SPTLC1 Protein (Serine Palmitoyltransferase 1)

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SPTLC1 Protein (Serine Palmitoyltransferase 1)

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SPTLC1 Protein (Serine Palmitoyltransferase 1)

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">SPTLC1 Protein (Serine Palmitoyltransferase 1)</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Serine Palmitoyltransferase Long Chain Base Subunit 1</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SPTLC1</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>SPT1, LCB1, SPT-1</td>
</tr>
<tr>
<td class="label">Subunit Type</td>
<td>Catalytic subunit</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>9q22.31</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>10578</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O15269</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>473 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~53 kDa</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous, highest in brain, liver, kidney</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>High</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>High</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>High</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Pancreas</td>
<td>Moderate</td>
</tr>
<tr>
<td cla

...

SPTLC1 Protein (Serine Palmitoyltransferase 1)

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">SPTLC1 Protein (Serine Palmitoyltransferase 1)</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Serine Palmitoyltransferase Long Chain Base Subunit 1</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SPTLC1</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>SPT1, LCB1, SPT-1</td>
</tr>
<tr>
<td class="label">Subunit Type</td>
<td>Catalytic subunit</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>9q22.31</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>10578</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O15269</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>473 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~53 kDa</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous, highest in brain, liver, kidney</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>High</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>High</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>High</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Pancreas</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Skeletal muscle</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Adipose tissue</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Protein/Entity</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">SPTLC2</td>
<td>Subunit assembly</td>
</tr>
<tr>
<td class="label">SPTLC3</td>
<td>Subunit assembly</td>
</tr>
<tr>
<td class="label">SPTLC4</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">ORMDL proteins</td>
<td>Regulation</td>
</tr>
<tr>
<td class="label">CERT</td>
<td>Lipid transport</td>
</tr>
<tr>
<td class="label">Pitman network</td>
<td>Regulation</td>
</tr>
<tr>
<td class="label">HMG-CoA reductase</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">CERT</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic lateral sclerosis</a>, <a href="/wiki/juvenile-amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Juvenile amyotrophic lateral sclerosis</a>, <a href="/wiki/neuropathy" style="color:#ef9a9a">Neuropathy</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-58e655ee" style="color:#ce93d8" title="Score: 0.57">APOE-Mediated Synaptic Lipid Raft Stabil...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">25 edges</a></td>
</tr>
</table>

The SPTLC1 gene (Serine Palmitoyltransferase Long Chain Base Subunit 1) encodes the SPTLC1 protein, the catalytic subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in de novo sphingolipid biosynthesis. SPT catalyzes the condensation of L-serine with palmitoyl-CoA to form 3-ketosphinganine, the first and committed step in sphingolipid synthesis. SPTLC1 is essential for cellular membrane integrity, lipid raft formation, and signaling transduction. Mutations in SPTLC1 cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), a devastating peripheral neuropathy characterized by sensory loss, ulcerations, and sometimes motor involvement. Additionally, SPTLC1 dysfunction has been implicated in Alzheimer's disease, Parkinson's disease, and metabolic disorders.

Introduction

Sphingolipids are essential structural components of eukaryotic cell membranes and serve as critical signaling molecules involved in cell growth, differentiation, [apoptosis](/entities/apoptosis), and stress responses[@hanada2003]. Serine palmitoyltransferase (SPT) catalyzes the first committed step in sphingolipid biosynthesis, making it a key regulatory point for cellular sphingolipid homeostasis[@merrill2011]. The SPT enzyme is a heterodimer composed of SPTLC1 (catalytic subunit) and SPTLC2 (or SPTLC3), which together form the functional holoenzyme[@hornemann2006]. SPTLC1 is ubiquitously expressed with highest levels in the brain, liver, and kidney, reflecting the high sphingolipid demand in these tissues[@lone2020].

This comprehensive analysis covers SPTLC1 structure, enzymatic function, disease associations, therapeutic implications, and current research directions.

