Abstract
We report the total synthesis of (R)-tuberculostearic acid-containing Mycobacterium tuberculosis phosphatidylglycerol (PG). The approach features a two-step synthesis of (R)-tuberculostearic acid, involving an (S)-citronellyl bromide linchpin, and the phosphoramidite-assisted assembly of the full PG structure. Collision-induced dissociation mass spectrometry of two chemically-synthesized PG acyl regioisomers revealed diagnostic product ions formed by preferential loss of carboxylate at the secondary (sn-2) position.
Highlights
Phosphatidylglycerols are phospholipids produced by a wide range of organisms including bacteria, fungi, plants and animals.[1]
PGs can be presented on several antigen presenting proteins of the cluster of differentiation 1 (CD1) class, CD1b3 and CD1d,4,5 where they are recognized by natural killer T cells and lipid-reactive T cells
The most efficient synthesis reported to date is that of Roberts and Baird who prepared TBSA in four steps from (S)-citronellyl bromide, in a route involving stepwise elongations using copper(I)-catalyzed cross-coupling and Wittig extension.[22]
Summary
Phosphatidylglycerols are phospholipids produced by a wide range of organisms including bacteria, fungi, plants and animals.[1]. Mtb PG occurs as a range of lipoforms including an abundant species that bears (R)-tuberculostearic acid (R-TBSA) at the sn-1 position, and palmitic acid at the sn-2 position,[4] a decoration that matches that of other phosphatidyl-containing lipids[9] such as phosphatidylethanolamine,[10] and phosphatidylinositol mannosides.[11] Possibly because of its role as a biosynthetic intermediate, Mtb PG occurs at low levels and the challenges of its isolation[4] from the natural source are compounded by the pathogenicity and low growth rate of Mtb. Recent work has shown that Mtb PG can be presented by the CD1d antigen presenting molecule to natural killer T cells that display ‘type II’ T cell receptors.[4] Type II NKT cells are distinguished from their better studied type I variants, by lacking reactivity to the prototypical NKT ligand α-galactosyl ceramide, and through possessing a diverse array of αβ chains that comprise the T cell receptor.[12] While most studies have focused on type I NKT cells, type II NKT cells are more abundant in humans, and are functionally distinct from type I NKT cells.[13] studies of type II NKT cells have been limited by a lack of well-defined lipid antigens
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