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1-Deoxysphingolipids Encountered Exogenously and Made de Novo: Dangerous Mysteries inside an Enigma.

Duan J, Merrill AH - J. Biol. Chem. (2015)

Bottom Line: The traditional backbones of mammalian sphingolipids are 2-amino, 1,3-diols made by serine palmitoyltransferase (SPT).These are rapidly N-acylated to 1-deoxy-"ceramides" with very uncommon biophysical properties.As components of food as well as endogenously produced, these substances are mysteries within an enigma.

View Article: PubMed Central - PubMed

Affiliation: From the Schools of Biology and Chemistry & Biochemistry, and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332.

No MeSH data available.


Related in: MedlinePlus

A schematic representation of the intestinal uptake, metabolism, effects on intestinal cells, and transport to blood and tissues of traditional sphingoid bases (sphingosine and sphinganine) and a synthetic 1-deoxy-sphingoid base (Enigmol). As shown on the right, traditional sphingoid bases are absorbed well from the lumen of the intestinal tract, but most are phosphorylated by sphingosine kinase (SphK) and degraded by S1P lyase. Nutritional studies have shown suppression of colon cancer by dietary sphingolipids, probably through the sphingoid base before phosphorylation and cleavage (94); however, if S1P accumulates (for example, due to defective S1P lyase), this can promote cancer (95). Shown on the left are findings with the synthetic 1-deoxy-sphingoid base Enigmol, which is absorbed more efficiently and transferred to blood and tissues, presumably because it cannot undergo phosphorylation and cleavage. Enigmol has also been shown to suppress intestinal tumorigenesis prostate cancer in animal models (91, 92). The color scheme is analogous to the one used in Figs. 1 and 3.
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Figure 4: A schematic representation of the intestinal uptake, metabolism, effects on intestinal cells, and transport to blood and tissues of traditional sphingoid bases (sphingosine and sphinganine) and a synthetic 1-deoxy-sphingoid base (Enigmol). As shown on the right, traditional sphingoid bases are absorbed well from the lumen of the intestinal tract, but most are phosphorylated by sphingosine kinase (SphK) and degraded by S1P lyase. Nutritional studies have shown suppression of colon cancer by dietary sphingolipids, probably through the sphingoid base before phosphorylation and cleavage (94); however, if S1P accumulates (for example, due to defective S1P lyase), this can promote cancer (95). Shown on the left are findings with the synthetic 1-deoxy-sphingoid base Enigmol, which is absorbed more efficiently and transferred to blood and tissues, presumably because it cannot undergo phosphorylation and cleavage. Enigmol has also been shown to suppress intestinal tumorigenesis prostate cancer in animal models (91, 92). The color scheme is analogous to the one used in Figs. 1 and 3.

Mentions: A synthetic 1-deoxysphingoid base, named Enigmol (Fig. 4), displayed tumor suppression with little toxicity when administered to mouse models for colon and prostate cancer (91, 92). Enigmol is not phosphorylated and is poorly N-acylated (93), and one of the most interesting findings from these in vivo studies was a high oral bioavailability versus traditional sphingoid bases. The likely explanation for this difference, which might apply to other 1-deoxy-sphingoid bases, is shown in Fig. 4. Traditional sphingoid bases are readily taken up by intestinal cells but mainly phosphorylated and degraded (94), which limits their effectiveness against colon cancer targets, but cleavage reduces the likelihood that the intermediate S1P will promote carcinogenesis (94, 95). Lacking the 1-hydroxyl group, 1-deoxysphingoid bases (at least as exemplified by Enigmol) are absorbed, escape phosphorylation and degradation, and appear in blood and tissues (91). Another factor affecting the absorption of these compounds is efflux via P-glycoprotein (96). All in all, the possible uptake of 1-deoxySL from food highlights the need for a better understanding of their effect(s) on health.


1-Deoxysphingolipids Encountered Exogenously and Made de Novo: Dangerous Mysteries inside an Enigma.

Duan J, Merrill AH - J. Biol. Chem. (2015)

A schematic representation of the intestinal uptake, metabolism, effects on intestinal cells, and transport to blood and tissues of traditional sphingoid bases (sphingosine and sphinganine) and a synthetic 1-deoxy-sphingoid base (Enigmol). As shown on the right, traditional sphingoid bases are absorbed well from the lumen of the intestinal tract, but most are phosphorylated by sphingosine kinase (SphK) and degraded by S1P lyase. Nutritional studies have shown suppression of colon cancer by dietary sphingolipids, probably through the sphingoid base before phosphorylation and cleavage (94); however, if S1P accumulates (for example, due to defective S1P lyase), this can promote cancer (95). Shown on the left are findings with the synthetic 1-deoxy-sphingoid base Enigmol, which is absorbed more efficiently and transferred to blood and tissues, presumably because it cannot undergo phosphorylation and cleavage. Enigmol has also been shown to suppress intestinal tumorigenesis prostate cancer in animal models (91, 92). The color scheme is analogous to the one used in Figs. 1 and 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4505451&req=5

Figure 4: A schematic representation of the intestinal uptake, metabolism, effects on intestinal cells, and transport to blood and tissues of traditional sphingoid bases (sphingosine and sphinganine) and a synthetic 1-deoxy-sphingoid base (Enigmol). As shown on the right, traditional sphingoid bases are absorbed well from the lumen of the intestinal tract, but most are phosphorylated by sphingosine kinase (SphK) and degraded by S1P lyase. Nutritional studies have shown suppression of colon cancer by dietary sphingolipids, probably through the sphingoid base before phosphorylation and cleavage (94); however, if S1P accumulates (for example, due to defective S1P lyase), this can promote cancer (95). Shown on the left are findings with the synthetic 1-deoxy-sphingoid base Enigmol, which is absorbed more efficiently and transferred to blood and tissues, presumably because it cannot undergo phosphorylation and cleavage. Enigmol has also been shown to suppress intestinal tumorigenesis prostate cancer in animal models (91, 92). The color scheme is analogous to the one used in Figs. 1 and 3.
Mentions: A synthetic 1-deoxysphingoid base, named Enigmol (Fig. 4), displayed tumor suppression with little toxicity when administered to mouse models for colon and prostate cancer (91, 92). Enigmol is not phosphorylated and is poorly N-acylated (93), and one of the most interesting findings from these in vivo studies was a high oral bioavailability versus traditional sphingoid bases. The likely explanation for this difference, which might apply to other 1-deoxy-sphingoid bases, is shown in Fig. 4. Traditional sphingoid bases are readily taken up by intestinal cells but mainly phosphorylated and degraded (94), which limits their effectiveness against colon cancer targets, but cleavage reduces the likelihood that the intermediate S1P will promote carcinogenesis (94, 95). Lacking the 1-hydroxyl group, 1-deoxysphingoid bases (at least as exemplified by Enigmol) are absorbed, escape phosphorylation and degradation, and appear in blood and tissues (91). Another factor affecting the absorption of these compounds is efflux via P-glycoprotein (96). All in all, the possible uptake of 1-deoxySL from food highlights the need for a better understanding of their effect(s) on health.

Bottom Line: The traditional backbones of mammalian sphingolipids are 2-amino, 1,3-diols made by serine palmitoyltransferase (SPT).These are rapidly N-acylated to 1-deoxy-"ceramides" with very uncommon biophysical properties.As components of food as well as endogenously produced, these substances are mysteries within an enigma.

View Article: PubMed Central - PubMed

Affiliation: From the Schools of Biology and Chemistry & Biochemistry, and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332.

No MeSH data available.


Related in: MedlinePlus