Affinage

SPTLC2

Serine palmitoyltransferase 2 · UniProt O15270

Length
562 aa
Mass
62.9 kDa
Annotated
2026-06-10
35 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPTLC2 is the catalytic subunit of serine palmitoyltransferase (SPT), the enzyme that catalyzes the first and committed step of de novo sphingolipid biosynthesis—the PLP-dependent condensation of palmitoyl-CoA and L-serine to 3-ketosphinganine (PMID:8058731). It functions as an obligate heterodimer with SPTLC1, the complex co-precipitating both partners together with SPT enzymatic activity, establishing the LCB1·LCB2 heterodimer as the functional enzyme (PMID:9837968). A single catalytic site lies at the subunit interface, where a conserved lysine in SPTLC2 forms a Schiff base with the PLP cofactor and a conserved histidine supports cofactor binding (PMID:11781309). Disease-causing missense mutations in SPTLC2 partition into two mechanistic classes: HSAN-I mutations clustered near the PLP pocket reduce canonical activity while conferring gain of alternative substrate specificity, mis-incorporating alanine to generate neurotoxic 1-deoxysphingolipids (PMID:20920666, PMID:24175284, PMID:23658386), whereas transmembrane-domain mutations cause juvenile/childhood ALS by escaping ORMDL-mediated feedback inhibition and driving unrestrained ceramide overproduction (PMID:38041684, PMID:40849231), with a distinct ALS variant increasing canonical sphingolipid output (PMID:38041679). SPTLC2 transcription is inducible: NFκB p65 binds the Sptlc2 promoter in response to LPS (PMID:21167294) and spliced XBP1 activates it under ER stress, linking SPTLC2-driven ceramide synthesis to hepatic insulin resistance (PMID:35513574). The enzyme is required cell-autonomously for CD8+ T cell metabolic fitness and effector responses (PMID:30952607) and for β-cell survival and glucose-regulated insulin secretion [PMID:bio_10.1101_2025.05.14.653935].

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1994 High

    Established that SPT, the committed enzyme of sphingolipid synthesis, requires two distinct subunits, identifying LCB2/SPTLC2 as one of them.

    Evidence Genetic overexpression and enzymatic assay in S. cerevisiae showing SPT induction needs co-expression of LCB1 and LCB2

    PMID:8058731

    Open questions at the time
    • Did not establish the physical nature of the LCB1-LCB2 association
    • Catalytic residues not yet mapped
  2. 1996 Medium

    Cloned the human ortholog and identified an LCB2-specific catalytic-domain motif shared with the aminolevulinate synthase superfamily, defining the catalytic signature of SPTLC2.

    Evidence cDNA cloning, cross-species yeast complementation, and sequence motif analysis

    PMID:8921873

    Open questions at the time
    • Motif inferred by homology rather than by direct active-site assignment
    • Single lab
  3. 1998 High

    Demonstrated that SPTLC2 and SPTLC1 physically associate as the functional SPT heterodimer, moving from genetic to biochemical proof.

    Evidence Reciprocal affinity co-precipitation and co-IP with co-precipitating SPT activity in mammalian cells

    PMID:9837968

    Open questions at the time
    • Stoichiometry and higher-order assembly not resolved
    • Role of accessory subunits not addressed
  4. 2002 High

    Localized the single SPT active site to the subunit interface and assigned the PLP-anchoring lysine and a critical histidine to SPTLC2, defining the catalytic mechanism.

    Evidence Site-directed mutagenesis, yeast genetics, activity assays and structural modeling

    PMID:11781309

    Open questions at the time
    • No experimental high-resolution structure of the mammalian complex
    • Contribution of each subunit to substrate binding not fully partitioned
  5. 2013 High

    Resolved the pathomechanism of HSAN-I SPTLC2 mutations as a shift in substrate specificity producing neurotoxic 1-deoxysphingolipids, with distinct mutations affecting canonical versus alternative activity differently.

    Evidence In vitro and cell-based SPT activity assays, bacterial structural mimics with ssSPT subunits, and patient plasma sphingolipidomics across multiple mutations (V359M, G382V, I504F, A182P)

    PMID:20920666 PMID:23658386 PMID:24175284

    Open questions at the time
    • Mechanism by which 1-deoxysphingolipids cause neurodegeneration not defined here
    • Bacterial mimic used as structural proxy for some assays
  6. 2010 Medium

    Showed SPTLC2 is transcriptionally inducible by inflammatory signaling, linking SPT output to NFκB activity.