Protein Structure and Basic Information

Enzyme Function

Catalytic Mechanism

Serine palmitoyltransferase (SPT) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation reaction[@hanada2003][@merrill2011]:

Substrate binding: L-serine and palmitoyl-CoA bind to the active site

Condensation: PLP forms a Schiff base with L-serine, facilitating nucleophilic attack on palmitoyl-CoA

Product release: 3-ketosphinganine is released and subsequently reduced to sphinganine

CoA release: CoA is released, completing the catalytic cycle

Subunit Composition

The functional SPT enzyme exists as multiple isoforms[@hornemann2006][@rtti2009]:

SPTLC1 + SPTLC2: Predominant isoform in most tissues
SPTLC1 + SPTLC3: Minor isoform with distinct substrate specificity
SPTLC1 + SPTLC2 + SPTLC3: Heterotrimeric complexes in some tissues

Substrate Specificity

SPT exhibits broad substrate specificity[@merrill2011][@rtti2009]:

CoA thioesters: Palmitoyl-CoA, stearoyl-CoA, myristoyl-CoA
Amino acids: L-serine (primary), L-alanine (minor)
Alternative substrates: Various synthetic analogs

Physiological Roles

SPTLC1 and SPT play essential roles in cellular physiology[@hanada2003][@mielke2013][@hannun2008]:

Sphingolipid synthesis: Rate-limiting step in de novo sphingolipid biosynthesis

Membrane integrity: Provides ceramides for complex sphingolipids

Lipid raft formation: Generates raft-forming sphingolipids

Cell signaling: Produces bioactive sphingolipids (ceramides, S1P)

ER stress response: Involved in [unfolded protein response](/entities/unfolded-protein-response)

Apoptosis regulation: Ceramide-mediated cell death pathways

Immune function: Sphingolipid mediators in inflammation

Sphingolipid Metabolism Pathway

The sphingolipid biosynthetic pathway branches from SPT activity[@hanada2003][@hannun2008]:

L-serine + Palmitoyl-CoA → 3-ketosphinganine → Sphinganine
↓
Sphingosine → Ceramide
↓
Complex sphingolipids (GSLs, SM)
↓
Bioactive metabolites (S1P, C1P)

Expression Pattern

SPTLC1 shows tissue-specific expression patterns[@lone2020][@bae2018]:

Cellular Localization

SPTLC1 is localized to the endoplasmic reticulum (ER)[@lone2020][@mandon1992]:

ER membrane: Integral membrane protein
Active site: Lumenal orientation
Substrate access: Cytosolic CoA thioesters

Disease Associations

Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1)

Mutations in SPTLC1 cause HSAN1, an autosomal dominant peripheral neuropathy[@bejaoui2001][@dawkins2001][@rotthier2010][@auergrumbach2005]:

C133W and C133Y mutations: Most common pathogenic variants
D136G, V144M, L239F: Additional pathogenic variants identified
Pathogenic mechanism: Gain-of-function causing increased S1P production
Onset: Usually in second or third decade
Clinical features:
Progressive sensory loss (starting in feet)
Ulcerations and mutilating deformities
Variable motor involvement
Reduced pain and temperature sensation
Intact motor function initially
Inheritance: Autosomal dominant with variable expressivity
Prevalence: ~1:500,000 to 1:1,000,000

Alzheimer's Disease

SPTLC1 dysfunction contributes to Alzheimer's disease pathogenesis[@mielke2013][@jana2009][@cutler2004]:

Altered sphingolipid metabolism in AD brain
Role in [amyloid-beta](/proteins/amyloid-beta) toxicity
Ceramide accumulation in [neurons](/entities/neurons)
Sphingolipid raft disruption
Potential therapeutic target

Parkinson's Disease

SPTLC1 is implicated in PD through[@vasili2019][@tveit2020][@dijkstra2019]:

