protein and acts at the cytoplasmic face of the ER. Dominant
  missense variants in SPTLC2 shift enzyme substrate specificity toward L-alanine/L-glycine,
  producing neurotoxic 1-deoxysphingolipids, and cause hereditary sensory and autonomic
  neuropathy type 1C (HSAN1C).
existing_annotations:
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      SPTLC2 is a subunit of the serine palmitoyltransferase (SPT) complex, forming the
      catalytic core together with SPTLC1. Phylogenetically inferred and strongly supported by
      experimental and structural evidence.
    action: ACCEPT
    reason: >-
      Correct and core. The catalytic heterodimer of SPTLC1 and SPTLC2 is the enzymatic core
      of the ER-localized SPT complex, established biochemically and by multiple cryo-EM
      structures.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each interacts with both hLCB1 and
    - reference_id: PMID:33558762
      supporting_text: form a dimer of heterodimers as the catalytic core
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      SPT catalyzes the first, committed step of de novo sphingoid base (long-chain base)
      biosynthesis, the pathway leading to sphingosine and other sphingoid bases.
    action: ACCEPT
    reason: >-
      Correct biological process. SPTLC2 initiates the pathway that produces the sphingoid
      base backbone; sphingosine biosynthesis is a direct downstream consequence of SPT
      activity.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: catalyzes the first committed step in
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Serine C-palmitoyltransferase activity is the defining molecular function of SPTLC2:
      PLP-dependent condensation of L-serine with palmitoyl-CoA to form 3-ketodihydrosphingosine.
      This is the exact current GOA MF term for this gene.
    action: ACCEPT
    reason: >-
      Core molecular function, phylogenetically inferred and supported by direct enzymatic
      assays. This is the catalytic activity of the SPTLC1/SPTLC2 core. (Strictly, catalysis
      requires the SPTLC1/SPTLC2 heterodimer, so contributes_to is the more precise qualifier;
      the function itself is unambiguously correct.)
    supported_by:
    - reference_id: PMID:9363775
      supporting_text: It catalyzes the pyridoxal-5'-phosphate-dependent condensation of
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      SPT initiates de novo sphingolipid synthesis, the pathway that generates the sphingoid
      base and, via subsequent enzymes, ceramide.
    action: ACCEPT
    reason: >-
      Correct. Ceramide biosynthesis begins with the SPT-catalyzed step; SPTLC2 is required
      for de novo ceramide production. Phylogenetically inferred and experimentally supported.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: catalyzes the first committed step in
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation of the core catalytic activity via combined automated methods
      (ARBA/RHEA/EC 2.3.1.50). Consistent with the experimentally verified function.
    action: ACCEPT
    reason: >-
      Correct core molecular function, mapped from EC 2.3.1.50 / RHEA:14761, which matches the
      experimentally established reaction.
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: condensing L-serine and activated acyl-CoA
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      SPTLC2 is a single-pass endoplasmic reticulum membrane protein, consistent with SPT
      acting at the ER.
    action: ACCEPT
    reason: >-
      Correct subcellular location, mapped from the UniProt subcellular location and supported
      by By-similarity and structural evidence.
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Generic transferase activity mapped from InterPro. This is a high-level parent of the
      specific serine C-palmitoyltransferase activity that is already annotated.
    action: MODIFY
    reason: >-
      Too general to be informative. The specific, correct molecular function
      (GO:0004758 serine C-palmitoyltransferase activity) is well established for this gene
      and should be used in its place.
    proposed_replacement_terms:
    - id: GO:0004758
      label: serine C-palmitoyltransferase activity
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: condensing L-serine and activated acyl-CoA
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: >-
      Electronic (ARBA) annotation that SPTLC2 is part of the serine palmitoyltransferase
      complex. Consistent with experimental and structural evidence.
    action: ACCEPT
    reason: >-
      Correct and core; duplicates the well-supported IBA/IDA complex annotations.
    supported_by:
    - reference_id: PMID:33558761
      supporting_text: which consists of catalytic components (SPTLC1
- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      SPTLC2 binds the PLP cofactor required for catalysis; the catalytic lysine (Lys379)
      forms a Schiff base with PLP. Mapped from InterPro and consistent with the cofactor
      requirement and structural/mutagenesis data.
    action: ACCEPT
    reason: >-
      Correct secondary molecular function. SPT is a PLP-dependent class-II aminotransferase;
      Lys379 is the PLP-binding N6-(pyridoxal phosphate)lysine, and K379A abolishes activity.