    Evidence p65 overexpression, promoter analysis and ChIP in LPS-treated macrophages with ceramide/sphingomyelin quantification

    PMID:21167294

    Open questions at the time
    • Selectivity for SPTLC2 over SPTLC1 mechanistically unexplained beyond promoter binding
    • Single lab
  7. 2019 High

    Established a cell-autonomous requirement for SPTLC2-driven sphingolipid flux in CD8+ T cell survival and effector function.

    Evidence T-cell-specific conditional KO mice with viral challenge, mTORC1/ER-stress readouts, and sphingolipid and ER-stress-inhibitor rescue

    PMID:30952607

    Open questions at the time
    • Which downstream sphingolipid species mediate the rescue not pinpointed
    • Link between mTORC1 dysregulation and ER stress not fully ordered
  8. 2022 Medium

    Connected ER-stress-driven SPTLC2 induction to a metabolic disease phenotype via the sXBP1-SPTLC2-ceramide axis.

    Evidence Promoter analysis, sXBP1 activation assay, and liver-specific transgenic mice with IRβ phosphorylation and ceramide measurement

    PMID:35513574

    Open questions at the time
    • Causality between ceramide species and IRβ dephosphorylation correlative
    • Single lab and overexpression model
  9. 2024 Medium

    Defined a second disease class for SPTLC2: transmembrane-domain gain-of-function mutations causing ALS through loss of ORMDL feedback inhibition and ceramide overproduction, mechanistically distinct from HSAN-I substrate shifting.

    Evidence Exome/genome sequencing, sphingolipidomics, and mutant expression in HEK cells, plus an additional ALS variant driving excess canonical synthesis

    PMID:38041679 PMID:38041684 PMID:40849231

    Open questions at the time
    • For some variants ORMDL3 regulatory loss proposed but not directly manipulated
    • Therapeutic implications (e.g., serine supplementation harm) predicted not demonstrated in vivo
  10. 2024 Medium

    Implicated SPTLC2 beyond canonical lipid metabolism by linking its enzymatic activity to oncogenic EGFR signaling.

    Evidence Co-IP of SPTLC2-EGFR with knockdown/overexpression and EGFR-FAK-HBEGF readouts in ovarian cancer migration and metastasis models

    PMID:39645550

    Open questions at the time
    • Whether the EGFR interaction is direct and stoichiometric versus activity-mediated unclear
    • Single lab
  11. 2025 Medium

    Demonstrated that de novo ceramide synthesis via SPTLC2 is required for β-cell survival and insulin secretion despite salvage-pathway compensation.

    Evidence β-cell-specific conditional KO mice with lipidomics, transcriptomics, histology and glucose tolerance testing (preprint)

    PMID:bio_10.1101_2025.05.14.653935

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Specific ceramide species responsible for β-cell loss not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SPTLC2 transmembrane mutations mechanistically uncouple the enzyme from ORMDL-mediated feedback, and whether HSAN-I versus ALS substrate/regulatory phenotypes can be distinguished structurally, remains unresolved.
  • No experimental structure of the mammalian SPT-ORMDL regulatory complex with disease mutations
  • Direct ORMDL3 manipulation not performed for all ALS variants

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0016874 ligase activity 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
EGFRORMDL3SPTLC1TLR4
Complex memberships
serine palmitoyltransferase (SPT) heterodimer