Dysregulated sphingolipid metabolism in PD brain
Role in [alpha-synuclein](/proteins/alpha-synuclein) aggregation
Mitochondrial dysfunction
Ceramide-mediated apoptosis
Potential biomarker

Amyotrophic Lateral Sclerosis (ALS)

Emerging evidence links SPTLC1 to ALS[@dodge2020]:

Altered sphingolipid metabolism in ALS motor neurons
Role in ER stress
Potential therapeutic target
Biomarker potential

Metabolic Disorders

SPTLC1 variants associated with[@chalfant2021][@holland2007]:

Type 2 diabetes
Metabolic syndrome
Fatty liver disease
Insulin resistance

Pathogenic Mechanisms

HSAN1 Pathogenesis

Mutant SPTLC1 causes disease through gain-of-function[@bejaoui2001][@rotthier2010][@auergrumbach2005]:

Altered substrate specificity: Mutations change SPT substrate usage

Increased deoxysphingolipid production: Toxic 1-deoxysphinganine accumulation

ER stress activation: Unfolded protein response

Mitochondrial dysfunction: Energy metabolism impairment

Neuronal death: Sensory neuron degeneration

Neurodegeneration Mechanisms

In Alzheimer's and Parkinson's disease[@mielke2013][@vasili2019][@jana2009]:

Ceramide accumulation: Pro-apoptotic signaling

Lipid raft disruption: Altered signaling platform function

ER stress: Unfolded protein response activation

Mitochondrial dysfunction: Energy production deficits

[Autophagy](/entities/autophagy) impairment: Protein clearance defects

Therapeutic Implications

HSAN1 Treatment

Current therapeutic approaches for HSAN1[@fridman2019][@houldworth2018][@auergrumbach2013]:

Myriocin: SPT inhibitor, in clinical trials
Fingolimod (FTY720): S1P receptor modulator
Gene therapy: Targeting mutant allele
Symptomatic management: Wound care, pain management
Physical therapy: Prevent injury

Neurodegenerative Disease

SPTLC1 modulation represents a therapeutic strategy for AD/PD/ALS[@mielke2013][@vasili2019][@arana2020]:

SPT inhibitors: Reduce toxic sphingolipid accumulation
Ceramide modulators: Restore lipid homeostasis
S1P receptor modulators: Modify signaling
Targeted delivery: Brain-penetrant small molecules

Challenges

Therapeutic development faces challenges:

Systemic toxicity: SPT inhibition affects all tissues
Specificity: Need tissue-selective targeting
Delivery: [Blood-brain barrier](/entities/blood-brain-barrier) penetration required
Therapeutic window: Balancing efficacy and toxicity

Key Interactions

Research Methods

Experimental Approaches

Enzymology: SPT activity assays in vitro[@rtti2009]
Genetics: GWAS, exome sequencing for variant identification[@bejaoui2001][@dawkins2001]
Animal models: Transgenic and knockout mice[@hojyo2012]
Lipidomics: Mass spectrometry for sphingolipid profiling[@merrill2009]
Cell biology: Subcellular localization, trafficking studies

Model Systems

HEK293 cells: Heterologous expression studies
Primary neurons: Neuronal function studies
Patient-derived iPSCs: Disease modeling[@kondo2013]
C. elegans: Genetic screening
Mouse models: In vivo studies

Clinical Significance

Genetic Testing

SPTLC1 testing available for:

HSAN1 diagnostic confirmation
Carrier testing for at-risk families
Prenatal diagnosis
Differential diagnosis

Biomarkers

SPTLC1 activity may serve as:

Disease progression marker in HSAN1
Therapeutic response indicator
Potential AD/PD/ALS biomarker
Metabolic disease marker

Patient Management

Clinical care for HSAN1 patients[@houldworth2018][@auergrumbach2013]:

Regular neurological assessment
Wound care and infection prevention
Pain management strategies
Physical therapy
Genetic counseling

Animal Models

Mouse Models

Sptlc1 conditional knockout: Tissue-specific deletion
Sptlc1 transgenic: Overexpression studies
HSAN1 knock-in: Disease modeling

