Fungal toxicity: Based in sphinganine

Lipidomics Gateway (1 May 2009) [doi:10.1038/lipidmaps.2009.5]

Ceramide synthases are inhibited by a family of cereal mold toxins, fumonisins, causing accumulation of a novel category of sphingoid base with potential for cell signaling

Sphingolipids are synthesized by acylation of sphingoid bases by ceramide synthases, enzymes that are potently inhibited by fumonisins. These mycotoxins cause accumulation of sphingoid bases, with toxic and carcinogenic consequences in farm animals and possibly humans. Now Riley and colleagues, in collaboration with the LIPID MAPS consortium, have characterized a novel category of sphingoid base, 1–deoxysphinganine, that accumulates after exposure to fumonisin. Reporting in the Journal of Biological Chemistry, they show that 1–deoxysphinganine and its N–acyl derivatives are normally produced in mammalian cells and are increased when levels of serine fall relative to alanine, with potential downstream signaling or metabolic consequences.

Structures of sphinganine and 1-deoxy-sphinganine, plus a scheme for the biosynthesis of 1-deoxySa and its accumulation in cells exposed to fumonisin B₁.

The toxicity of fumonisins, particularly in liver and kidney, is attributed to accumulation of sphinganine and sphingosine owing to blocked conversion of these bases to ceramides, dihydroceramides and other sphingolipids. A mystery peak in the chromatograms of extracts from fumonisin-treated cells suggested that a novel sphingoid base was also accumulating. Riley and colleagues found that both sphinganine and this unidentified compound failed to accumulate when serine palmitoyltransferase (SPT) was inhibited. SPT catalyzes condensation of serine with palmitoyl-CoA in the production of sphinganine. Mass spectrometry confirmed that the peak was produced by a sphingoid base, 1-deoxysphinganine (1-deoxySa). Although existing in other organisms, this base was previously only detected in mammalian cells with a defect in the SPTLC1 gene, the basis for hereditary sensory neuropathy type 1. This study detected it in a range of mammalian cell lines, and in mice treated with fumonisin. With the use of SPT-deficient cell lines and isotope-labeled substrates, the team confirmed that 1-deoxySa is produced by SPT, surprisingly with the use of alanine rather than serine.

Ceramide synthase activity converts 1-deoxySa to 1-deoxy-dihydroceramide (1-deoxyDHCer). Analysis of ceramide species with and without fumonisin treatment and the addition of exogenous 1-deoxySa indicated that cells usually produce substantial amounts of the latter, but that it is acylated to 1-deoxyDHCer. The study showed that the cellular toxicities of 1-deoxySa and sphinganine were comparable, although 1-deoxySa was more cytotoxic in a prostate cancer cell line. Both bases accumulated to a similar extent in the livers of mice fed with fumonisin, suggesting that both compounds may contribute to the toxicity of fumonisins.

The missing hydroxyl group of 1-deoxySa removes a phosphorylation site that is necessary for catabolism of sphinganine and sphingosine. Likewise, 1-deoxyDHCer might be desaturated to 1-deoxyceramides but it cannot lead to formation of the usual complex sphingolipids. The metabolic fate of these compounds is therefore unknown but they could have effects on membrane structure or cell signaling. As 1-deoxySa is preferentially formed by SPT when levels of serine are reduced compared with alanine, this could represent a serine-sensing system worthy of further investigation.

Emma Leah