Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004758 serine C-palmitoyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred contribution to serine C-palmitoyltransferase activity as a subunit of the SPT complex. SPTSSA is a non-catalytic accessory subunit that is required for full activity of the catalytic SPTLC1-SPTLC2/3 core, so the contributes_to qualifier is exactly right. Reason: SPTSSA is an accessory subunit that stimulates and shapes SPT catalysis but does not independently catalyze the reaction; the IBA contributes_to annotation captures this correctly and is supported by biochemistry and structural biology. Supporting Evidence: PMID:19416851 each substantially enhance the activity of mammalian SPT PMID:33558762 SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity
GO:0017059 serine palmitoyltransferase complex	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred membership in the serine palmitoyltransferase complex. Cryo-EM structures directly place SPTSSA in the human SPT holocomplex with SPTLC1, SPTLC2 (or SPTLC3) and ORMDL3. Reason: SPTSSA is a bona fide subunit of the SPT complex, confirmed by multiple cryo-EM structures and ComplexPortal (CPX-6663, CPX-6665). The GO definition of GO:0017059 explicitly lists SPTSSA/SPTSSB as regulatory activator components. Supporting Evidence: PMID:33558762 SPTLC1 and SPTLC2 form a dimer of heterodimers as the catalytic core PMID:33558761 ssSPTa engages SPTLC2 and shapes the tunnel
GO:0046513 ceramide biosynthetic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically inferred involvement in ceramide biosynthesis. SPT catalyzes the first committed step upstream of ceramide, so SPTSSA (as an SPT subunit) contributes upstream to ceramide production, but ceramide synthesis itself requires several additional dedicated enzymes. Reason: SPTSSA acts only at the first step of sphingolipid biosynthesis; ceramide is a downstream product requiring 3-ketodihydrosphingosine reductase and ceramide synthases. The involvement is real but indirect, so this is best kept as a non-core downstream process, with sphingolipid biosynthetic process (GO:0030148) as the core BP. Supporting Evidence: PMID:37308477 catalyzes the first and rate-limiting step of de novo sphingolipid biosynthesis by condensation of serine and palmitoyl-CoA to generate 3-keto-dihydrosphingosine
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation to ER membrane from the UniProt subcellular-location mapping. SPTSSA is a multi-pass ER membrane protein, experimentally confirmed. Reason: Consistent with the experimental subcellular location (PubMed:23510452) and with the SPT complex residing in the ER membrane. The IEA mapping is correct. Supporting Evidence: file:human/SPTSSA/SPTSSA-uniprot.txt SUBCELLULAR LOCATION Endoplasmic reticulum membrane
GO:0005515 protein binding	IPI PMID:19416851 Identification of small subunits of mammalian serine palmito...	MARK AS OVER ANNOTATED	Summary: IPI protein-binding annotation supported by interaction with SPTLC1 (UniProtKB:O15269), the catalytic-core subunit of SPT. This is a biologically meaningful interaction, but the bare protein binding term is uninformative. Reason: The SPTSSA-SPTLC1 interaction is real and important, but GO:0005515 protein binding conveys no functional information. The meaningful content (SPT complex membership) is already captured by GO:0017059. Per curation policy the annotation is retained rather than removed, but flagged as an uninformative over-annotation. Supporting Evidence: PMID:19416851 each interacts with both hLCB1 and hLCB2 as assessed by positive split ubiquitin 2-hybrid analysis
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IPI protein-binding annotations from the HuRI human binary interactome map (CYSRT1, GET1, HERPUD2, RHBDL1). These are high-throughput yeast two-hybrid hits of uncertain physiological significance for this ER membrane protein. Reason: Bare protein binding is uninformative and these are large-scale binary-screen hits with no established functional consequence for SPTSSA. Retained per policy but flagged; not used for core function. Supporting Evidence: PMID:32296183 a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
GO:0005515 protein binding	IPI PMID:33558762 Structural insights into the assembly and substrate selectiv...	MARK AS OVER ANNOTATED	Summary: IPI protein-binding annotation supported by the cryo-EM structure showing SPTSSA (SPTssa) as a subunit engaging the SPTLC1/SPTLC2 catalytic core within the SPT-ORMDL3 complex. Reason: The physical association is genuine and structurally defined, but the bare protein binding term is uninformative; the functional content is captured by SPT complex membership (GO:0017059) and the contributes_to catalytic annotation. Retained per policy but flagged. Supporting Evidence: PMID:33558762 SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity
GO:0006665 sphingolipid metabolic process	IEA GO_REF:0000041	ACCEPT	Summary: Electronic annotation to sphingolipid metabolic process from the UniPathway mapping. SPTSSA participates in de novo sphingolipid metabolism as an SPT subunit. Reason: Correct but general parent process of the more specific sphingolipid biosynthetic process; consistent with SPT function at the first step of the pathway. Supporting Evidence: file:human/SPTSSA/SPTSSA-uniprot.txt PATHWAY Lipid metabolism; sphingolipid metabolism
GO:0004758 serine C-palmitoyltransferase activity	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	ACCEPT	Summary: Direct-assay annotation of serine C-palmitoyltransferase activity from the original functional characterization, where reconstituted SPT isozymes containing ssSPTa were assayed for enzyme activity and acyl-CoA preference. The activity is a property of the assembled complex; SPTSSA is the accessory subunit required for full activity. Reason: The reconstituted SPT isozyme assay (with ssSPTa) demonstrates the complex-level palmitoyltransferase activity. Since SPTSSA is non-catalytic, the contributes_to form is more precise, but this enables IDA (from a curator who read the full text) is retained as reflecting the assayed complex activity. Supporting Evidence: PMID:19416851 each substantially enhance the activity of mammalian SPT
GO:0005789 endoplasmic reticulum membrane	NAS PMID:33558761 Structural insights into the regulation of human serine palm...	ACCEPT	Summary: Non-traceable-author-statement annotation (ComplexPortal) placing SPTSSA in the ER membrane, consistent with the SPT holocomplex residing in the ER. Reason: Consistent with the experimentally established ER membrane localization and with the structural work on the ER-resident SPT complex. Supporting Evidence: PMID:33558761 the first and rate-limiting step of sphingolipid synthesis is catalyzed by the serine palmitoyltransferase holocomplex