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 LCB2 (yeast ortholog of SPTLC2) encodes a subunit of serine palmitoyltransferase (SPT, EC 2.3.1.50), the enzyme that catalyzes the first and committed step in sphingolipid synthesis: condensation of palmitoyl-CoA and serine to form 3-ketosphinganine. Overproduction of SPT activity required co-expression of both LCB1 and LCB2, providing genetic evidence that both encode subunits of the same enzyme. Genetic overexpression in Saccharomyces cerevisiae; enzymatic activity assay Proceedings of the National Academy of Sciences of the United States of America High 8058731
1996 Human SPTLC2 (hLCB2) was cloned and shown to be the mammalian ortholog of yeast LCB2. A conserved 56-residue motif unique to LCB2 proteins functionally substituted for the corresponding region of S. cerevisiae Lcb2p, and contains a peptide sequence identified as part of the catalytic domain of the aminolevulinate synthase superfamily, establishing this motif as the catalytic domain signature of SPTLC2. cDNA cloning; cross-species functional complementation in yeast; sequence motif analysis Gene Medium 8921873
1998 SPTLC2 (LCB2) and SPTLC1 (LCB1) physically interact to form the SPT heterodimeric complex. Affinity-tagged LCB1 co-precipitated endogenous LCB2, and anti-LCB2 antibody co-immunoprecipitated both SPT enzymatic activity and LCB1, demonstrating the LCB1·LCB2 heterodimer is the functional SPT enzyme. Affinity co-precipitation; co-immunoprecipitation with SPT activity assay; mammalian (CHO) cell mutant complementation The Journal of biological chemistry High 9837968
2002 SPT is an Lcb1p·Lcb2p heterodimer with a single active site at the subunit interface. The PLP cofactor forms a Schiff's base with a conserved lysine in Lcb2p (SPTLC2 ortholog). A conserved histidine in Lcb2p is also critical for PLP binding. Mutations in Lcb1p near this active site dominantly inactivate SPT by ~50% when co-expressed with wild-type, and mutant Lcb1p retains interaction with Lcb2p. Site-directed mutagenesis; yeast genetics; SPT activity assays; structural modeling The Journal of biological chemistry High 11781309
2010 Missense mutations in SPTLC2 (V359M, G382V, I504F) cause HSAN-I by (i) partial to complete loss of canonical SPT activity (palmitoyl-CoA + serine) and (ii) gain of alternative substrate specificity, incorporating alanine instead of serine to produce the neurotoxic metabolite 1-deoxy-sphinganine. This establishes altered substrate specificity as the common pathomechanism for HSAN-I. In vitro SPT activity assay; cell-based activity assay; mass spectrometric sphingolipid profiling in patient cells and plasma American journal of human genetics High 20920666
2010 Endotoxin (LPS) upregulates Sptlc2 mRNA and protein in macrophages via NFκB; the p65 subunit of NFκB directly binds the Sptlc2 promoter (demonstrated by ChIP), leading to increased SPT activity and elevated cellular ceramide and sphingomyelin levels. Sptlc1 is not regulated by this pathway. NFκB pharmacological inhibition; p65 overexpression; promoter analysis; chromatin immunoprecipitation (ChIP); ceramide/sphingomyelin quantification Prostaglandins & other lipid mediators Medium 21167294
2013 The three HSAN-I-associated hLCB2a (SPTLC2) mutations (V359M, G382V, I504F) map to the active site region near the PLP cofactor binding pocket. These mutations reduce affinity for both substrates, perturb PLP cofactor binding, and decrease SPT enzyme activity; the most severe (I504F/G385F in bacterial mimic) causes insoluble protein expression. Activity assays in the presence of small SPT subunits (ssSPTa and ssSPTb) confirmed all three mutations decrease enzyme activity. Bacterial SPT structural mimic mutagenesis; in vitro activity assays with ssSPT subunits; structural modeling based on Sphingomonas paucimobilis SPT crystal structure BioMed research international Medium 24175284
2013 A novel SPTLC2 mutation (A182P) causes HSAN-I with a distinct biochemical profile: reduced canonical SPT activity but markedly increased alternative (alanine-utilizing) activity, producing greatly elevated 1-deoxysphingolipid levels. This confirms alanine mis-incorporation as the shared pathomechanism and demonstrates that different SPTLC2 mutations can differentially affect canonical versus alternative substrate use. Cell-free and cell-based SPT activity assays; plasma 1-deoxysphingolipid quantification by mass spectrometry Neurology Medium 23658386