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: N6-(pyridoxal phosphate)lysine
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: Name=pyridoxal 5'-phosphate;
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Electronic (ARBA) annotation to sphingoid base biosynthesis, consistent with the SPT
      catalytic role at the head of the pathway.
    action: ACCEPT
    reason: >-
      Correct; duplicates the IBA/IDA sphingosine biosynthetic process annotations.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: catalyzes the first committed step in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19416851
  qualifier: enables
  review:
    summary: >-
      IntAct-derived binary interaction with SPTLC1 (O15269). The biologically meaningful
      capture of this interaction is membership in the serine palmitoyltransferase complex
      (GO:0017059), which is separately annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' is uninformative and does not convey the specific function. The
      SPTLC1-SPTLC2 interaction forms the SPT catalytic core and is already captured by the
      more informative part_of serine palmitoyltransferase complex annotation. Retained (not
      removed) per policy on experimental IPI annotations.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each interacts with both hLCB1 and
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33558762
  qualifier: enables
  review:
    summary: >-
      IntAct-derived binary interaction with SPTLC1 (O15269), from the SPT-ORMDL3 cryo-EM study.
      The informative capture is complex membership (GO:0017059).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare 'protein binding'; the specific, informative annotation is part_of
      the serine palmitoyltransferase complex. Retained per policy.
    supported_by:
    - reference_id: PMID:33558762
      supporting_text: form a dimer of heterodimers as the catalytic core
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: >-
      IntAct-derived binary interaction with SPTLC1 (O15269) from the OpenCell endogenous
      tagging / IP-MS interactome dataset.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare 'protein binding' from a high-throughput interactome; the specific
      SPTLC1 interaction is already better captured by part_of serine palmitoyltransferase
      complex. Retained per policy.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: systematically map the localization and interactions of human proteins
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Automatic transfer (Ensembl Compara) from mouse ortholog of the core biological process:
      de novo sphingolipid biosynthesis.
    action: ACCEPT
    reason: >-
      Correct core biological process; SPT catalyzes the first, committed, rate-limiting step
      of de novo sphingolipid biosynthesis. Duplicates the IDA/TAS annotations.
    supported_by:
    - reference_id: PMID:33558762
      supporting_text: rate-limiting step in the de novo biosynthesis of all sphingolipids
- term:
    id: GO:0060612
    label: adipose tissue development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Transferred from mouse ortholog (P97363); SPT/de novo sphingolipid synthesis is reported
      to be important for adipogenesis. This is a peripheral, tissue-level developmental role,
      not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      A By-similarity/orthology-transferred developmental process. Plausible but downstream of
      the enzyme's catalytic role and not a core SPTLC2 function; keep as non-core.
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: Crucial
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway mapping to the broad sphingolipid metabolic process. This is the parent of
      the more specific, and already-annotated, sphingolipid biosynthetic process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not wrong, but less informative than the biosynthetic-process child term
      (GO:0030148), which is separately and better annotated. Keep as non-core parent.
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: Lipid metabolism; sphingolipid metabolism.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:33558761
  qualifier: located_in
  review:
    summary: >-
      ER membrane localization asserted from the structural study of the human SPT complex.
    action: ACCEPT
    reason: >-
      Correct subcellular location; the SPT holocomplex is an ER-membrane complex. Duplicates
      other ER membrane annotations.
    supported_by:
    - reference_id: PMID:33558761
      supporting_text: and rate-limiting step of sphingolipid synthesis is catalyzed by the serine
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IPI
  original_reference_id: PMID:19416851
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal-curated membership of SPTLC2 in the serine palmitoyltransferase complex,
      based on the biochemical characterization of the SPT complex.
