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1-Deoxysphingolipids (1-deoxySLs)

Summary

1-Deoxysphingolipids (1-deoxySLs) are atypical, bioactive lipids formed when serine palmitoyltransferase (SPT) mis-incorporates L-alanine instead of L-serine during the first step of de novo sphingolipid synthesis. Lacking the C1-hydroxyl group of canonical sphingolipids, 1-deoxySLs cannot be converted into complex sphingolipids or degraded by standard catabolic pathways, leading to toxic intracellular accumulation. Their synthesis and subsequent elongation by ELOVL1 and CERS2 drive neurotoxicity, causing conditions such as Hereditary Sensory Neuropathy Type 1 (HSAN1).

Synthesis and Metabolism

The synthesis of 1-deoxySLs begins with the condensation of palmitoyl-CoA and L-alanine (catalyzed by SPT), yielding 1-deoxysphinganine (1-deoxySa, m18:0). - Elongation and Acylation: Like canonical sphinganine, 1-deoxySa is acylated by ceramide synthases (CERS) to form 1-deoxydihydroceramides (1-deoxyDHCer, m18:0/xx:y). - Desaturation: Unlike canonical DHCer, which is converted to ceramide by DEGS1, 1-deoxyDHCer is not a substrate for DEGS1. Instead, it is desaturated by fatty acyl desaturase 3 (FADS3), introducing a $\Delta 14Z$ double bond to form 1-deoxysphingosine (1-deoxySo) derivatives. - Degradation Resistance: The lack of the C1-hydroxyl group prevents the phosphorylation of 1-deoxySLs into sphingosine-1-phosphate (S1P), rendering them resistant to degradation by S1P lyase.

Mechanisms of Toxicity

A CRISPRi screen identified the fatty acid elongation pathway—specifically ELOVL1 (elongation of very long-chain fatty acids protein 1) and CERS2 (ceramide synthase 2)—as primary drivers of 1-deoxySL toxicity. - Very Long-Chain 1-deoxyDHCer: The toxicity of 1-deoxySa is mediated by its conversion to very long-chain (VLC) species, particularly nervonyl-1-deoxyDHCer (m18:0/24:1) and lignoceryl-1-deoxyDHCer (m18:0/24:0). - Mitochondrial Dysfunction: Accumulation of VLC 1-deoxyDHCer disrupts mitochondrial membrane integrity, triggering the opening of the mitochondrial permeability transition pore (mPTP) and BAX-mediated apoptotic cell death. - Therapeutic Targets: Pharmacological or genetic inhibition of ELOVL1 (e.g., using ELOVL1 inhibitor Compound 22) or CERS2 prevents VLC 1-deoxyDHCer accumulation and rescues cellular/neuronal models from toxicity.

  • Hornemann Lab — investigates atypical sphingolipid synthesis, metabolism and toxicity.

Citations

  • Majcher, A., Karsai, G., Yusifov, E., Schaettin, M., Malagola, E., Horvath, P., Li, J., Rodriguez-Gallardo, S., Shimizu, K., Zhibo, G., Dubey, R., Peterson, T., Harayama, T., & Hornemann, T. (2025). Very long-chain fatty acids drive 1-deoxySphingolipid toxicity. Nature Communications, 16:11650. Source paper: 41467_2025_Article_66687.pdf