Disease relevance of Dihydrosphingosine

• A Bacillus subtilis mutant spnA95 was isolated as resistant at 30 degrees C to the protein kinase C (PKC) inhibitor, sphinganine, and temperature sensitive for growth [1].
• Priming was not altered by pertussis toxin or intracellular calcium chelation, but the PAF receptor antagonist WEB 2086 and the protein kinase C (PKC) inhibitors sphinganine and staurosporine significantly inhibited the primed response [2].
• Our previous work has shown that a number of sphingolipid metabolites including sphingosine, sphinganine, and other long-chain bases potently induced apoptosis in human hepatoma cells [3].
• The results show that the traditional method reduced the total fumonisins in tortillas and reduced the sphinganine elevation (a biomarker closely correlated with fumonisin toxicity) in cells treated with extracts of tortillas compared with cells treated with extracts of contaminated maize [4].
• Washed cells of Bacteroides melaninogenicus are unable to incorporate the sphingolipid precursor 3-ketodihydrosphingosine (3KDS) or dihydrosphingosine into the complete sphingolipids ceramide phosphorylethanolamine (CPE) and ceramide phosphorylglycerol (CPG), whereas growing cultures are able to do so [5].

High impact information on Dihydrosphingosine

• In Arnt-null epidermis, 4-sphingenine was largely replaced by sphinganine and the amounts of ceramides with 4-hydroxysphinganine were greatly decreased, suggesting deficiency of dihydroceramide desaturases that catalyze the formation of both 4-sphingenyl and 4-hydroxysphinganyl moieties [6].
• Compared with vehicle-treated controls, gammaT treatment led to pronounced dihydroceramide and dihydrosphingosine accumulation, which preceded morphological and biochemical manifestations of apoptosis [7].
• Structurally, these mycotoxins resemble the sphingoid bases, sphingosine and sphinganine, that are reported to play critical roles in cell communication and signal transduction [8].
• Fusarium moniliforme toxins (fumonisins) and Alternaria alternata lycopersici (AAL) toxins are members of a new class of sphinganine analog mycotoxins that occur widely in the food chain [8].
• In the present study, we investigated the mechanism by which sphingosine and its analogues, dihydrosphingosine and phytosphingosine, inhibit polymorphonuclear leukocyte (PMN) phagocytosis of IgG-opsonized erythrocytes (EIgG) and inhibit ERK1 and ERK2 phosphorylation [9].

Chemical compound and disease context of Dihydrosphingosine

• Sphingosine and other long-chain bases (including sphinganine, dimethylsphingosine and stearylamine), but not octylamine (a short-chain analogue of sphinganine), induced apoptosis in Hep3B hepatoma cells [10].
• In this study the disruption in sphinganine (Sa) and sphingosine (So) levels in plasma and urine was measured in vervet monkeys (Cercopithecus aethiops) dosed with repeated gavages of 1mg fumonisin B1 (FB1)/kg body weight three times/week continuously over a 51-day period [11].
• Exogenous sphingosylphosphocholine analogues and naturally occurring sphingomyelin stimulated the neurite outgrowth in cultured murine neuroblastoma cell lines, NS-20Y, Neuro2a, and N1E-115, whereas exogenous sphinganine at a non-cytotoxic concentration inhibited the neurite outgrowth in NS-20Y and Neuro2a cells [12].
• Type C Niemann-Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver [13].
• When Bacteroides was grown in a medium supplemented with labelled palmitic acid, this fatty acid was utilized for acylation reactions and to a large extent for the de novo synthesis of sphinganine [14].

Biological context of Dihydrosphingosine

• We now report that another PKC inhibitor, sphinganine, also inhibits the effect of TPA on action potential height and calcium current in cultured bag cell neurons, and that N-acetylsphinganine, an inactive sphinganine analog, fails to inhibit the effects of PKC activators [15].
• Consistently, reduction of free sphinganine levels stimulates cell polarity development [16].
• In addition, there was no effect of sphinganine on cell viability in this concentration range [17].
• They stimulated PMN to increase the availability of PDB binding sites by a sphinganine-sensitive mechanism, but their actions differed from those of ionophores [18].
• After 24 h, low concentrations of sphinganine (1-5 microM blocked both cell adherence and the inhibition of growth in response to phorbol 12-myristate 13-acetate, as measured by cell number and acid phosphatase activity [19].

