Regulation of de novo sphingolipid biosynthesis and the toxic consequencesof its disruption

Complex sphingolipids are 'built' on highly bioactive backbones (sphingoid bases and ceramides) that can cause cell death when the amounts are elevate d by turnover of complex sphingolipids, disruption of normal sphingolipid m etabolism, or over-induction of sphingolipid biosynthesis de novo. Under no rmal conditions, it appears that the bioactive intermediates of this pathwa y (3-keto-sphinganine, sphinganine and ceramides) are kept at relatively lo w 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 inte rmediates. Recent work has also revealed that diverse agonists and stresses (cytokines, UV light, glucocorticoids, heat shock and toxic compounds) mod ulate SPT activity by induction of SPTLC2 gene transcription and/or post-tr anslational modification. Mutation of the SPTLC1 component of SPT has also been shown to cause hereditary sensory neuropathy type I, possibly via aber rant oversynthesis of sphingolipids. Another key step of the pathway is the acylation of sphinganine (and sphingosine in the recycling pathway) by cer amide synthase, and up-regulation of this enzyme (or its inhibition to caus e accumulation of sphinganine) can also be toxic for cells. Since it appear s that most, if not all, tissues synthesize sphingolipids de novo, it may n ot be surprising that disruption of this pathway has been implicated in a w ide spectrum of disease.