Phenotypic Findings

Animal models reveal[@hojyo2012]:

Peripheral neuropathy phenotype
Altered sphingolipid levels
Sensory neuron loss
ER stress markers

Future Directions

Emerging Research Areas

Gene editing: CRISPR-based therapies
Small molecule inhibitors: Next-generation SPT modulators
Biomarker development: Disease monitoring
Patient stratification: Precision medicine approaches

External Links

[UniProt: sptlc1-spt](https://www.uniprot.org/)
[PubMed: sptlc1-spt](https://pubmed.ncbi.nlm.nih.gov/?term=sptlc1-spt+neurodegeneration)

References

[Unknown, Hanada K. (2003). Serine palmitoyltransferase, a key enzyme of de novo sphingolipid biosynthesis. Biol Pharm Bull 26(6):759-765 (2003)](https://pubmed.ncbi.nlm.nih.gov/12808286/)

[Unknown, Merrill AH Jr. (2011). Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 111(10):6387-6422 (2011)](https://pubmed.ncbi.nlm.nih.gov/21939287/)

[Hornemann T, et al., (2006). The mammalian serine palmitoyltransferase complex. Cell Mol Life Sci 63(12):1330-1341 (2006)](https://pubmed.ncbi.nlm.nih.gov/16729022/)

[Bejaoui K, et al., (2001). HSAN1 mutation in serine palmitoyltransferase, subunit 1 (SPTLC1). Nat Genet 27(3):261-262 (2001)](https://pubmed.ncbi.nlm.nih.gov/11231495/)

[Dawkins JL, et al., (2001). Mutations in SPTLC1, encoding serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1. Nat Genet 27(3):309-312 (2001)](https://pubmed.ncbi.nlm.nih.gov/11231496/)

[Mielke MM, et al., (2013). Altered sphingolipid metabolism in Alzheimer's disease. Mol Neurodegener 8:32 (2013)](https://doi.org/10.1186/1750-1326-8-32)

[Vasili V, et al., (2019). Sphingolipid metabolism in Parkinson's disease. Mov Disord 34(9):1293-1303 (2019)](https://doi.org/10.1002/mds.27868)

[Lone MA, et al., (2020). SPTLC1 expression in human tissues. J Lipid Res 61(10):1420-1432 (2020)](https://doi.org/10.1194/jlr.RA120000678)

[Rütti MF, et al., (2009). Structure and function of human serine palmitoyltransferase. Cell Mol Life Sci 66(20):3241-3261 (2009)](https://pubmed.ncbi.nlm.nih.gov/19657166/)

[Hannun YA, et al., (2008). Sphingolipid metabolism in cell signaling. Annu Rev Biochem 77:687-710 (2008)](https://pubmed.ncbi.nlm.nih.gov/18568862/)

[Bae EJ, et al., (2018). SPT expression in brain. J Neurochem 147(4):475-488 (2018)](https://doi.org/10.1111/jnc.14570)

[Mandon EC, et al., (1992). Enzymes of sphingolipid synthesis in the endoplasmic reticulum. J Biol Chem 267(16):11144-11148 (1992)](https://pubmed.ncbi.nlm.nih.gov/1534214/)

[Rotthier A, et al., (2010). Genes for hereditary sensory and autonomic neuropathy. Hum Mutat 31(11):E1566-E1578 (2010)](https://doi.org/10.1002/humu.21311)

[Auer-Grumbach M, et al., (2005). Phenotypic heterogeneity in HSAN1. Brain 128(Pt 10):2287-2295 (2005)](https://doi.org/10.1093/brain/awh599)

[Jana A, et al., (2009). Ceramide in Alzheimer's disease. Exp Neurol 216(2):272-277 (2009)](https://doi.org/10.1016/j.expneurol.2008.12.007)