GO:0017059 serine palmitoyltransferase complex	IPI PMID:19416851 Identification of small subunits of mammalian serine palmito...	ACCEPT	Summary: SPT complex membership demonstrated by the original identification of ssSPTa as an SPT subunit that interacts with hLCB1 (SPTLC1) and hLCB2 (SPTLC2) and forms part of the SPT holoenzyme. Reason: Well-supported experimental annotation of complex membership; SPTSSA is a core structural component of SPT. Supporting Evidence: PMID:19416851 each interacts with both hLCB1 and hLCB2 as assessed by positive split ubiquitin 2-hybrid analysis
GO:0017059 serine palmitoyltransferase complex	IPI PMID:33558761 Structural insights into the regulation of human serine palm...	ACCEPT	Summary: SPT complex membership demonstrated by cryo-EM structures of the human SPT holocomplex containing ssSPTa together with SPTLC1, SPTLC2 and ORMDL3. Reason: Directly supported by high-resolution structures of the assembled complex. Supporting Evidence: PMID:33558761 the serine palmitoyltransferase holocomplex, which consists of catalytic components (SPTLC1 and SPTLC2) and regulatory components (ssSPTa and ORMDL3)
GO:0046512 sphingosine biosynthetic process	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	KEEP AS NON CORE	Summary: Involvement in sphingosine biosynthesis via the SPT-catalyzed first committed step. Sphingosine is a downstream product formed after several additional enzymatic steps. Reason: SPTSSA contributes upstream (first step of the pathway) but sphingosine formation requires multiple downstream enzymes; keep as a non-core downstream process rather than the core function. Supporting Evidence: PMID:37308477 condensation of serine and palmitoyl-CoA to generate 3-keto-dihydrosphingosine
GO:0046512 sphingosine biosynthetic process	IDA PMID:33558761 Structural insights into the regulation of human serine palm...	KEEP AS NON CORE	Summary: Second IDA annotation (ComplexPortal) for involvement in sphingosine biosynthesis via the ER SPT complex characterized structurally in this paper. Reason: As above, involvement is upstream and indirect; retained as a non-core downstream process. Supporting Evidence: PMID:33558761 the first and rate-limiting step of sphingolipid synthesis is catalyzed by the serine palmitoyltransferase holocomplex
GO:0005789 endoplasmic reticulum membrane	EXP PMID:23510452 Identification of small subunit of serine palmitoyltransfera...	ACCEPT	Summary: Experimental localization of ssSPTa to the ER membrane. This is the anchor experimental annotation supporting the ER membrane localization propagated by other evidence codes. Reason: Directly demonstrated experimentally; SPTSSA is a multi-pass ER membrane protein. Supporting Evidence: file:human/SPTSSA/SPTSSA-uniprot.txt SUBCELLULAR LOCATION Endoplasmic reticulum membrane
GO:0004758 serine C-palmitoyltransferase activity	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	ACCEPT	Summary: Direct-assay annotation with the contributes_to qualifier, accurately capturing that SPTSSA contributes to, but does not independently enable, the serine C-palmitoyltransferase activity of the SPT complex. Reason: This is the most precise molecular-function annotation for SPTSSA, a non-catalytic accessory subunit that is required for full SPT activity and sets acyl-CoA specificity. Selected as the core molecular-function evidence. Supporting Evidence: PMID:19416851 each substantially enhance the activity of mammalian SPT PMID:33558762 SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity
GO:0006686 sphingomyelin biosynthetic process	IDA PMID:30242129 Complex formation of sphingomyelin synthase 1 with glucosylc...	MARK AS OVER ANNOTATED	Summary: IDA annotation to sphingomyelin biosynthetic process citing PMID:30242129. That paper is about the SMS1-GCS (sphingomyelin synthase 1 / glucosylceramide synthase) heteromeric complex controlling the metabolic fate of ceramide in the Golgi; SPTSSA/ssSPTa is not mentioned anywhere in the full text. Reason: The cited full-text paper does not study SPTSSA, and sphingomyelin synthesis is a distant downstream Golgi process (SM synthase acts on ceramide many steps after SPT). This is an over-annotation. Per curation policy for experimental annotations it is flagged rather than removed, but it should not be treated as a function of SPTSSA. Supporting Evidence: PMID:30242129 Sphingomyelin synthase 1 (SMS1) and glucosylceramide synthase (GCS) are key enzymes that catalyze the conversion of Cer to SM and GlcCer
GO:0046513 ceramide biosynthetic process	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	KEEP AS NON CORE	Summary: IDA involvement in ceramide biosynthesis via the SPT first committed step characterized in the original ssSPTa paper. Reason: Involvement is upstream and indirect (ceramide requires downstream reductase and ceramide synthases); retained as a non-core downstream process, with sphingolipid biosynthetic process as the core BP. Supporting Evidence: PMID:19416851 Serine palmitoyltransferase (SPT) catalyzes the first committed step in sphingolipid biosynthesis
GO:0006688 glycosphingolipid biosynthetic process	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	KEEP AS NON CORE	Summary: IDA involvement in glycosphingolipid biosynthesis via the SPT first committed step. Glycosphingolipids are far-downstream products built on glucosylceramide. Reason: SPTSSA contributes only at the pathway entry point; glycosphingolipid synthesis requires many additional, dedicated glycosyltransferases. Retained as a non-core downstream process. Supporting Evidence: PMID:19416851 Serine palmitoyltransferase (SPT) catalyzes the first committed step in sphingolipid biosynthesis
GO:0017059 serine palmitoyltransferase complex	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	ACCEPT	Summary: IDA SPT complex membership from the original ssSPTa identification, where ssSPTa was shown to be part of the SPT holoenzyme and to interact with both catalytic subunits. Reason: Well-supported experimental complex-membership annotation. Supporting Evidence: PMID:19416851 each interacts with both hLCB1 and hLCB2 as assessed by positive split ubiquitin 2-hybrid analysis