    action: ACCEPT
    reason: >-
      Correct and core complex membership. SPTLC2 forms the catalytic core with SPTLC1.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each interacts with both hLCB1 and
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IPI
  original_reference_id: PMID:33558761
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal-curated membership of SPTLC2 in the SPT complex, based on the cryo-EM
      structures of the human SPT holocomplex.
    action: ACCEPT
    reason: >-
      Correct and core complex membership, established by the SPT holocomplex structures.
    supported_by:
    - reference_id: PMID:33558761
      supporting_text: which consists of catalytic components (SPTLC1
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: involved_in
  review:
    summary: >-
      Direct assay: SPT isozymes containing SPTLC2 produce long-chain (sphingoid) bases;
      SPTLC2 is required for sphingoid base biosynthesis.
    action: ACCEPT
    reason: >-
      Correct; SPTLC2-containing SPT generates the sphingoid base backbone. Supported by
      long-chain base profiling of reconstituted isozymes.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: differences in acyl-CoA preference
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:33558761
  qualifier: involved_in
  review:
    summary: >-
      Structural/biochemical study of the human SPT holocomplex confirming its role in the
      de novo sphingolipid (sphingoid base) synthesis pathway.
    action: ACCEPT
    reason: >-
      Correct; SPTLC2 within the SPT holocomplex catalyzes the committed step generating
      sphingoid bases.
    supported_by:
    - reference_id: PMID:33558761
      supporting_text: and rate-limiting step of sphingolipid synthesis is catalyzed by the serine
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ER membrane localization inferred by sequence similarity from mouse ortholog (P97363).
    action: ACCEPT
    reason: >-
      Correct subcellular location; consistent with the ER-membrane SPT complex. Duplicates
      other ER membrane annotations.
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: contributes_to
  review:
    summary: >-
      Direct enzymatic characterization of reconstituted SPT isozymes containing SPTLC2,
      demonstrating serine C-palmitoyltransferase activity. contributes_to correctly reflects
      that catalysis is a property of the SPTLC1/SPTLC2 heterodimer.
    action: ACCEPT
    reason: >-
      Core molecular function with direct experimental support and the strictly correct
      contributes_to qualifier for a subunit of a catalytic complex.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: catalyzes the first committed step in
- term:
    id: GO:0006686
    label: sphingomyelin biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:30242129
  qualifier: involved_in
  review:
    summary: >-
      Sphingomyelin biosynthesis is a downstream branch of the sphingolipid pathway (ceramide
      -> sphingomyelin, at the Golgi, via SMS1). SPT provides the initial sphingoid base/ceramide
      precursor at the ER but does not itself synthesize sphingomyelin.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream pathway involvement rather than a direct/core SPTLC2 molecular role. The cited
      paper concerns the SMS1-GCS complex; SM synthesis depends on the de novo ceramide
      supplied by SPT (condensation of serine and palmitoyl-CoA in the ER). Keep as non-core.
    supported_by:
    - reference_id: PMID:30242129
      supporting_text: cytosolic leaflet of the ER bilayer
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: involved_in
  review:
    summary: >-
      SPTLC2-containing SPT initiates de novo synthesis of the sphingoid base that is
      converted to ceramide by downstream enzymes.
    action: ACCEPT
    reason: >-
      Correct; ceramide biosynthesis is initiated by the SPT step catalyzed by SPTLC1/SPTLC2.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: catalyzes the first committed step in
- term:
    id: GO:0006688
    label: glycosphingolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: involved_in
  review:
    summary: >-
      Glycosphingolipids are downstream products of the sphingolipid pathway; the sphingoid
      bases generated by SPT feed into glycosphingolipid synthesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream branch of the pathway rather than a direct SPTLC2 function. SPT supplies the
      long-chain-base precursor; glycosphingolipid-specific steps are catalyzed by other
      enzymes. Keep as non-core.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: differences in acyl-CoA preference
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: part_of
  review:
    summary: >-
      Direct identification of SPTLC2 in the SPT complex.