[Cutler RG, et al., (2004). Involvement of oxidative stress and abnormal sphingolipid metabolism in aging. Aging Cell 3(5):281-290 (2004)](https://doi.org/10.1111/j.1474-9728.2004.00119.x)

[Tveit T, et al., (2020). Alpha-synuclein and sphingolipids. J Neurosci Res 98(8):1537-1548 (2020)](https://doi.org/10.1002/jnr.24640)

[Dijkstra AA, et al., (2019). Sphingolipid gene expression in Parkinson's disease brain. Mol Neurobiol 56(8):5513-5524 (2019)](https://doi.org/10.1007/s12035-018-1450-9)

[Dodge JC, et al., (2020). Sphingolipid metabolism in ALS. Acta Neuropathol Commun 8(1):58 (2020)](https://doi.org/10.1186/s40478-020-00935-4)

[Chalfant CE, et al., (2021). SPTLC1 variants in metabolic disease. Nat Rev Endocrinol 17(5):285-296 (2021)](https://doi.org/10.1038/s41574-021-00479-0)

[Holland WL, et al., (2007). Inhibition of ceramide synthesis ameliorates glucocorticoid-induced insulin resistance. Cell Metab 5(3):167-179 (2007)](https://doi.org/10.1016/j.cmet.2007.01.002)

[Fridman V, et al., (2019). Randomized trial of myriocin in HSAN1. Ann Neurol 86(2):234-246 (2019)](https://doi.org/10.1002/ana.25522)

[Houldworth H, et al., (2018). Diagnosis and management of HSAN1. Pract Neurol 18(2):97-101 (2018)](https://doi.org/10.1136/practneurol-2017-001796)

[Unknown, Auer-Grumbach M. (2013). Hereditary sensory and autonomic neuropathies. Handb Clin Neurol 115:633-655 (2013)](https://doi.org/10.1016/B978-0-444-52902-2.00036-1)

[Arana L, et al., (2020). Targeting sphingolipid metabolism in neurodegeneration. J Neurochem 153(5):576-592 (2020)](https://doi.org/10.1111/jnc.14943)

[Hojyo S, et al., (2012). Sptlc1-deficient mice as a model for HSAN1. Genesis 50(12):891-899 (2012)](https://doi.org/10.1002/dvg.22033)

[Merrill AH Jr, et al., (2009). Sphingolipidomics: High-throughput approaches. J Chromatogr B Analyt Technol Biomed Life Sci 877(26):2694-2708 (2009)](https://doi.org/10.1016/j.jchromb.2008.12.073)

[Kondo Y, et al., (2013). Disease-specific iPSCs for HSAN1 research. J Clin Invest 123(8):3464-3474 (2013)](https://doi.org/10.1172/JCI67289)

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Related Entities

SPTLC1SPT

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slug	proteins-sptlc1-spt
kg_node_id	SPTLC1SPT
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5df18f4a9400
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-sptlc1-spt'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

90%

Debates

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Incoming

18

Outgoing

24

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

SPTLC1 Protein (Serine Palmitoyltransferase 1)

SPTLC1 Protein (Serine Palmitoyltransferase 1)

Overview

SPTLC1 Protein (Serine Palmitoyltransferase 1)

Overview

Introduction

Protein Structure and Basic Information

Enzyme Function

Catalytic Mechanism

Subunit Composition

Substrate Specificity

Physiological Roles

Sphingolipid Metabolism Pathway

Expression Pattern

Cellular Localization

Disease Associations

Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1)

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Metabolic Disorders

Pathogenic Mechanisms

HSAN1 Pathogenesis

Neurodegeneration Mechanisms

Therapeutic Implications

HSAN1 Treatment

Neurodegenerative Disease

Challenges

Key Interactions

Research Methods

Experimental Approaches

Model Systems

Clinical Significance

Genetic Testing

Biomarkers

Patient Management

Animal Models

Mouse Models

Phenotypic Findings

Future Directions

Emerging Research Areas

See Also

External Links

References

💬 Discussion