GO:0098554 cytoplasmic side of endoplasmic reticulum membrane	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	ACCEPT	Summary: Localization to the cytoplasmic face of the ER membrane, consistent with the SPT catalytic reaction (condensation of L-serine and cytosolic palmitoyl-CoA) occurring on the cytosolic leaflet of the ER, and with the SPTSSA topology (both termini cytoplasmic). Reason: Consistent with SPTSSA membrane topology (cytoplasmic N- and C-termini, two TM helices) and with the cytosolic-leaflet site of SPT catalysis. Supporting Evidence: PMID:30242129 Cer is synthesized de novo in the cytosolic leaflet of the ER bilayer by sequential enzyme reactions that are initiated by the condensation of serine and palmitoyl-CoA file:human/SPTSSA/SPTSSA-uniprot.txt TOPO_DOM 58..71
GO:0005515 protein binding	IPI PMID:23510452 Identification of small subunit of serine palmitoyltransfera...	MARK AS OVER ANNOTATED	Summary: IPI protein-binding annotation supported by interaction with MBOAT7/LPIAT1 (UniProtKB:Q96N66). This is a functionally meaningful, SPT-independent interaction relevant to MBOAT7 localization, but the bare protein binding term is uninformative. Reason: The MBOAT7 interaction is genuine and biologically interesting, but GO:0005515 protein binding is uninformative; the functional content is better captured by the intracellular protein localization (GO:0008104) annotation. Retained per policy but flagged. Supporting Evidence: PMID:23510452 ssSPTa co-immunoprecipitated and colocalized with LPIAT1 in cultured mammalian cells
GO:0005783 endoplasmic reticulum	IDA PMID:23510452 Identification of small subunit of serine palmitoyltransfera...	ACCEPT	Summary: Direct-assay localization to the endoplasmic reticulum, the parent compartment of the more specific ER membrane annotation. Reason: Correct; consistent with the experimentally established ER membrane localization of this multi-pass membrane protein. Supporting Evidence: file:human/SPTSSA/SPTSSA-uniprot.txt SUBCELLULAR LOCATION Endoplasmic reticulum membrane
GO:0008104 intracellular protein localization	IDA PMID:23510452 Identification of small subunit of serine palmitoyltransfera...	KEEP AS NON CORE	Summary: Involvement in intracellular protein localization, reflecting ssSPTa's SPT-independent role in facilitating MBOAT7/LPIAT1 localization to mitochondria-associated ER membranes (MAM). Knockdown of ssSPTa reduced LPIAT1 protein in the crude mitochondrial fraction and reduced LPIAT1-dependent incorporation of arachidonic acid into phosphatidylinositol. Reason: This is a genuine secondary, SPT-independent function of SPTSSA supported by experimental data, but it is distinct from and subordinate to its core role in sphingolipid biosynthesis as an SPT subunit. Supporting Evidence: PMID:23510452 facilitating the MAM localization of LPIAT1
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-428127	ACCEPT	Summary: Traceable-author-statement (Reactome) localization to the ER membrane, consistent with all other localization evidence. Reason: Consistent with the experimental ER membrane localization and the Reactome sphingolipid de novo biosynthesis pathway in which SPT acts. Supporting Evidence: file:human/SPTSSA/SPTSSA-uniprot.txt SUBCELLULAR LOCATION Endoplasmic reticulum membrane
GO:0004758 serine C-palmitoyltransferase activity	IDA PMID:25691431 ORMDL/serine palmitoyltransferase stoichiometry determines e...	ACCEPT	Summary: IDA annotation of serine C-palmitoyltransferase activity assigned by MGI citing PMID:25691431, a study of ORMDL/SPT stoichiometry and its effect on sphingolipid biosynthesis. The complex-level SPT activity assayed there depends on the ssSPTa-containing SPT complex. Reason: The paper assays SPT enzyme activity in the context of the SPT-ORMDL complex, which contains ssSPTa; the curator (MGI) had access to the full text. As for the other GO:0004758 entries, the contributes_to form is more precise for this non-catalytic subunit, but the annotation reflects real complex activity and is retained. Supporting Evidence: PMID:25691431 negative homeostatic regulators of the initiating enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT)
GO:0046513 ceramide biosynthetic process	IDA PMID:25691431 ORMDL/serine palmitoyltransferase stoichiometry determines e...	KEEP AS NON CORE	Summary: Involvement in ceramide biosynthesis (acts_upstream_of_or_within) via the SPT-catalyzed entry step, assigned by MGI citing the ORMDL3/SPT stoichiometry study. Reason: SPTSSA acts upstream of ceramide as the entry point of the pathway; the acts_upstream_of_or_within qualifier is appropriate, but this downstream process is non-core relative to the sphingolipid biosynthetic process. Supporting Evidence: PMID:25691431 the initiating enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT)
GO:0030148 sphingolipid biosynthetic process	TAS PMID:19416851 Identification of small subunits of mammalian serine palmito...	ACCEPT	Summary: Traceable-author-statement involvement in sphingolipid biosynthetic process. This is the core biological process for SPTSSA; as an SPT subunit it participates in the first, rate-limiting step of de novo sphingolipid biosynthesis. Reason: This is the most accurate and appropriately general BP for SPTSSA, directly reflecting its role in the SPT complex at the entry point of sphingolipid biosynthesis. Selected as the core biological process. Supporting Evidence: PMID:19416851 Serine palmitoyltransferase (SPT) catalyzes the first committed step in sphingolipid biosynthesis
GO:0008047 enzyme activator activity	IDA PMID:19416851 Identification of small subunits of mammalian serine palmito...	NEW	Summary: Proposed molecular function capturing the subunit-specific role of SPTSSA as a non-catalytic activator of the SPT complex. SPTSSA (ssSPTa) is not itself a transferase; rather, it binds the SPTLC1-SPTLC2 catalytic core, is required for full SPT activity, and stimulates catalysis while setting acyl-CoA substrate specificity. This is more informative about SPTSSA's own function than the complex-level catalytic term (GO:0004758), which SPTSSA only contributes to. Reason: SPTSSA is an accessory activator subunit; enzyme activator activity (a molecular-function regulator that increases a catalytic activity) precisely describes its distinct role, complementing the contributes_to serine C-palmitoyltransferase activity annotation. Supported by biochemistry (activity enhancement) and structural biology (engaging SPTLC2 and shaping the substrate tunnel). Supporting Evidence: PMID:19416851 each substantially enhance the activity of mammalian SPT PMID:33558762 SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity

