Disease relevance of phytosphingosine

• In vivo, calcineurin mediates prolonged dephosphorylation of Slm1 and Slm2 during heat stress, and this response can be mimicked by exogenous addition of the sphingoid base phytosphingosine [1].
• Here, we showed that phytosphingosine treatment in combination with gamma-radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner [2].
• Phytosphingosine compounds show the same type of fragmentation without additional dehydration if a neutral matrix is used [3].
• However, further binding assays using reference glycosphingolipids showed that the enterohemorrhagic E. coli also bound to lactosylceramide with phytosphingosine and/or hydroxy fatty acids, suggesting that the minimal structural element recognized is a correctly presented lactosyl unit [4].
• Phytosphingosine stimulates the differentiation of human keratinocytes and inhibits TPA-induced inflammatory epidermal hyperplasia in hairless mouse skin [5].

High impact information on phytosphingosine

• Responses of human NK T cells to these synthetic glycolipids, consisting of certain alpha-anomeric sugars conjugated to an acylated phytosphingosine base, required presentation by antigen-presenting cells expressing the major histocompatibility complex class I-like CD1d protein [6].
• Here we show that microsomes or detergent extracts from lag1lac1 double mutants lack an activity transferring C26 fatty acids from C26-coenzyme A onto dihydrosphingosine or phytosphingosine [7].
• Taken together, these results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with gamma-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent PARP-1 activation [2].
• Here we show that dihydrosphingosine (DHS) and phytosphingosine (PHS), two major sphingoid bases of fungi, have potent fungicidal activity with remarkably high structural and stereochemical specificity against Aspergillus nidulans [8].
• N-Acetylsphingosine, N-acetylphytosphingosine, phytosphingosine, sphingosine, and dihydrosphingosine, but not N-acetyldihydrosphingosine, inhibited phagocytosis of EIgG [9].

Chemical compound and disease context of phytosphingosine

• Sphingolipid long chain bases (LCBs) in Saccharomyces cerevisiae, dihydrosphingosine (DHS) and phytosphingosine (PHS) and their phosphates (DHS-P and PHS-P) are thought to play roles in heat stress [10].
• Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As(2)O(3)) enhanced cell death of naturally As(2)O(3)-resistant human myeloid leukemia cells [11].

Biological context of phytosphingosine

• We previously demonstrated that the phytosphingosine-induced apoptosis was accompanied by the concomitant induction of both the caspase-8-mediated and mitochondrial activation-mediated apoptosis pathways [12].
• The strain containing Cln3-1 was found to be resistant to cell cycle arrest induced by exogenous phytosphingosine, indicating that Cln3 acts downstream of the sphingoid bases in this response [13].
• These phenotypes include reduced VLCFA synthesis, accumulation of high levels of dihydrosphingosine and phytosphingosine, and accumulation of medium-chain ceramides [14].
• Here we show that, in Saccharomyces cerevisiae, phytosphingosine, a putative sphingolipid second messenger, mediates heat stress signaling and activates ubiquitin-dependent proteolysis via the endocytosis vacuolar degradation and 26 S proteasome pathways [15].
• Gene expression profile comparisons of sensitive and resistant yeast cells exposed to FTY720 and phytosphingosine highlight a number of similarities [16].

Anatomical context of phytosphingosine

• Phytosphingosine caused strong induction of caspase-8 activity and caspase-independent Bax translocation to the mitochondria [12].
• Yeast 1,3-beta-glucan synthase activity is inhibited by phytosphingosine localized to the endoplasmic reticulum [17].
• The biosynthesis of sphinganine and 4-D-hydroxysphinganine was studied in rat liver microsomes and whole cells of yeast (Hansenula ciferri) [18].
• Phytosphingosine induced mitochondrial translocation of Bax from the cytosol without changes in the protein levels of Bcl-2, Bcl-xL, and Bax [19].
• Tetraacetyl phytosphingosine-induced caspase activation and apoptosis occur through G2 arrest in human keratinocyte HaCaT cells [20].

Associations of phytosphingosine with other chemical compounds

• The ceramide portion consisted of 4-D-hydroxysphinganine as the sole long chain base, and the fatty acid consisted of predominantly tetracosanoic acid, deduced from both composition analysis and negative secondary ion mass spectrometry [21].
• In this report, we compare the effects of the natural yeast sphingolipid phytosphingosine with FTY720 in Saccharomyces cerevisiae [16].
• The TSC10/YBR265w gene was found to encode 3-ketosphinganine reductase, the enzyme that catalyzes the second step in the synthesis of phytosphingosine, the long chain base found in yeast sphingolipids [22].
• Importantly, YPC1p also has reverse activity, catalyzing synthesis of phytoceramide from palmitic acid and phytosphingosine [23].
• In this study of phytosphingosine (PHS)-resistant yeast mutants, we isolated mutants for PDR5, an ABC transporter involved in drug efflux as well as in the flop of phosphatidylethanolamine [24].

Gene context of phytosphingosine

• Genetic analysis revealed that the PHS-resistant phenotypes exhibited by the pdr5 mutants were dependent on Rsb1p, a putative LCB-specific transporter/translocase [24].
• To identify genes involved in LCBP signaling and in regulation of LCBP synthesis, we performed transposon mutagenesis in cells lacking the LCBP lyase DPL1 and LCBP phosphatase LCB3 genes and screened for phytosphingosine-resistant clones [25].
• Regulation of the sphingoid long-chain base kinase Lcb4p by ergosterol and heme: studies in phytosphingosine-resistant mutants [25].
• In addition, a close inspection of TAT1 and TAT2 transporters following exposure to phytosphingosine indicates that TAT1 protein is degraded in a similar fashion upon treatment with FTY720 and phytosphingosine [16].
• SUR2 catalyzes conversion of dihydrosphingosine to phytosphingosine [26].

Analytical, diagnostic and therapeutic context of phytosphingosine

• The long-chain base was further analysed by gas-chromatography/mass spectrometry and was found to be phytosphingosine [27].
• A new sensitive assay method for sphingoids, 4-D-hydroxysphinganine, sphingosine, and sphinganine, involving reversed phase HPLC was described [28].
• From a study of three human volunteers, average concentrations of free long-chain bases in the stratum corneum were found to be 2.8, 1.2 and 0.5 nmol/mg of protein for phytosphingosine, sphingosine and sphinganine, respectively [29].
• An agar dilution test for minimum inhibitory concentration (MIC) investigation of phytosphingosine base, phytosphingosine lactic acid salt, phytosphingosine HCl, and phytosphingosine glycolic acid salt was carried out using D.S.T. agar containing 2% olive oil and 0.2% Tween 80, to allow growth of the lipophilic yeast [30].
• On thin layer chromatography, the Rf for CAEP-IIM was smaller than the Rf for CAEP-IM because of an increase of 22.0% in 2OH-16:0 FA, plus 29.2% trihydroxy bases (phytosphingosine) [31].

References