    action: ACCEPT
    reason: >-
      Correct and core complex membership; duplicates other well-supported complex annotations.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each interacts with both hLCB1 and
- 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: >-
      SPT acts on the cytosolic face of the ER membrane, where de novo sphingolipid synthesis
      is initiated by condensation of L-serine and palmitoyl-CoA.
    action: ACCEPT
    reason: >-
      Correct and appropriately specific location of activity; the initial condensation step
      occurs on the cytoplasmic/cytosolic leaflet of the ER.
    supported_by:
    - reference_id: PMID:30242129
      supporting_text: cytosolic leaflet of the ER bilayer
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25332431
  qualifier: contributes_to
  review:
    summary: >-
      Study of de novo sphingolipid synthesis via SPT (mouse liver); serine
      C-palmitoyltransferase activity is the SPT function, with SPTLC2 contributing to the
      catalytic heterodimer.
    action: ACCEPT
    reason: >-
      Correct core molecular function with the appropriate contributes_to qualifier.
    supported_by:
    - reference_id: PMID:25332431
      supporting_text: overexpression of serine palmitoyltransferase to elevate de novo sphingolipid
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-428127
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion placing the SPTLC complexes / acyl-CoA transfer onto serine
      at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct subcellular location; consistent with all other ER-membrane evidence.
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:26573920
  qualifier: enables
  review:
    summary: >-
      Study of the HSAN1C variant p.(Arg183Trp) demonstrating SPT catalytic activity of SPTLC2
      and its alteration by the disease variant (increased 1-deoxysphingolipid formation).
    action: ACCEPT
    reason: >-
      Correct core molecular function, supported by in vitro activity measurements of WT vs
      variant SPTLC2.
    supported_by:
    - reference_id: PMID:26573920
      supporting_text: produced elevated amounts of 1-deoxysphingolipids in vitro
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:26573920
  qualifier: involved_in
  review:
    summary: >-
      SPTLC2 is directly implicated in de novo sphingolipid biosynthesis; the disease variant
      perturbs the pathway output (accumulation of 1-deoxysphingolipids).
    action: ACCEPT
    reason: >-
      Correct core biological process, supported by direct metabolite measurements.
    supported_by:
    - reference_id: PMID:26573920
      supporting_text: produced elevated amounts of 1-deoxysphingolipids in vitro
- term:
    id: GO:0060612
    label: adipose tissue development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Inferred by sequence similarity from mouse ortholog (P97363); a peripheral tissue-level
      developmental role attributed to SPT/de novo sphingolipid synthesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      By-similarity developmental process; downstream of and secondary to the catalytic
      function. Keep as non-core.
    supported_by:
    - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
      supporting_text: Crucial
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25691431
  qualifier: contributes_to
  review:
    summary: >-
      SPT (with SPTLC2 in the catalytic core) catalyzes the initiating step of sphingolipid
      biosynthesis; this study examines ORMDL/SPT stoichiometry and its effect on that activity.
    action: ACCEPT
    reason: >-
      Correct core molecular function with the appropriate contributes_to qualifier for a
      subunit of the catalytic complex.
    supported_by:
    - reference_id: PMID:25691431
      supporting_text: negative homeostatic regulators of the initiating
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:25691431
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      SPT activity (initiating step) acts upstream of ceramide biosynthesis; modulating
      ORMDL/SPT stoichiometry affects downstream sphingolipid (ceramide) production.
    action: ACCEPT
    reason: >-
      Correct; SPTLC2 acts upstream of ceramide biosynthesis by generating the sphingoid base
      precursor. acts_upstream_of_or_within is an appropriate causal qualifier here.
    supported_by:
    - reference_id: PMID:25691431
      supporting_text: negative homeostatic regulators of the initiating
- term:
    id: GO:1904504
    label: positive regulation of lipophagy
  evidence_type: IDA
  original_reference_id: PMID:25332431
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      In mouse liver, overexpression of SPT to elevate de novo sphingolipid synthesis induced
      autophagy. This links elevated SPT/sphingolipid flux to autophagy/lipophagy, but is an
      indirect, downstream physiological consequence rather than a direct SPTLC2 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Indirect regulatory effect via elevated sphingolipid/ceramide levels, from a mouse-liver
      overexpression study; not a direct molecular role of SPTLC2. Keep as non-core.