Core Functions

As the accessory/regulatory small subunit of the serine palmitoyltransferase (SPT) complex, SPTSSA is required for full SPT catalytic activity and sets the acyl-CoA chain-length specificity (favoring C16 palmitoyl-CoA), thereby driving the first, rate-limiting step of de novo sphingolipid biosynthesis in the ER membrane.

Molecular Function:

enzyme activator activity

Directly Involved In:

sphingolipid biosynthetic process

Cellular Locations:

endoplasmic reticulum membrane

In Complex:

serine palmitoyltransferase complex

Supporting Evidence:

PMID:19416851
each substantially enhance the activity of mammalian SPT
PMID:33558761
ssSPTa engages SPTLC2 and shapes the tunnel
PMID:33558762
SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

PMID:19416851

Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities.

PMID:23510452

Identification of small subunit of serine palmitoyltransferase a as a lysophosphatidylinositol acyltransferase 1-interacting protein.

PMID:25691431

ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis.

PMID:30242129

Complex formation of sphingomyelin synthase 1 with glucosylceramide synthase increases sphingomyelin and decreases glucosylceramide levels.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33558761

Structural insights into the regulation of human serine palmitoyltransferase complexes.

PMID:33558762

Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex.

PMID:37308477

Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.

Reactome:R-HSA-428127

SPTLC complexes transfer acyl-CoA onto serine

file:human/SPTSSA/SPTSSA-uniprot.txt

UniProtKB Q969W0 (SPTSA_HUMAN) Serine palmitoyltransferase small subunit A

📚 Additional Documentation

Notes

(SPTSSA-notes.md)

SPTSSA (ssSPTa) review notes

UniProtKB:Q969W0 — Serine palmitoyltransferase small subunit A (ssSPTa). 71 aa, two
predicted transmembrane helices, ER membrane. HGNC:20361. Formerly C14orf147 / SSSPTA.

Core biology (verified)

SPTSSA is a small regulatory/accessory subunit of the serine palmitoyltransferase
(SPT) complex. The catalytic core is the SPTLC1 + SPTLC2 (or SPTLC3) heterodimer;
SPTSSA (or its paralog SPTSSB) is a small subunit that is required for full SPT
activity and determines the acyl-CoA chain-length specificity of the complex.
SPTSSA is itself non-catalytic — it "stimulates the catalytic activity and plays a role
in substrate specificity" (UniProt FUNCTION, based on PubMed:19416851, PubMed:33558761).

Discovery paper PMID:19416851 (Han et al. 2009, PNAS): identified ssSPTa and ssSPTb,
each of which "substantially enhance the activity of mammalian SPT" and "confer full
enzyme activity"; the two isoforms differ in acyl-CoA preference. SPTLC1-SPTLC2-SPTSSA
strongly prefers C16-CoA (palmitoyl-CoA) [UniProt FUNCTION synthesis of this paper].
Cached publication is ABSTRACT-ONLY (full_text_available: false); the abstract
supports the enhancement/substrate-specificity claims. Many GOA IDA annotations
(UOS_MCB, UniProtKB, ComplexPortal) cite this paper — curators read the full text.
Structural papers PMID:33558761 (Wang et al.), PMID:33558762 (Li et al.),
PMID:37308477 (Xie et al.): cryo-EM of the human SPT holocomplex.
"ssSPTa engages SPTLC2 and shapes the tunnel to determine substrate specificity"
(33558761 abstract). "SPTssa participates in acyl-CoA coordination, thereby stimulating
the SPT activity and regulating the substrate selectivity" (33558762 abstract).
Complex composed of SPTLC1, SPTLC2 (or SPTLC3) and SPTssa (or SPTssb), plus ORMDL
regulatory subunit (37308477 full text). SITE 28 in UniProt "defines the length of the
acyl chain-binding pocket, determining the acyl-CoA substrate preference"; MUTAGEN M28K
strongly decreases SPT catalytic activity (PubMed:33558762).

Localization

ER membrane, multi-pass membrane protein (UniProt SUBCELLULAR LOCATION,
ECO:0000269|PubMed:23510452). Topology: cytoplasmic 1-12, TM 13-29, lumenal 30-34, TM
35-57, cytoplasmic 58-71. So the N- and C-termini face the cytoplasm; GOA carries
"cytoplasmic side of endoplasmic reticulum membrane" (GO:0098554, is_active_in). Also
ER (GO:0005783) and ER membrane (GO:0005789) from multiple sources.

Second, independent function (MBOAT7/LPIAT1)

PMID:23510452 (Hirata et al. 2013): ssSPTa was found as an MBOAT7 (LPIAT1)-interacting
protein by split-ubiquitin Y2H; co-IP and colocalization confirmed. Knockdown of ssSPTa
decreased LPIAT1-dependent incorporation of arachidonic acid into PI and reduced LPIAT1
protein in the crude mitochondrial fraction, suggesting ssSPTa facilitates MBOAT7
localization to mitochondria-associated membranes (MAM). This is the basis for the
"intracellular protein localization" (GO:0008104) IDA and the MBOAT7/Q96N66 protein
binding IPI. This is a genuine, SPT-independent activity for the SAME gene.

Disease

SPTSSA variants cause complex hereditary spastic paraplegia (SPG90A dominant, SPG90B
recessive), a juvenile-ALS-like / HSP-spectrum neurodegenerative disorder, via
dysregulation of SPT (impaired ORMDL3 down-regulation → increased sphingolipid
synthesis). PMID:36718090 (Srivastava et al. 2023, Brain) — NOT in publications cache;
supported by UniProt DISEASE + VARIANT/MUTAGEN annotations. Not directly a GO annotation
but informs the biological description.