Anatomical context of Dihydrosphingosine

• Conditions were developed to prolong the ability of sphinganine, a potent inhibitor of protein kinase C, to block the phorbol ester-induced adherence of HL-60 cells beyond 24 h [20].
• Nonselective inhibition of neutrophil functions by sphinganine [21].
• Thus, established cell lines whose growth is very sensitive to long-chain amino alcohols can be cultivated with sphinganine (sphingosine) analogues at concentrations which suppress endogenous sphinganine production but support continued synthesis of complex sphingolipids [22].
• Fumonisin B1 inhibited ceramide synthase in mouse brain microsomes with a competitive-like kinetic behavior with respect to both sphinganine and stearoyl-CoA [23].
• Furthermore, the suppression of CYP2C11 by C2-Cer (and C2-DHCer) is probably mediated by free sphingoid bases, rather than the short chain Cer directly, because both are hydrolyzed by hepatocytes and increase cellular levels of sphingosine and sphinganine [24].

Associations of Dihydrosphingosine with other chemical compounds

• Both FB1 and, to a lesser extent, AP1 inhibit ceramide synthase due to structural similarities between fumonisins (as 1-deoxy-analogs of sphinganine) and sphingoid bases [25].
• Surprisingly, both the synthetic threo- isomer and the naturally occurring erythro- isomer of dihydrosphingosine and sphingosine (D-erythro-sphingosine, L-threo-sphingosine, DL-threo-dihydrosphingosine, and DL-erythro-dihydrosphingosine) were readily phosphorylated in intact Swiss 3T3 cells [26].
• In this report we demonstrated that sphinganine, an inhibitor of PKC that is mechanistically and structurally distinct from 1-(5-isoquinoline sulfonyl)-2-methylpiperazine-HCl (H-7), also blocks 1,25-(OH)2D3 induction of HL-60 cell differentiation [27].
• Furthermore, sphinganine inhibited exocytosis elicited by the calcium ionophore ionomycin [21].
• Using stereoisomers of dihydrosphingosine, together with specific inhibitors and a mutant defective for sphingolipid synthesis, we now show that ceramides and/or inositol sphingolipids are indispensable for GPI-anchored protein transport [28].

Gene context of Dihydrosphingosine

• DPL1, the structural gene for dihydrosphingosine phosphate lyase, was selected as a high copy number snc1-M43A suppressor [29].
• In contrast to YPC1p, YDC1p had only minor in vitro reverse activity of catalyzing dihydroceramide formation from a free fatty acid and dihydrosphingosine and no activity with phytosphingosine [30].
• S. cerevisiae cells lacking the TSC3 gene have a temperature-sensitive lethal phenotype that is reversed by supplying 3-ketosphinganine, dihydrosphingosine, or phytosphingosine in the growth medium [31].
• Mutants defective in both YSR2 and SUR2, which accumulated dihydrosphingosine 1-phosphate only, grew poorly [32].
• Sphinganine causes early activation of JNK and p38 MAPK and inhibition of AKT activation in HT-29 human colon cancer cells [33].

Analytical, diagnostic and therapeutic context of Dihydrosphingosine

• Quantification of sphingosine and sphinganine from crude lipid extracts by HPLC electrospray ionization tandem mass spectrometry [34].
• A method was developed for quantitative analysis of molecular species of ceramide (N-acyl-sphingosine) and dihydroceramide (N-acyl sphinganine) by high performance liquid chromatography (HPLC) [35].
• Here we describe a cross-sectional study of 265 residents of Linxian, People's Republic of China, which examines potential demographic, physiologic and dietary correlates of serum sphinganine and sphingosine in this population [36].
• Here we report that SPC-100270 has similar beneficial effects following liver transplantation in vivo [37].
• NCTR measured sphinganine concentrations in the livers of mice and in the livers and kidneys of rats in conjunction with a tumour bioassay [38].

References