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Sphingosine 1-phosphate: synthesis and release - …

2.1 Synthesis of L-Serine Derived ThiolEster...6
2.2 Cross Coupling Reactions...8
2.3 Asymmetric Reduction...9
2.4 Completion of Total Synthesis of(-)-D-erythro-Sphingosine...12
2.5 Synthesis Sphingosine Derivatives...13

T1 - The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension

AB - Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and othershave demonstratedthatS1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI.

Synthesis of Sphingosine and the Ceramides

Mendelson K, Evans T and Hla T:Sphingosine 1-phosphate signalling. Development. 141:5–9. 2014. :  :

Strub GM, Paillard M, Liang J, Gomez L,Allegood JC, Hait NC, Maceyka M, Price MM, Chen Q, Simpson DC, etal: Sphingosine-1-phosphate produced by sphingosine kinase 2 inmitochondria interacts with prohibitin 2 to regulate complex IVassembly and respiration. FASEB J. 25:600–612. 2011. : :

Alvarez SE, Harikumar KB, Hait NC,Allegood J, Strub GM, Kim EY, Maceyka M, Jiang H, Luo C, Kordula T,et al: Sphingosine-1-phosphate is a missing cofactor for the E3ubiquitin ligase TRAF2. Nature. 465:1084–1088. 2010. : :

Sphingosine 1 phosphate receptor modulators and methods …

KW - Sphingosine kinase

HFD, high fatdiet; c-JNK, c-Jun N-terminal kinase; GSIS, glucose-stimulatedinsulin secretion; KIP2, cyclin-dependent kinase inhibitor p57;PI3K, phosphatidylinositol 3-kinase; JTE-013, S1P2R antagonist;ATM, adipose tissue macrophage; ROS, reactive oxygen species;VPC23019, S1P3R antagonist; AKT, protein kinase B; ERK,extracellular regulated protein kinases; GSK3α/β, glycogen synthasekinase 3α/β; CTGF, connective tissue growth factor; p38 MAPK, p38mitogen-activated protein kinase.

S1P contributes to the protective role of HDL. Tong () found that HDLin diabetic patients with elevated S1P levels exhibited morepowerful protective effects, inducing COX-2 expression and PGI2release from human umbilical vein endothelial cells, than controlHDL through the activation of S1P1R/3R. Additionally, S1Pcompensated for the reduction in COX-2 expression through glycatedHDL by phosphorylating the ERK/MAPK-CREB pathway (). These findings confirmed theprotective role of HDL-binding S1P in patients with type 2 diabetesmellitus, suggesting a possible novel therapeutic target. There isno S1P in HDL in apoM mice, whereas HDL intransgenic mice overexpressing human apoM has an increased S1Pcontent, indicating that the bridge between HDL and S1P in plasmais apoM. The 1.7-Å structure of the S1P-apoM complex suggests thatS1P specifically interacts with an amphiphilic pocket in thelipocalin fold of apoM. Human apoM(+) HDL induced S1P1Rinternalization, downstream MAPK and Akt activation, endothelialcell migration, and formation of endothelial adherence junctions,whereas apoM(−) HDL did not. Moreover, the HDL fraction ofapoM(−/−) mice which lacked S1P showed dampened basal endothelialbarrier function in lung tissue. This demonstrated that apoM is anessential vascular protective constituent of HDL by delivering S1Pto the S1P1R on endothelial cells ().

KW - S1P receptor 2
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Sphingosine-1-phosphate receptor - Wikipedia

Venkataraman K, Lee YM, Michaud J,Thangada S, Ai Y, Bonkovsky HL, Parikh NS, Habrukowich C and Hla T:Vascular endothelium as a contributor of plasma sphingosine1-phosphate. Circ Res. 102:669–676. 2008. : :

Sphingosine 1-phosphate induced synthesis of …

Pappu R, Schwab SR, Cornelissen I, PereiraJP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG andCoughlin SR: Promotion of lymphocyte egress into blood and lymph bydistinct sources of sphingosine-1-phosphate. Science. 316:295–298.2007. : :

Sphingosine 1-Phosphate Mobilizes Sequestered …

Pham TH, Baluk P, Xu Y, Grigorova I,Bankovich AJ, Pappu R, Coughlin SR, McDonald DM, Schwab SR andCyster JG: Lymphatic endothelial cell sphingosine kinase activityis required for lymphocyte egress and lymphatic patterning. J ExpMed. 207:17–27. 2010. : :

SELECTIVE SPHINGOSINE 1 PHOSPHATE RECEPTOR …

Baranowski M, Górski J, Klapcinska B,Waskiewicz Z and Sadowska-Krepa E: Ultramarathon run markedlyreduces plasma sphingosine-1-phosphate concentration. Int J SportNutr Exerc Metab. 24:148–156. 2014. :

Ceramide and sphingosine-1-phosphate in cancer, two …

Mendoza A, Bréart B, Ramos-Perez WD, PittLA, Gobert M, Sunkara M, Lafaille JJ, Morris AJ and Schwab SR: Thetransporter Spns2 is required for secretion of lymph but not plasmasphingosine-1-phosphate. Cell Rep. 2:1104–1110. 2012. : :

Ceramide and sphingosine-1-phosphate in cancer, ..

Knapp M, Lisowska A, Zabielski P, Musiał Wand Baranowski M: Sustained decrease in plasmasphingosine-1-phosphate concentration and its accumulation in bloodcells in acute myocardial infarction. Prostaglandins Other LipidMediat. 106:53–61. 2013. : :

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