GOA annotation assessment summary

serine C-palmitoyltransferase activity GO:0004758: correct at complex level. SPTSSA is
a non-catalytic activator, so contributes_to is the accurate qualifier. IBA
(contributes_to) ACCEPT. IDA enables (UniProt) and IDA contributes_to (UOS_MCB,
x2) — accessory subunit does not independently enable catalysis, but curators read the
full text; ACCEPT the contributes_to forms; the bare enables (UniProt IDA, MGI IDA)
is defensible as complex-level activity, ACCEPT (do not remove experimental).
serine palmitoyltransferase complex GO:0017059 (part_of): well supported by structures
and ComplexPortal (CPX-6663, CPX-6665). ACCEPT all.
ER membrane GO:0005789 (located_in): ACCEPT (EXP PMID:23510452 is the anchor; IEA,
NAS, TAS all consistent). ER GO:0005783 IDA ACCEPT. cytoplasmic side of ER membrane
GO:0098554 is_active_in IDA: ACCEPT (consistent with topology).
BP: sphingolipid biosynthetic process GO:0030148 (TAS) — core, ACCEPT. ceramide
biosynthetic process GO:0046513, sphingosine biosynthetic process GO:0046512,
glycosphingolipid biosynthetic process GO:0006688, sphingomyelin biosynthetic process
GO:0006686, sphingolipid metabolic process GO:0006665 — all downstream of SPT; the
gene contributes to the whole sphingolipid biosynthetic network. Keep GO:0030148 as
core; the more specific downstream branches are best treated as non-core / over-
annotated because SPTSSA acts only at the first committed step and the downstream
products (SM, GlcCer, sphingosine) require many other enzymes.
GO:0006686 sphingomyelin biosynthetic process cites PMID:30242129 (SMS1-GCS
complex); SPTSSA is NOT mentioned anywhere in that full-text paper -> over-annotated
(MARK_AS_OVER_ANNOTATED; experimental, so not REMOVE).
protein binding GO:0005515 (IPI): SPTLC1 (O15269), MBOAT7 (Q96N66), and several HuRI
hits (CYSRT1, GET1, HERPUD2, RHBDL1). SPTLC1 and MBOAT7 are biologically meaningful;
bare protein binding is uninformative -> MARK_AS_OVER_ANNOTATED (per policy, not
REMOVE), captured better by complex membership / MBOAT7 localization role.
intracellular protein localization GO:0008104 (IDA, PMID:23510452): the MBOAT7-MAM
localization role; KEEP_AS_NON_CORE (secondary, SPT-independent function).