    supported_by:
    - reference_id: PMID:25332431
      supporting_text: induces autophagy in the liver
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:25332431
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      SPT activity (with SPTLC2) drives de novo sphingolipid biosynthesis; overexpression
      elevates de novo sphingolipid production in liver.
    action: ACCEPT
    reason: >-
      Correct core biological process. acts_upstream_of_or_within is a valid causal qualifier
      for the enzyme initiating the pathway.
    supported_by:
    - reference_id: PMID:25332431
      supporting_text: overexpression of serine palmitoyltransferase to elevate de novo sphingolipid
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:20920666
  qualifier: enables
  review:
    summary: >-
      Characterization of HSAN1C variants (V359M, G382V, I504F) demonstrating that SPTLC2
      supplies SPT catalytic activity, with disease variants causing partial-to-complete loss
      of normal activity and accumulation of 1-deoxysphinganine.
    action: ACCEPT
    reason: >-
      Correct core molecular function, supported by in vitro/in vivo activity measurements of
      WT vs disease-variant SPTLC2.
    supported_by:
    - reference_id: PMID:20920666
      supporting_text: atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: enables
  review:
    summary: >-
      Direct enzymatic assay of reconstituted SPT isozymes containing SPTLC2 establishing
      serine C-palmitoyltransferase activity.
    action: ACCEPT
    reason: >-
      Core molecular function with direct experimental support.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: catalyzes the first committed step in
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:19416851
  qualifier: involved_in
  review:
    summary: >-
      Traceable assertion that SPTLC2-containing SPT functions in de novo sphingolipid
      biosynthesis.
    action: ACCEPT
    reason: >-
      Correct core biological process; duplicates the IDA/IEA sphingolipid biosynthetic
      process annotations.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: catalyzes the first committed step in
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:9363775
  qualifier: enables
  review:
    summary: >-
      Original cloning/characterization paper establishing that the human/murine LCB2 genes
      encode serine palmitoyltransferase, the PLP-dependent enzyme condensing L-serine and
      palmitoyl-CoA to 3-oxosphinganine.
    action: ACCEPT
    reason: >-
      Correct core molecular function; foundational traceable assertion for SPTLC2 catalytic
      activity.
    supported_by:
    - reference_id: PMID:9363775
      supporting_text: It catalyzes the pyridoxal-5'-phosphate-dependent condensation of
    - reference_id: PMID:9363775
      supporting_text: the human and murine LCB2 genes
core_functions:
- description: >-
    Serine C-palmitoyltransferase: the PLP-dependent catalytic subunit (with SPTLC1) of the
    serine palmitoyltransferase complex that condenses L-serine with palmitoyl-CoA to form
    3-ketodihydrosphingosine, the first committed and rate-limiting step of de novo
    sphingolipid biosynthesis, at the ER membrane.
  molecular_function:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  directly_involved_in:
  - id: GO:0030148
    label: sphingolipid biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  supported_by:
  - reference_id: PMID:19416851
    supporting_text: catalyzes the first committed step in
  - reference_id: PMID:9363775
    supporting_text: It catalyzes the pyridoxal-5'-phosphate-dependent condensation of
- description: >-
    Pyridoxal 5'-phosphate binding: SPTLC2 binds the PLP cofactor essential for catalysis via
    the catalytic Lys379 that forms a Schiff base with PLP.
  molecular_function:
    id: GO:0030170
    label: pyridoxal phosphate binding
  supported_by:
  - reference_id: file:human/SPTLC2/SPTLC2-uniprot.txt
    supporting_text: N6-(pyridoxal phosphate)lysine
proposed_new_terms: []
suggested_questions:
- question: >-
    What determines the relative contribution of SPTLC2 vs SPTLC3 to the human sphingolipid
    long-chain-base pool in different tissues?
