Disease relevance of sphingosine

• We studied the metabolism of radioactively labeled safingol (l-threo-dihydrosphingosine) in primary cultured neurons, B104 neuroblastoma cells, and Swiss 3T3 fibroblasts, and compared it to that of its natural stereoisomer d-erythro-dihydrosphingosine [1].
• Events linking disruption of sphingolipid metabolism and fumonisin toxicity are not fully understood; however, Sa and So were shown to bind mouse recombinant peroxisome proliferator-activated receptor alpha (PPARalpha) in vitro [2].
• Using recombinant AtLCBK1 protein from Escherichia coli cells, we confirmed that the enzyme specifically phosphorylated D-erythro-dihydrosphingosine (DHS), but not N-acetyl-DHS or D-threo-DHS [3].
• In adult male rats, dietary exposure to fumonisin induces a significant increase in both SA concentrations and SA/SO ratio in kidney, but not in liver and brain, as well as a significant reduction of body weight gain [4].

High impact information on sphingosine

• Substrate specificity studies were performed, and the enzyme showed the highest activity with d-erythro-sphingosine (Km of 0.16 mol %, and Vmax of 0.3 micromol/min/mg), but d-erythro-dihydrosphingosine and the three unnatural stereoisomers of sphingosine were poor substrates [5].
• Expression of SPHK2 in HEK 293 cells resulted in elevated SPP levels. d-erythro-dihydrosphingosine was a better substrate than d-erythro-sphingosine for SPHK2 [6].
• Hepatotoxicity found in FB1- and CM-fed WT and PPARalpha-null mice was similar, qualitatively different from that found in WY-treated animals, and characterized by increased Sa concentration, apoptosis, and cell proliferation [2].
• This study was conducted to investigate the differential time- and dose-dependent changes in Sa, sphingosine (So), sphinganine 1-phosphate (Sa-1-P), and sphingosine 1-phosphate (So-1-P) in kidney, liver, serum, and heart of male Sprague-Dawley rats (3-4 weeks old) fed diets containing 1.1, 13.5, and 88.6 mug/g of total FB for 10 days [7].
• D-erythro-sphingosine, D-erythro-N,N-dimethylsphingosine (D-erythro-DMS) and D-erythro-dihydrosphingosine (D-erythro-DHS) significantly inhibited mastoparan-, but not Na3VO4-, stimulated arachidonic acid release in PC12 cells [8].

Chemical compound and disease context of sphingosine

• The sphingolipid, sphinganine (Sa), was significantly (P < 0.0001) increased in treated cells but there was no significant difference between the toxic and non-toxic dose levels implying that the increased Sa level alone is not responsible for the in vitro toxicity [9].

Biological context of sphingosine

• This review summarizes current knowledge regarding the role of these sphingolipids metabolites in the actions of growth factors and focuses on the second messenger roles of sphingosine and its metabolite, SPP, in the regulation of cell growth [10].
• The ratio of Sa and So significantly increases in all tissues already after 2-day treatment thus indicating that the metabolism of sphingolipids may have an important role in the DNA damage caused by FB(1) [11].
• Safingol (Saf) is directed against the regulatory domain, whereas chelerythrine (Che) interacts with the catalytic domain of PKC [12].
• The 50% inhibitory concentrations (IC50) were between 3.8-8.6 microM for Saf and 8.5-13.6 microM for Che with no relationship to PKC activity or cisplatin sensitivity of the respective cell lines [12].

Anatomical context of sphingosine

• These results establish that fumonisin B1 and D-erythro-sphinganine allow accelerated passage of macromolecules across the endothelium [13].
• The fact that FB1 alters brain Sa levels and Sa/So ratios indicates that sphingolipid metabolism in the central nervous system of developing rats is vulnerable to FB1 exposure [14].
• FB(1) treatment produces in the forebrain and brainstem: (i) an increase in SA levels and SA/SO ratio, (ii) a reduction in myelin deposition, and (iii) an impairment of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) activity [4].

Associations of sphingosine with other chemical compounds

• The enzyme was found to utilize D-erythro-sphinganine (with half-maximal activity observed at a substrate concentration of approximately 60 microM) and either NADPH (K(m)=33 microM) or NADH (K(m)=58 microM) as substrates [15].
• The ratio of Sa and So concentrations and parameters of oxidative status (catalytic activity of catalase and the concentrations of protein carbonyls and malondialdehyde, MDA) were measured in plasma and liver and kidney homogenates, while DNA damage was measured in liver and kidney using the comet assay [11].

Gene context of sphingosine

• The Sa concentration was significantly (P < 0.01) increased in all the cultures treated with the different structurally related compounds, while only AP1 increased the So concentration significantly (P < 0.05) above the control [16].
• Association of FB1 effects on the offspring with maternal hepatoxicity and with alteration of Sa/So ratio in maternal but not fetal liver supported the earlier claim that FB1 effects on the mouse offspring are mediated by maternal hepatotoxicity [17].

Analytical, diagnostic and therapeutic context of sphingosine

• After cessation of treatment, the Sa/So ratio returned to normal in kidney after a period of 1-3 weeks [18].

References