Sphingosine chain

Other compound classes in the synthesis of which chiral 3-carbon synthons were used include sphingosine chains (32), 3-amino-2-azetidinones (33), (3,y-unsaturated-a-amino acids 34), fluorinated macrocyclic bis(indolyl) maleimides35, fluorocyclopropyl alcohols (36), l-O-phosphocholine-2-O-acyl-octadecanes and l-Ophosphocholine-2-N-acyl-octadecane (37) diacyl glycerols 38-42) and analogs of fragments of leukotriene-B4 43). 

The crystal structure of mouse CDld/3/TCR (V 38.2) was solved by Patel et al. and Aspeslagh et in 2011, independently [48,49]. In comparison with mouse CDld/2/TCR (V 38.2) ternary complex, a major movement of the sugar head group was not found however, a small structural difference was observed [6,48,49]. Conformation of the 3-hydroxy groups of each phyto-sphingosine chains is obviously different [6]. It has not been clarified yet why this small conformational difference causes different cytokine profiles. It should be added that the NKT-TCR affinity for the CDld/3 was estimated by surface plasmon resonance (SPR) analysis in 2011 and was lower than that of the CDld/2 complex [48]. 

The 35-hydroxy group of the sphingosine chain is essential. Existence of the 3-hydroxy group is necessary to make a stable complex with CDld, and to stimulate NKT cells. The 4-hydroxy group is important for the gly-colipid to be recognized by human NKT-TCR. 

FIGURE 1.21 How to draw a ceramide molecule. Draw a sphingosine chain as explained in Kg. 1.18 (just omit one H atom of the -NH2 group). Add the C16 0 acyl chain. If the ceramide is a HFA, add the OH group on the acyl chain (in a of the carbonyl group). 

Indeed a glycosphingolipid can be considered in three domains (Figure 1). The first is the carbohydrate, which acts as receptor for ligand recognition the second is the fatty acid (possibly sphingosine chain) which modulates the carbohydrate receptor function and the third is the sphingosine (and ceramide) breakdown products which act as lipid second messengers. 

Glycerolipids are derivatives of glycerol and fatty acids 34 In sphingolipids, the long-chain aminodiol sphingosine serves as the lipid backbone 37... 

The amino group of sphingosine is acylated with long-chain fatty acids and the N-acylated product is termed a ceramide (Fig. 3-3). C-l of ceramide is linked to different... 

Figure 12.12 Sphingomyelins. Sphingomyelins are esters of a ceramide and phospho-ryl choline. However, similar compounds are ceramide-1-phosphoryl ethanolamines and phosphono forms of sphingolipids. Ceramides W-acyl-sphingosines) are amides of a long chain di- or trihydroxy base containing 12 to 22 carbon atoms, of which sphingosine (4-sphingenine) is the commonest, and a long chain fatty acid whose acyl chain is shown by R1. This may contain up to 26 carbon atoms.

De Jonge, S., Van Overmeire, 1., Poulton, S., Hendrix, J., Busson, R., Van Calenbergh, S., De Keukeleire, D., Spiegel, S. Herdewijn, P., 1999, Structure-activity relationship of short-chain sphingoid bases as inhibitors of sphingosine kinase, Bioorg. Med. Chem. Lett. 9 3175-3180. 

The naturally occurring fatty acids are carboxylic acids with unbranched hydrocarbon chains of 4-24 carbon atoms. They are present in all organisms as components of fats and membrane lipids, in these compounds, they are esterified with alcohols (glycerol, sphingosine, or cholesterol). However, fatty acids are also found in small amounts in unesterified form. In this case, they are known as free fatty adds (FFAs). As free fatty acids have strongly amphipathic properties (see p. 28), they are usually present in protein-bound forms. 

Attachment of another long-chain fatty acid in an amide linkage to the amino group of sphingosine forms a ceramide, the parent compound for many of the physiologically important sphingolipids. 

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