Serine palmitoyltransferase long chain base subunit 2 - rate-limiting enzyme in sphingolipid synthesis
SPTLC2 (Serine Palmitoyltransferase Long Chain Base Subunit 2) is a key enzyme in sphingolipid biosynthesis. [1]
| Gene | [SPTLC2](/genes/sptlc2) |
| UniProt | [UniProt:O15230](https://www.uniprot.org/uniprot/O15230) |
| PDB IDs | [PDB:2JFX](https://www.rcsb.org/structure/2JFX), [PDB:5UV6](https://www.rcsb.org/structure/5UV6), [PDB:6G97](https://www.rcsb.org/structure/6G97) |
| Molecular Weight | 62 kDa |
| Localization | Endoplasmic reticulum (ER) membrane |
| Protein Family | Serine palmitoyltransferase family |
SPTLC2 contains the catalytic domain that binds pyridoxal phosphate (PLP) as a cofactor. The enzyme forms a heterodimer with SPTLC1, and both subunits are required for functional enzyme activity. The transmembrane regions anchor the protein to the ER membrane.
SPTLC2 undergoes N-glycosylation and is subject to regulation by phosphorylation.
Serine palmitoyltransferase (SPT) catalyzes the first and rate-limiting step in de novo sphingolipid biosynthesis, condensing palmitoyl-CoA with serine to form 3-ketosphinganine. SPTLC2 is the catalytic subunit that forms a heterodimer with SPTLC1. Sphingolipids are essential components of neuronal membranes, lipid rafts, and myelin sheaths. In the nervous system, SPT activity regulates ceramide and sphingosine-1-phosphate levels that control neuronal survival, axonal guidance, and synaptic function [1].
Mutations in SPTLC2 cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), characterized by loss of pain and temperature sensation, ulcers, and motor complications [2]. These mutations alter SPT substrate specificity, leading to accumulation of toxic deoxysphingolipids that are neurotoxic. Elevated ceramide levels from dysregulated SPT activity contribute to neurodegeneration in Alzheimer's disease through promoting amyloid-beta aggregation and synaptic dysfunction [3]. SPTLC2 variants have also been implicated in Parkinson's disease risk.
Myriocin and other SPT inhibitors reduce toxic deoxysphingolipid accumulation and are being explored for HSAN1 treatment [4]. Substrate reduction therapy using SPT modulators shows promise in preclinical neurodegeneration models. Small interfering RNA approaches to silence mutant SPTLC2 alleles are under development.
Bode et al. SPTLC2 mutations cause hereditary sensory neuropathy type 1 (2010). 2010. ↩︎