deoxysphingolipids

Deoxysphingolipids are a class of sphingolipids distinguished by the absence of the C1 hydroxyl group on the sphingoid base. They include 1-deoxysphinganine and related molecules that can be N-acylated to form deoxydihydroceramides, but they do not enter the normal pathways to create mature complex sphingolipids such as ceramides, sphingomyelins, or glycosphingolipids.

Biosynthesis of deoxysphingolipids occurs when the enzyme serine palmitoyltransferase (SPT) uses non-serine substrates, most notably alanine or glycine, instead of serine. This noncanonical condensation yields 1-deoxysphinganine, which can be further acylated by ceramide synthases to produce various deoxydihydroceramides. The lack of the C1 hydroxyl group prevents typical downstream processing, leading to accumulation of these atypical sphingolipids.

Clinically, deoxysphingolipids are relevant as biomarkers and potential mediators of disease. Elevated plasma levels are characteristic of hereditary sensory and autonomic neuropathy type 1 (HSAN1), particularly in individuals with mutations in SPTLC1 or SPTLC2 that increase substrate promiscuity. They are also observed in metabolic conditions such as diabetes and may correlate with neuropathic symptoms. Their accumulation is thought to contribute to cellular dysfunction and neurotoxicity, in part by perturbing membrane properties and signaling.

Research and therapeutic implications focus on reducing deoxysphingolipid production or mitigating their effects. Strategies include restoring serine availability to favor canonical SPT activity, though results vary across models and patients. Deoxysphingolipids remain a topic of active investigation in sphingolipid biology and neuropathy.