Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption.
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.
Linn
S C
SC
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kim
H S
HS
Keane
E M
EM
Andras
L M
LM
Wang
E
E
Merrill
A H
AH
D000217:Acyltransferases / Q000502:physiology; D000818:Animals; D006801:Humans; D008954:Models, Biological; D010088:Oxidoreductases / Q000502:physiology; D051102:Serine C-Palmitoyltransferase; D013107:Sphingolipids / Q000096:biosynthesis*
D013107:Sphingolipids; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D000217:Acyltransferases; C495089:SPTLC2 protein, human; D051102:Serine C-Palmitoyltransferase