- question: >-
    How do individual HSAN1C variants quantitatively shift the L-serine vs L-alanine/L-glycine
    selectivity of the SPTLC1/SPTLC2 active site?
suggested_experiments:
- description: >-
    Reconstitute defined SPTLC1-SPTLC2-SPTSSA/B(+/-ORMDL3) complexes and measure serine vs
    alanine/glycine incorporation and acyl-CoA chain-length preference for WT and HSAN1C
    variants.
- description: >-
    Structure-guided mutagenesis of the substrate tunnel to map residues controlling
    1-deoxysphingolipid production.
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  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:19416851
  title: Identification of small subunits of mammalian serine palmitoyltransferase
    that confer distinct acyl-CoA substrate specificities.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes the SPTLC1/SPTLC2 catalytic core, SPT complex composition,
      and acyl-CoA substrate specificity determined by small subunits. Primary support for
      catalytic activity, complex membership, and sphingoid base biosynthesis.
- id: PMID:20920666
  title: Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary
    sensory and autonomic neuropathy type I.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. HSAN1C-causing SPTLC2 variants; disease variants cause loss of normal
      SPT activity and accumulation of neurotoxic 1-deoxysphinganine.
- id: PMID:25332431
  title: Autophagy regulates sphingolipid levels in the liver.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Mouse-liver study; SPT overexpression elevates de novo sphingolipid
      synthesis and induces autophagy. Basis for the (non-core) lipophagy and adipose/sphingolipid
      annotations; effect is indirect/downstream.
- id: PMID:25691431
  title: ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3
    expression on sphingolipid biosynthesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. ORMDLs are negative homeostatic regulators of SPT, the initiating enzyme
      of sphingolipid biosynthesis. Supports the SPT catalytic and upstream-of-ceramide roles.
- id: PMID:26573920
  title: The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory
    Neuropathy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. HSAN1C variant p.(Arg183Trp); variant protein produced elevated
      1-deoxysphingolipids in vitro, confirming altered SPT activity of SPTLC2.
- id: PMID:30242129
  title: Complex formation of sphingomyelin synthase 1 with glucosylceramide synthase
    increases sphingomyelin and decreases glucosylceramide levels.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Concerns the Golgi SMS1-GCS complex (downstream sphingomyelin/glucosylceramide
      branching), not SPTLC2 directly; cited for de novo ceramide originating at the ER by
      condensation of serine and palmitoyl-CoA. Supports keeping the sphingomyelin-biosynthesis
      annotation as non-core.
- id: PMID:33558761
  title: Structural insights into the regulation of human serine palmitoyltransferase
    complexes.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Cryo-EM structures of the human SPT holocomplex (SPTLC1, SPTLC2, ssSPTa,
      ORMDL3); establishes complex composition, ER localization, and the rate-limiting nature
      of the SPT step.
- id: PMID:33558762
  title: Structural insights into the assembly and substrate selectivity of human
    SPT-ORMDL3 complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Cryo-EM of the human SPT-ORMDL3 complex; SPTLC1 and SPTLC2 form a dimer
      of heterodimers as the catalytic core; substrate binding (PLP-L-serine, palmitoyl-CoA
      analogue) and mutagenesis (incl. K379) support catalytic and PLP-binding functions.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. High-throughput endogenous-tagging interactome/localization resource;
      source of the IntAct SPTLC1 interaction call. Uninformative as a bare 'protein binding'
      annotation on its own.
- id: PMID:9363775
  title: Human and murine serine-palmitoyl-CoA transferase--cloning, expression and
    characterization of the key enzyme in sphingolipid synthesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Original cloning/characterization establishing that human/murine LCB2
      (SPTLC2) encodes serine palmitoyltransferase catalyzing PLP-dependent condensation of
      L-serine and palmitoyl-CoA to 3-oxosphinganine.
- id: Reactome:R-HSA-428127
  title: SPTLC complexes transfer acyl-CoA onto serine
  findings: []
- id: file:human/SPTLC2/SPTLC2-uniprot.txt
  title: UniProt entry O15270 (SPTC2_HUMAN), Serine palmitoyltransferase 2
  findings: []