2019 SPTLC2 expression is induced by antigen stimulation and inflammation in T cells. T-cell-specific Sptlc2 ablation in mice reduces sphingolipid biosynthetic flux, causes prolonged mTORC1 activation, ER stress, and CD8+ T cell death, impairing antiviral T cell expansion and effector function. Supplementing sphingolipids or pharmacologically inhibiting ER stress-induced cell death rescues protective CD8+ T cell responses. T-cell-specific conditional knockout mice; viral infection model; sphingolipid supplementation rescue; pharmacological ER stress inhibition; mTORC1 signaling assays Immunity High 30952607
2022 ER stress upregulates Sptlc2 transcription through the spliced form of XBP1 (sXBP1), which binds the Sptlc2 promoter, increasing SPT activity and ceramide/dihydroceramide levels in hepatocytes. Liver-specific Sptlc2 transgenic mice show elevated hepatic ceramide, elevated fasting glucose, and reduced phosphorylation of insulin receptor β (IRβ), establishing a mechanistic link between SPTLC2-driven ceramide synthesis and hepatic insulin resistance. Promoter analysis; sXBP1 transcriptional activation assay; liver-specific transgenic mice; insulin signaling (IRβ phosphorylation) measurement; ceramide quantification Experimental & molecular medicine Medium 35513574
2024 A recurrent de novo gain-of-function SPTLC2 mutation (c.203T>G, p.Met68Arg) lies within a transmembrane domain and is proposed to render the SPT complex irresponsive to negative regulation by ORMDL3, leading to unrestrained ceramide and complex sphingolipid overproduction in patient plasma and in mutant-expressing HEK cells, causing juvenile ALS. Whole-genome/exome sequencing; sphingolipidomics (LC-HRMS); HEK cell expression of mutant SPTLC2; Sanger sequencing for de novo confirmation Journal of neurology, neurosurgery, and psychiatry Medium 38041684
2024 The SPTLC2 variant p.Glu260Lys (c.778G>A) causes juvenile ALS through excess canonical sphingolipid biosynthesis (elevated ceramides), mechanistically distinct from HSAN-causing SPTLC2 variants (which shift substrate specificity to produce 1-deoxysphingolipids). Serine supplementation—therapeutic in HSAN—is predicted to exacerbate SPT-ALS by further driving sphingolipid overproduction. Clinical genetic testing; plasma and fibroblast sphingolipid measurement; biochemical investigation of patient-derived cells Journal of neurology, neurosurgery, and psychiatry Medium 38041679
2025 A novel SPTLC2 variant (p.T66R) in a transmembrane domain reduces inhibitory regulation of SPT by ORMDL proteins, leading to unrestrained SPT activity and excess sphingolipid production, causing childhood-onset ALS. This functionally differs from HSAN-associated SPTLC2 variants. Whole-exome sequencing; UPLC-MS/MS sphingolipid profiling; mutant cell line functional studies; ORMDL3 regulation assay Journal of neuromuscular diseases Medium 40849231
2024 SPTLC2 directly binds EGFR in ovarian cancer cells (demonstrated by co-immunoprecipitation), and its serine palmitoyltransferase enzymatic activity is required for activation of an EGFR-FAK-HBEGF signaling axis that promotes clonogenic growth, migration, and metastasis. Co-immunoprecipitation (SPTLC2-EGFR); SPTLC2 knockdown and overexpression; in vitro clonogenic and migration assays; in ovo and xenograft metastasis models Oncogene Medium 39645550
2019 SPTLC2 promotes neuronal apoptosis via the TLR4 signaling pathway; co-immunoprecipitation identified physical interaction between SPTLC2 and TLR4 pathway components. miR-124-3p negatively regulates SPTLC2 expression (validated by dual luciferase reporter assay) and suppresses SPTLC2-mediated apoptosis through this pathway. Co-immunoprecipitation; dual luciferase reporter assay; TUNEL staining; western blot; primary neuron injury model Neurochemical research Low 31372925
2025 β-cell-selective deletion of Sptlc2 in mice (Sptlc2ΔIns1) causes marked reductions in ceramide and sphingomyelin levels in islets (despite compensatory upregulation of salvage and sphingomyelinase pathway enzymes), a ~80% loss of β-cell mass, and profound impairment of glucose-regulated insulin secretion and glucose tolerance—establishing that de novo ceramide synthesis via SPTLC2/SPT2 is required for normal β-cell survival and function. β-cell-specific conditional knockout (Cre-lox); metabolic phenotyping; ceramide/sphingomyelin quantification; transcriptomics; histology; glucose tolerance testing bioRxivpreprint Medium bio_10.1101_2025.05.14.653935
2006 The mouse SPTLC2 promoter contains initiator and downstream promoter elements within the proximal 335 bp, including two proximal GC boxes that cooperatively stimulate transcription, as determined by deletion analysis and site-directed mutagenesis of luciferase reporter constructs. Luciferase reporter assay; deletion analysis; site-directed mutagenesis of promoter elements FEBS letters Medium 17070807

