Sphingosines

FIGURE8.il Formation of an amide linkage between a fatty acid and sphingosine produces a ceramide. 

Sphingomyelins are the second major group of phospholipids. These compounds have sphingosine or a related dihydroxyamine as their backbone and are particularly abundant in brain and nerve tissue, where they are a major constituent of the coating around nerve fibers. 

Sphingomyelin (Section 27.3) A phospholipid that has sphingosine as its backbone. 

Sphingomyelin, 1066-1067 Sphingosine, structure of, 1067 Spin density surface, allylic radical, 342... 

Scheme 2.32 Stereodivergent synthesis of threo- and erythro-sphingosines 124.

No biosynthetic experiments have been reported for these compounds, but they probably all share the same biosynthetic mechanism. One possibility is that they are generated by cyclization of an a-amino-p-keto carboxyl intermediate that would arise from threonine (136) and sphingosine (131) for 139 and 130, respectively (Figure 11.23). Alternatively, cyclization may precede oxidation, with an aziridine intermediate being formed. 

Edg receptors are a group of recently discovered G-protein coupled receptors, which mediate the action of lysophospholipids (sphingosine-1 -phosphate, lysophosphatidic acid). Tachykinins and their Receptors... 

Lipid phosphate phosphohydrolases (LPPs), formerly called type 2 phosphatidate phosphohydrolases (PAP-2), catalyse the dephosphorylation of bioactive phospholipids (phosphatidic acid, ceramide-1-phosphate) and lysophospholipids (lysophosphatidic acid, sphingosine-1-phosphate). The substrate selectivity of individual LPPs is broad in contrast to the related sphingosine-1-phosphate phosphatase. LPPs are characterized by a lack of requirement for Mg2+ and insensitivity to N-ethylmaleimide. Three subtypes (LPP-1, LPP-2, LPP-3) have been identified in mammals. These enzymes have six putative transmembrane domains and three highly conserved domains that are characteristic of a phosphatase superfamily. Whether LPPs cleave extracellular mediators or rather have an influence on intracellular lipid phosphate concentrations is still a matter of debate. 

G-protein-coupled receptors (GPCRs), although some of them additionally play a role in intracellular signal transduction. Sphingosine-1-phosphate (SIP) and... 

SIP is formed from sphingosine by sphingosine kinases (SphKs). Degradation of SIP occurs either reversibly by lipid phosphate phosphohydrolases (LPPs) and SIP phosphatases (SPPs), or irreversibly by SIP lyase (SPL) (Fig. 1). The localization of SIP production is highly important since SIP plays a role both as extracellular mediator and as intracellular... 

Brinkmann V, Cyster JG, Hla T (2004) FTY720 sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 4 1019-1025... 

Parrill AL, Sardar VM, Yuan H (2004) Sphingosine 1-phosphate and lysophosphatidic acid receptors agonist and antagonist binding and progress toward development of receptor-specific ligands. Semin Cell Dev Biol 15 467-476... 

Sphingosine kinases (SphKs) catalyse the phosphorylation of sphingosine to sphingosine-1 -phosphate (SIP). 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

Amines, amino acids, amides [1, 2] e.g. chloramphenicol, creatine, adenine, guanine histidine, phenylalanine, sphingosine... 

The aziridine-2-carboxaldehyde 56 can also serve as synthon for the synthesis of sphingosines, which are important biomembrane constituents [64]. One possible route involves the addition of an alanate to the aldehyde. In a later stage of this synthetic plan the aziridine can be opened, either via the intermediacy of an oxazoline or directly with dilute acid. Unfortunately, the reaction of aldehyde 56 with a vinylalanate has a poor diastereoselectivity of 3 2. Therefore, an alternative approach was considered, namely one involving the addition of a vinylzinc reagent to the aldehyde thereby employing our N-tritylaziridinediphenyl-methanol 51 as the chiral catalyst. Gratifyingly, only one diastereomer was obtained. Reductive removal of the trityl function, acetylation of the hydroxy... 

Sphingosine precursors were prepared by Davis et al. [66]. The vinylaziri-dine 20, which is a precursor for the azirine-containing natural product dysi-dazirine (see Sect. 2.5, Scheme 10), also can serve as a precursor for L-threo-sphingosines (Scheme 46). 

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