📄 View Raw YAML

id: Q969W0
gene_symbol: SPTSSA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SPTSSA (ssSPTa, small subunit of serine palmitoyltransferase A) is a small
  (71 aa) multi-pass endoplasmic reticulum membrane protein that is a regulatory/accessory
  subunit of the serine palmitoyltransferase (SPT) complex. The catalytic core of SPT is
  the SPTLC1-SPTLC2 (or SPTLC1-SPTLC3) heterodimer, which condenses L-serine and
  palmitoyl-CoA in the first, rate-limiting step of de novo sphingolipid biosynthesis.
  SPTSSA is itself non-catalytic but is required for full SPT activity; it engages SPTLC2,
  shapes the acyl-CoA binding tunnel, and thereby sets the acyl-CoA chain-length
  specificity of the complex, with the SPTLC1-SPTLC2-SPTSSA isozyme strongly preferring
  C16 palmitoyl-CoA. Within the SPT holocomplex SPTSSA works alongside the ORMDL
  negative-regulatory subunits. Independently of its role in the SPT complex, SPTSSA
  interacts with MBOAT7/LPIAT1 and facilitates its localization to mitochondria-associated
  ER membranes, influencing arachidonic-acid remodeling of phosphatidylinositol. Loss or
  variation of SPTSSA dysregulates sphingolipid synthesis and causes a complex hereditary
  spastic paraplegia / juvenile-ALS-like neurodegenerative disorder (SPG90A/SPG90B).
existing_annotations:
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetically inferred contribution to serine C-palmitoyltransferase
      activity as a subunit of the SPT complex. SPTSSA is a non-catalytic accessory
      subunit that is required for full activity of the catalytic SPTLC1-SPTLC2/3 core,
      so the contributes_to qualifier is exactly right.
    action: ACCEPT
    reason: SPTSSA is an accessory subunit that stimulates and shapes SPT catalysis but
      does not independently catalyze the reaction; the IBA contributes_to annotation
      captures this correctly and is supported by biochemistry and structural biology.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each substantially enhance the activity of mammalian SPT
    - reference_id: PMID:33558762
      supporting_text: SPTssa participates in acyl-CoA coordination, thereby stimulating
        the SPT activity and regulating the substrate selectivity
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetically inferred membership in the serine palmitoyltransferase
      complex. Cryo-EM structures directly place SPTSSA in the human SPT holocomplex with
      SPTLC1, SPTLC2 (or SPTLC3) and ORMDL3.
    action: ACCEPT
    reason: SPTSSA is a bona fide subunit of the SPT complex, confirmed by multiple
      cryo-EM structures and ComplexPortal (CPX-6663, CPX-6665). The GO definition of
      GO:0017059 explicitly lists SPTSSA/SPTSSB as regulatory activator components.
    supported_by:
    - reference_id: PMID:33558762
      supporting_text: SPTLC1 and SPTLC2 form a dimer of heterodimers as the catalytic
        core
    - reference_id: PMID:33558761
      supporting_text: ssSPTa engages SPTLC2 and shapes the tunnel
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred involvement in ceramide biosynthesis. SPT catalyzes
      the first committed step upstream of ceramide, so SPTSSA (as an SPT subunit)
      contributes upstream to ceramide production, but ceramide synthesis itself requires
      several additional dedicated enzymes.
    action: KEEP_AS_NON_CORE
    reason: SPTSSA acts only at the first step of sphingolipid biosynthesis; ceramide is a
      downstream product requiring 3-ketodihydrosphingosine reductase and ceramide
      synthases. The involvement is real but indirect, so this is best kept as a non-core
      downstream process, with sphingolipid biosynthetic process (GO:0030148) as the core
      BP.
    supported_by:
    - reference_id: PMID:37308477
      supporting_text: catalyzes the first and rate-limiting step of de novo sphingolipid
        biosynthesis by condensation of serine and palmitoyl-CoA to generate
        3-keto-dihydrosphingosine
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation to ER membrane from the UniProt subcellular-location
      mapping. SPTSSA is a multi-pass ER membrane protein, experimentally confirmed.
    action: ACCEPT
    reason: Consistent with the experimental subcellular location (PubMed:23510452) and
      with the SPT complex residing in the ER membrane. The IEA mapping is correct.
    supported_by:
    - reference_id: file:human/SPTSSA/SPTSSA-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION Endoplasmic reticulum membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19416851
  qualifier: enables
  review:
    summary: IPI protein-binding annotation supported by interaction with SPTLC1
      (UniProtKB:O15269), the catalytic-core subunit of SPT. This is a biologically
      meaningful interaction, but the bare protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The SPTSSA-SPTLC1 interaction is real and important, but GO:0005515 protein
      binding conveys no functional information. The meaningful content (SPT complex
      membership) is already captured by GO:0017059. Per curation policy the annotation is
      retained rather than removed, but flagged as an uninformative over-annotation.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each interacts with both hLCB1 and hLCB2 as assessed by positive
        split ubiquitin 2-hybrid analysis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IPI protein-binding annotations from the HuRI human binary interactome map
      (CYSRT1, GET1, HERPUD2, RHBDL1). These are high-throughput yeast two-hybrid hits of
      uncertain physiological significance for this ER membrane protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative and these are large-scale binary-screen
      hits with no established functional consequence for SPTSSA. Retained per policy but
      flagged; not used for core function.
    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:33558762
  qualifier: enables
  review:
    summary: IPI protein-binding annotation supported by the cryo-EM structure showing
      SPTSSA (SPTssa) as a subunit engaging the SPTLC1/SPTLC2 catalytic core within the
      SPT-ORMDL3 complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: The physical association is genuine and structurally defined, but the bare
      protein binding term is uninformative; the functional content is captured by SPT
      complex membership (GO:0017059) and the contributes_to catalytic annotation.
      Retained per policy but flagged.
    supported_by:
    - reference_id: PMID:33558762
      supporting_text: SPTssa participates in acyl-CoA coordination, thereby stimulating
        the SPT activity and regulating the substrate selectivity
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: Electronic annotation to sphingolipid metabolic process from the UniPathway
      mapping. SPTSSA participates in de novo sphingolipid metabolism as an SPT subunit.
    action: ACCEPT
    reason: Correct but general parent process of the more specific sphingolipid
      biosynthetic process; consistent with SPT function at the first step of the pathway.
    supported_by:
    - reference_id: file:human/SPTSSA/SPTSSA-uniprot.txt
      supporting_text: PATHWAY Lipid metabolism; sphingolipid metabolism
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: enables
  review:
    summary: Direct-assay annotation of serine C-palmitoyltransferase activity from the
      original functional characterization, where reconstituted SPT isozymes containing
      ssSPTa were assayed for enzyme activity and acyl-CoA preference. The activity is a
      property of the assembled complex; SPTSSA is the accessory subunit required for full
      activity.
    action: ACCEPT
    reason: The reconstituted SPT isozyme assay (with ssSPTa) demonstrates the
      complex-level palmitoyltransferase activity. Since SPTSSA is non-catalytic, the
      contributes_to form is more precise, but this enables IDA (from a curator who read
      the full text) is retained as reflecting the assayed complex activity.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each substantially enhance the activity of mammalian SPT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:33558761
  qualifier: located_in
  review:
    summary: Non-traceable-author-statement annotation (ComplexPortal) placing SPTSSA in
      the ER membrane, consistent with the SPT holocomplex residing in the ER.
    action: ACCEPT
    reason: Consistent with the experimentally established ER membrane localization and
      with the structural work on the ER-resident SPT complex.
    supported_by:
    - reference_id: PMID:33558761
      supporting_text: the first and rate-limiting step of sphingolipid synthesis is
        catalyzed by the serine palmitoyltransferase holocomplex
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IPI
  original_reference_id: PMID:19416851
  qualifier: part_of
  review:
    summary: SPT complex membership demonstrated by the original identification of ssSPTa
