Complex
sphingolipids are 'built' on highly bioactive backbones (sphingoid bases and
ceramides) that can cause cell death when the amounts are elevated by turnover of complex
sphingolipids, disruption of normal
sphingolipid metabolism, or over-induction of
sphingolipid biosynthesis de novo. Under normal conditions, it appears that the bioactive intermediates of this pathway (3-ketosphinganine,
sphinganine and
ceramides) are kept at relatively low levels. Both the intrinsic activity of
serine palmitoyltransferase (SPT) and the availability of its substrates (especially
palmitoyl-CoA) can have toxic consequences for cells by increasing the production of cytotoxic intermediates. Recent work has also revealed that diverse agonists and stresses (
cytokines, UV light,
glucocorticoids, heat shock and toxic compounds) modulate SPT activity by induction of SPTLC2 gene transcription and/or post-translational modification. Mutation of the SPTLC1 component of SPT has also been shown to cause
hereditary sensory neuropathy type I, possibly via aberrant oversynthesis of
sphingolipids. Another key step of the pathway is the acylation of
sphinganine (and
sphingosine in the recycling pathway) by
ceramide synthase, and up-regulation of this
enzyme (or its inhibition to cause accumulation of
sphinganine) can also be toxic for cells. Since it appears that most, if not all, tissues synthesize
sphingolipids de novo, it may not be surprising that disruption of this pathway has been implicated in a wide spectrum of disease.