Chemistry and biology of sphingolipids

Significant progress has been made in the last decade in both the chemical synthetic methodologies and the biological functional elucidation of sphingolipids. Various sphingolipids from lower organisms were identified and total synthesises have been successfully achieved for most of them using various asymmetric synthetic protocols. These methodologies can be applied to the synthesis of other small-molecule analogs of sphingolipids for the determination of individual receptor function. The rapid progress in annotating the biological functions of sphingolipids and their receptors has significantly contributed to our understanding of sphingolipids in physiological and pathological conditions. The recently finished human genome and developments in bioinformatics tools allow the discovery of a new family of receptors of putative lipid receptors (Fig. 4).1 Among these receptors, only some ligands derived from nature have been discovered at high affinity. Many of the reported ligands for these receptors are of low affinity. These may be due to inefficiency of coupling of receptors to heterotrimeric G-proteins in heterologous cell systems or yet-to-be-discovered high affinity natural ligands. Given subnanomolar binding and activation of S1P receptors by S1P, the search for natural high affinity ligands remains a challenging task in the future, suggesting the structural diversity of lipid-signaling molecules and their importance in biology. In addition to S1P receptors, many of these family receptors may play important roles in immunoregulation, obesity/diabetes, cardiovascular remodeling, and tumor invasion. Deletion of G2A in mice results in delayed onset of multisystem autoimmune disease after 1 year of age. 13 GPR40, a free fatty acid receptor, has been shown to mediate insulin secretion from pancreatic β-cells in the presence of high concentrations of glucose.76 GPR41, another free fatty acid receptor, could mediate leptin secretion in response to fatty acids in mice.77 All these data suggest that, in addition to nuclear hormone receptors, GPCR may represent another pathway for cells to sensitize lipids to regulate physiological processes in vivo. Therefore, the achievements in both chemical synthesis and biological discovery of lipid receptors in the human genome will lead to rapid progress in lipid research in the near future. © 2005 Published by Elsevier Ltd.