      as an SPT subunit that interacts with hLCB1 (SPTLC1) and hLCB2 (SPTLC2) and forms
      part of the SPT holoenzyme.
    action: ACCEPT
    reason: Well-supported experimental annotation of complex membership; SPTSSA is a
      core structural component of SPT.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each interacts with both hLCB1 and hLCB2 as assessed by positive
        split ubiquitin 2-hybrid analysis
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IPI
  original_reference_id: PMID:33558761
  qualifier: part_of
  review:
    summary: SPT complex membership demonstrated by cryo-EM structures of the human SPT
      holocomplex containing ssSPTa together with SPTLC1, SPTLC2 and ORMDL3.
    action: ACCEPT
    reason: Directly supported by high-resolution structures of the assembled complex.
    supported_by:
    - reference_id: PMID:33558761
      supporting_text: the serine palmitoyltransferase holocomplex, which consists of
        catalytic components (SPTLC1 and SPTLC2) and regulatory components (ssSPTa and
        ORMDL3)
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: involved_in
  review:
    summary: Involvement in sphingosine biosynthesis via the SPT-catalyzed first committed
      step. Sphingosine is a downstream product formed after several additional enzymatic
      steps.
    action: KEEP_AS_NON_CORE
    reason: SPTSSA contributes upstream (first step of the pathway) but sphingosine
      formation requires multiple downstream enzymes; keep as a non-core downstream
      process rather than the core function.
    supported_by:
    - reference_id: PMID:37308477
      supporting_text: condensation of serine and palmitoyl-CoA to generate
        3-keto-dihydrosphingosine
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:33558761
  qualifier: involved_in
  review:
    summary: Second IDA annotation (ComplexPortal) for involvement in sphingosine
      biosynthesis via the ER SPT complex characterized structurally in this paper.
    action: KEEP_AS_NON_CORE
    reason: As above, involvement is upstream and indirect; retained as a non-core
      downstream process.
    supported_by:
    - reference_id: PMID:33558761
      supporting_text: the first and rate-limiting step of sphingolipid synthesis is
        catalyzed by the serine palmitoyltransferase holocomplex
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:23510452
  qualifier: located_in
  review:
    summary: Experimental localization of ssSPTa to the ER membrane. This is the anchor
      experimental annotation supporting the ER membrane localization propagated by other
      evidence codes.
    action: ACCEPT
    reason: Directly demonstrated experimentally; SPTSSA is a multi-pass ER membrane
      protein.
    supported_by:
    - reference_id: file:human/SPTSSA/SPTSSA-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION 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-assay annotation with the contributes_to qualifier, accurately
      capturing that SPTSSA contributes to, but does not independently enable, the
      serine C-palmitoyltransferase activity of the SPT complex.
    action: ACCEPT
    reason: This is the most precise molecular-function annotation for SPTSSA, a
      non-catalytic accessory subunit that is required for full SPT activity and sets
      acyl-CoA specificity. Selected as the core molecular-function evidence.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each substantially enhance the activity of mammalian SPT
    - reference_id: PMID:33558762
      supporting_text: SPTssa participates in acyl-CoA coordination, thereby stimulating
        the SPT activity and regulating the substrate selectivity
- term:
    id: GO:0006686
    label: sphingomyelin biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:30242129
  qualifier: involved_in
  review:
    summary: IDA annotation to sphingomyelin biosynthetic process citing PMID:30242129.
      That paper is about the SMS1-GCS (sphingomyelin synthase 1 / glucosylceramide
      synthase) heteromeric complex controlling the metabolic fate of ceramide in the
      Golgi; SPTSSA/ssSPTa is not mentioned anywhere in the full text.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited full-text paper does not study SPTSSA, and sphingomyelin synthesis
      is a distant downstream Golgi process (SM synthase acts on ceramide many steps after
      SPT). This is an over-annotation. Per curation policy for experimental annotations it
      is flagged rather than removed, but it should not be treated as a function of SPTSSA.
    supported_by:
    - reference_id: PMID:30242129
      supporting_text: Sphingomyelin synthase 1 (SMS1) and glucosylceramide synthase (GCS)
        are key enzymes that catalyze the conversion of Cer to SM and GlcCer
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: involved_in
  review:
    summary: IDA involvement in ceramide biosynthesis via the SPT first committed step
      characterized in the original ssSPTa paper.
    action: KEEP_AS_NON_CORE
    reason: Involvement is upstream and indirect (ceramide requires downstream reductase
      and ceramide synthases); retained as a non-core downstream process, with sphingolipid
      biosynthetic process as the core BP.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: Serine palmitoyltransferase (SPT) catalyzes the first committed step
        in sphingolipid biosynthesis
- term:
    id: GO:0006688
    label: glycosphingolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: involved_in
  review:
    summary: IDA involvement in glycosphingolipid biosynthesis via the SPT first committed
      step. Glycosphingolipids are far-downstream products built on glucosylceramide.
    action: KEEP_AS_NON_CORE
    reason: SPTSSA contributes only at the pathway entry point; glycosphingolipid synthesis
      requires many additional, dedicated glycosyltransferases. Retained as a non-core
      downstream process.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: Serine palmitoyltransferase (SPT) catalyzes the first committed step
        in sphingolipid biosynthesis
- term:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: part_of
  review:
    summary: IDA SPT complex membership from the original ssSPTa identification, where
      ssSPTa was shown to be part of the SPT holoenzyme and to interact with both
      catalytic subunits.
    action: ACCEPT
    reason: Well-supported experimental complex-membership annotation.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each interacts with both hLCB1 and hLCB2 as assessed by positive
        split ubiquitin 2-hybrid analysis
- 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: Localization to the cytoplasmic face of the ER membrane, consistent with the
      SPT catalytic reaction (condensation of L-serine and cytosolic palmitoyl-CoA)
      occurring on the cytosolic leaflet of the ER, and with the SPTSSA topology (both
      termini cytoplasmic).
    action: ACCEPT
    reason: Consistent with SPTSSA membrane topology (cytoplasmic N- and C-termini, two TM
      helices) and with the cytosolic-leaflet site of SPT catalysis.
    supported_by:
    - reference_id: PMID:30242129
      supporting_text: Cer is synthesized de novo in the cytosolic leaflet of the ER
        bilayer by sequential enzyme reactions that are initiated by the condensation of
        serine and palmitoyl-CoA
    - reference_id: file:human/SPTSSA/SPTSSA-uniprot.txt
      supporting_text: TOPO_DOM        58..71
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23510452
  qualifier: enables
  review:
    summary: IPI protein-binding annotation supported by interaction with MBOAT7/LPIAT1
      (UniProtKB:Q96N66). This is a functionally meaningful, SPT-independent interaction
      relevant to MBOAT7 localization, but the bare protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The MBOAT7 interaction is genuine and biologically interesting, but GO:0005515
      protein binding is uninformative; the functional content is better captured by the
      intracellular protein localization (GO:0008104) annotation. Retained per policy but
      flagged.
    supported_by:
    - reference_id: PMID:23510452
      supporting_text: ssSPTa co-immunoprecipitated and colocalized with LPIAT1 in
        cultured mammalian cells
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23510452
  qualifier: located_in
  review:
    summary: Direct-assay localization to the endoplasmic reticulum, the parent
      compartment of the more specific ER membrane annotation.
    action: ACCEPT
    reason: Correct; consistent with the experimentally established ER membrane
      localization of this multi-pass membrane protein.
    supported_by:
    - reference_id: file:human/SPTSSA/SPTSSA-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION Endoplasmic reticulum membrane
- term:
    id: GO:0008104
    label: intracellular protein localization
  evidence_type: IDA
  original_reference_id: PMID:23510452
  qualifier: involved_in
  review:
    summary: Involvement in intracellular protein localization, reflecting ssSPTa's