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 The LCB2 gene of Saccharomyces and the related LCB1 gene encode subunits of serine palmitoyltransferase, the initial enzyme in sphingolipid synthesis. Proceedings of the National Academy of Sciences of the United States of America 188 8058731
1998 Mammalian cell mutants resistant to a sphingomyelin-directed cytolysin. Genetic and biochemical evidence for complex formation of the LCB1 protein with the LCB2 protein for serine palmitoyltransferase. The Journal of biological chemistry 165 9837968
2010 Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. American journal of human genetics 153 20920666
2002 Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase. The Journal of biological chemistry 92 11781309
1996 Sphingolipid synthesis: identification and characterization of mammalian cDNAs encoding the Lcb2 subunit of serine palmitoyltransferase. Gene 63 8921873
2019 Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness. Immunity 41 30952607
2013 Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2. Neurology 38 23658386
2010 Endotoxin activates de novo sphingolipid biosynthesis via nuclear factor kappa B-mediated upregulation of Sptlc2. Prostaglandins & other lipid mediators 35 21167294
2009 The LCB2 subunit of the sphingolip biosynthesis enzyme serine palmitoyltransferase can function as an attenuator of the hypersensitive response and Bax-induced cell death. The New phytologist 31 19076721
2009 Analysis of development of lesions in mice with serine palmitoyltransferase (SPT) deficiency -Sptlc2 conditional knockout mice-. Experimental animals 24 19897935
2022 Upregulation of the serine palmitoyltransferase subunit SPTLC2 by endoplasmic reticulum stress inhibits the hepatic insulin response. Experimental & molecular medicine 19 35513574
2015 The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy. Neuromolecular medicine 18 26573920
2002 Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy. Neuromuscular disorders : NMD 17 12207934
2019 A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C. Neuromolecular medicine 16 30955194
2024 Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis. Journal of neurology, neurosurgery, and psychiatry 12 38041679
2020 Hepatic Expression of the Serine Palmitoyltransferase Subunit Sptlc2 Reduces Lipid Droplets in the Liver by Activating VLDL Secretion. Journal of lipid and atherosclerosis 11 32821738
2013 The pyridoxal 5'-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT): effects of the small subunits and insights from bacterial mimics of human hLCB2a HSAN1 mutations. BioMed research international 11 24175284
2024 Recurrent de-novo gain-of-function mutation in SPTLC2 confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis. Journal of neurology, neurosurgery, and psychiatry 10 38041684
2023 Mutation screening of SPTLC1 and SPTLC2 in amyotrophic lateral sclerosis. Human genomics 10 36966328
2024 SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis. Annals of clinical and translational neurology 9 38316966
2021 Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort. Journal of the neurological sciences 8 34090020
2019 The Effect of SPTLC2 on Promoting Neuronal Apoptosis is Alleviated by MiR-124-3p Through TLR4 Signalling Pathway. Neurochemical research 7 31372925
2024 SPTLC2 drives an EGFR-FAK-HBEGF signaling axis to promote ovarian cancer progression. Oncogene 5 39645550
2006 Functional characterization of the promoter for the mouse SPTLC2 gene, which encodes subunit 2 of serine palmitoyltransferase. FEBS letters 5 17070807
2025 Puerarin Targets HIF-1α to Modulate Hypoxia-Related Sphingolipid Metabolism in Diabetic Hepatopathy via the SPTLC2/Ceramide Pathway. Pharmaceuticals (Basel, Switzerland) 4 40143173
2023 SPTLC2 ameliorates chondrocyte dysfunction and extracellular matrix metabolism disturbance in vitro and in vivo in osteoarthritis. Experimental cell research 3 36828166
2023 Specific Deoxyceramide Species Correlate with Expression of Macular Telangiectasia Type 2 (MacTel2) in a SPTLC2 Carrier HSAN1 Family. Genes 3 37107689
1997 Serine palmitoyltransferase (scs1/lcb2) mutants have elevated copy number of the L-A dsRNA virus. Yeast (Chichester, England) 2 9133733
2025 Renshenjian decoction alleviates diabetes via HIF-1α/SPTLC2 pathway by targeting ceramide synthesis. Journal of ethnopharmacology 1 40316155
2025 Using multiple computer-predicted structures as molecular replacement models: application to the antiviral mini-protein LCB2. IUCrJ 0 40549150
2025 Characterization of novel and recurrent SPTLC2 variants in childhood-onset amyotrophic lateral sclerosis: Insights into sphingolipid dysregulation. Journal of neuromuscular diseases 0 40849231
2025 Characterization of SPTLC2 as a key driver promoting microglial activation and energy metabolism reprogramming after ischemic stroke through bulk and single-cell analyses combined with experimental validation. Cell biology and toxicology 0 41055763
2025 Fresh Ginseng Reduces Sphingosine Secretion Through Ubiquitin Degradation of SPTLC2 to Antagonize the Progression of Non-Small Cell Lung Cancer. Phytotherapy research : PTR 0 41265852
2025 LuQi formula mitigates ventricular remodeling in myocardial infarction via SPTLC2-regulated de novo ceramide synthesis. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41270392
2012 Cloning, expression and characterization of serine palmitoyltransferase (SPT)-like gene subunit (LCB2) from marine Emiliania huxleyi virus (Coccolithovirus). Acta oceanologica Sinica = Hai yang xue bao 0 32226188

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