Chemical Tools to Investigate Sphingolipid Metabolism and Functions

Abstract

Sphingolipids comprise an important group of biomolecules, some of which have been shown to play important roles in the regulation of many cell functions. From a structural standpoint, they all share a long 2-amino-1,3-diol chain, which can be either saturated (sphinganine), hydroxylated at C4 (phytosphingosine), or unsaturated at C4 (sphingosine) as in most mammalian cells. N-acylation of sphingosine leads to ceramide, a key intermediate in sphingolipid metabolism that can be enzymatically modified at the C1-OH position to other biologically important sphingolipids, such as sphingomyelin or glycosphingolipids. In addition, both ceramide and sphingosine can be phosphorylated at C1-OH to give ceramide-1-phosphate and sphingosine-1-phosphate, respectively. To better understand the biological and biophysical roles of sphingolipids, many efforts have been made to design synthetic analogues as chemical tools able to unravel their structure-activity relationships, and to alter their cellular levels. This last approach has been thoroughly studied by the development of specific inhibitors of some key enzymes that play an important role in biosynthesis or metabolism of these intriguing lipids. With the above premises in mind, the aim of this review is to collect, in a systematic way, the recent efforts described in the literature leading to the development of new chemical entities specifically designed to achieve the above goals.

A Straightforward Protocol for the Solution‐Phase Parallel Synthesis of Ceramide Analogues

“…Melting points were determined with a SMP10 melting point apparatus and are uncorrected. Chemical shifts are reported in parts per million (ppm) relative to the singlet at δ = 7.24 ppm of CHCl 3 and 3.31 ppm of MeOH for 1 H NMR and to the centre line of the triplet at δ = 77.0 ppm of CDCl 3 was cleaned by washing several times with aqueous 1  HCl and rinsed with water until neutral pH, followed by drying in vacuo for 15 h. Amberlyst A15 resin was conditioned as described in the literature. [17] Amberlyst A21, IRA900, and PS-EDC resins were used as received.…”

“…1 H NMR (400 MHz, CDCl 3 ): δ = 6.37 (br., 1 H), 4.00 (dd, J = 11.5 Hz, JЈ = 3.0 Hz, 1 H), 3.94 (m, 1 H), 3.82 (m, 1 H), 3.68 (dd, J = 11.5 Hz, JЈ = 3. …”

“…In order to better understand the biological and biophysical roles of sphingolipids, many efforts have been made to design analogues to enable a detailed study of the structure-activity relationships. [3] Very recently, we reported on a new class of sphingosine-1-phosphate and ceramide analogues that incorporate a bioisosteric sulfur atom as part of the sphingoid backbone. [4,5] On the basis of these precedents, we became interested in "second generation" analogues containing both a sulfur atom and the 3-hydroxy motif present in natural sphingolipids.…”

The sphingolipid salvage pathway in ceramide metabolism and signaling

“…The following approaches are recommended in order to ascertain the operation of the salvage pathway and its contribution to ceramide synthesis: i) Fumonisin B1-sensitive/ myriocin-insensitive formation of ceramide The ceramide salvage pathway differs from the ceramide de novo pathway in metabolic features (catabolism vs anabolism), but these pathways share a singular step where longchain sphingoid bases are acylated to ceramide in a (dihydro)ceramide synthase-dependent manner. A number of metabolic inhibitors have been discovered to block particular catalytic steps in these pathways [59], and two of the best-studied inhibitors of ceramide synthesis are myriocin/ISP-1 [60] and fumonisin B1 [57]. The former is a selective inhibitor of serine palmitoyltransferase, being selectively capable of blocking the de novo pathway for ceramide synthesis.…”

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

“…Recent reviews by Delgado et al provide an overview of inhibitors of SL metabolic enzymes. [183,184] …”