      SPT-independent role in facilitating MBOAT7/LPIAT1 localization to
      mitochondria-associated ER membranes (MAM). Knockdown of ssSPTa reduced LPIAT1
      protein in the crude mitochondrial fraction and reduced LPIAT1-dependent
      incorporation of arachidonic acid into phosphatidylinositol.
    action: KEEP_AS_NON_CORE
    reason: This is a genuine secondary, SPT-independent function of SPTSSA supported by
      experimental data, but it is distinct from and subordinate to its core role in
      sphingolipid biosynthesis as an SPT subunit.
    supported_by:
    - reference_id: PMID:23510452
      supporting_text: facilitating the MAM localization of LPIAT1
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-428127
  qualifier: located_in
  review:
    summary: Traceable-author-statement (Reactome) localization to the ER membrane,
      consistent with all other localization evidence.
    action: ACCEPT
    reason: Consistent with the experimental ER membrane localization and the Reactome
      sphingolipid de novo biosynthesis pathway in which SPT acts.
    supported_by:
    - reference_id: file:human/SPTSSA/SPTSSA-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION Endoplasmic reticulum membrane
- term:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25691431
  qualifier: enables
  review:
    summary: IDA annotation of serine C-palmitoyltransferase activity assigned by MGI
      citing PMID:25691431, a study of ORMDL/SPT stoichiometry and its effect on
      sphingolipid biosynthesis. The complex-level SPT activity assayed there depends on
      the ssSPTa-containing SPT complex.
    action: ACCEPT
    reason: The paper assays SPT enzyme activity in the context of the SPT-ORMDL complex,
      which contains ssSPTa; the curator (MGI) had access to the full text. As for the
      other GO:0004758 entries, the contributes_to form is more precise for this
      non-catalytic subunit, but the annotation reflects real complex activity and is
      retained.
    supported_by:
    - reference_id: PMID:25691431
      supporting_text: negative homeostatic regulators of the initiating enzyme in
        sphingolipid biosynthesis, serine palmitoyltransferase (SPT)
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:25691431
  qualifier: acts_upstream_of_or_within
  review:
    summary: Involvement in ceramide biosynthesis (acts_upstream_of_or_within) via the
      SPT-catalyzed entry step, assigned by MGI citing the ORMDL3/SPT stoichiometry study.
    action: KEEP_AS_NON_CORE
    reason: SPTSSA acts upstream of ceramide as the entry point of the pathway; the
      acts_upstream_of_or_within qualifier is appropriate, but this downstream process is
      non-core relative to the sphingolipid biosynthetic process.
    supported_by:
    - reference_id: PMID:25691431
      supporting_text: the initiating enzyme in sphingolipid biosynthesis, serine
        palmitoyltransferase (SPT)
- term:
    id: GO:0030148
    label: sphingolipid biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:19416851
  qualifier: involved_in
  review:
    summary: Traceable-author-statement involvement in sphingolipid biosynthetic process.
      This is the core biological process for SPTSSA; as an SPT subunit it participates in
      the first, rate-limiting step of de novo sphingolipid biosynthesis.
    action: ACCEPT
    reason: This is the most accurate and appropriately general BP for SPTSSA, directly
      reflecting its role in the SPT complex at the entry point of sphingolipid
      biosynthesis. Selected as the core biological process.
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: Serine palmitoyltransferase (SPT) catalyzes the first committed step
        in sphingolipid biosynthesis
- term:
    id: GO:0008047
    label: enzyme activator activity
  evidence_type: IDA
  original_reference_id: PMID:19416851
  qualifier: enables
  review:
    summary: Proposed molecular function capturing the subunit-specific role of SPTSSA as
      a non-catalytic activator of the SPT complex. SPTSSA (ssSPTa) is not itself a
      transferase; rather, it binds the SPTLC1-SPTLC2 catalytic core, is required for full
      SPT activity, and stimulates catalysis while setting acyl-CoA substrate specificity.
      This is more informative about SPTSSA's own function than the complex-level catalytic
      term (GO:0004758), which SPTSSA only contributes to.
    action: NEW
    reason: SPTSSA is an accessory activator subunit; enzyme activator activity (a
      molecular-function regulator that increases a catalytic activity) precisely describes
      its distinct role, complementing the contributes_to serine C-palmitoyltransferase
      activity annotation. Supported by biochemistry (activity enhancement) and structural
      biology (engaging SPTLC2 and shaping the substrate tunnel).
    supported_by:
    - reference_id: PMID:19416851
      supporting_text: each substantially enhance the activity of mammalian SPT
    - reference_id: PMID:33558762
      supporting_text: SPTssa participates in acyl-CoA coordination, thereby stimulating
        the SPT activity and regulating the substrate selectivity
core_functions:
- description: As the accessory/regulatory small subunit of the serine palmitoyltransferase
    (SPT) complex, SPTSSA is required for full SPT catalytic activity and sets the acyl-CoA
    chain-length specificity (favoring C16 palmitoyl-CoA), thereby driving the first,
    rate-limiting step of de novo sphingolipid biosynthesis in the ER membrane.
  molecular_function:
    id: GO:0008047
    label: enzyme activator activity
  contributes_to_molecular_function:
    id: GO:0004758
    label: serine C-palmitoyltransferase activity
  in_complex:
    id: GO:0017059
    label: serine palmitoyltransferase complex
  directly_involved_in:
  - id: GO:0030148
    label: sphingolipid biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:19416851
    supporting_text: each substantially enhance the activity of mammalian SPT
  - reference_id: PMID:33558761
    supporting_text: ssSPTa engages SPTLC2 and shapes the tunnel
  - reference_id: PMID:33558762
    supporting_text: SPTssa participates in acyl-CoA coordination, thereby stimulating the
      SPT activity and regulating the substrate selectivity
references:
- 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: 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: Primary discovery paper for ssSPTa/SPTSSA as an SPT activator subunit;
      cached entry is abstract-only but abstract directly supports the activation and
      substrate-specificity claims.
- id: PMID:23510452
  title: Identification of small subunit of serine palmitoyltransferase a as a lysophosphatidylinositol
    acyltransferase 1-interacting protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes experimental ER membrane localization and an SPT-independent
      role in MBOAT7/LPIAT1 localization to mitochondria-associated membranes.
- 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: Studies SPT activity in the SPT-ORMDL context (which includes ssSPTa);
      cited by MGI IDA annotations. Cached entry is abstract-only.
- 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: MISCITED
    review_notes: Full text does not mention SPTSSA/ssSPTa; the paper concerns the SMS1-GCS
      Golgi complex. The GOA sphingomyelin biosynthetic process IDA citing this paper is an
      over-annotation for SPTSSA.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI large-scale binary interactome; source of several uninformative
      protein binding IPI hits of uncertain physiological relevance.
- id: PMID:33558761
  title: Structural insights into the regulation of human serine palmitoyltransferase
    complexes.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cryo-EM structures confirming SPT complex membership and the
      substrate-specificity role of ssSPTa (engages SPTLC2, shapes the tunnel).
- 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: Structural and biochemical confirmation of the activator /
      substrate-selectivity role of SPTssa; MUTAGEN M28K abolishes complex activity.
- id: PMID:37308477
  title: Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid
    homeostasis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Confirms SPT complex composition (SPTLC1, SPTLC2/3, SPTssa/ssb) and
      pathway context; ceramide-sensing regulation is mediated by ORMDL rather than SPTSSA.
- id: Reactome:R-HSA-428127
  title: SPTLC complexes transfer acyl-CoA onto serine
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Reactome reaction for the SPT-catalyzed condensation step; source of the
      TAS ER membrane localization annotation.
- id: file:human/SPTSSA/SPTSSA-uniprot.txt
  title: UniProtKB Q969W0 (SPTSA_HUMAN) Serine palmitoyltransferase small subunit A
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: UniProt curated record; source for localization, topology, complex
      composition, interactions, and disease.

SPTSSA

Gene Description