| Until the late 1970s lipids were primarily thought to serve as inert structural components of cellular membranes. However, at that time reports accumulated pointing towards an important role of lipids in cell signaling. The milestone for a central role of lipids in signal transduction was manifested by the discovery of the phosphoinositide cycle. It was recognized that phosphatidylinositol 4,5-bisphosphate was hydrolyzed by a phospholipase C (PLC) to liberate the hydrophilic head group inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG) from the lipid backbone. IP3 interacts with an intracellular membrane receptor and leads to a mobilization of Ca2+, whereas DAG directly binds to and activates protein kinase C (PKC) and thus initiates a separate signal transduction cascade.Later on, arachidonic acid and phospholipids, released by the action of phospholipase A2, found acceptance as important lipid second messengers and intracellular modulators. Arachidonic acid also serves as a precursor of an extended class of eicosanoids, each possessing an own plasma membrane or internal receptor, thus directing the signal flow towards a specific cell response.Other lipid signaling molecules include phosphatidic acid (PA), a reaction product of phospholipase D, lyso-PA, platelet-activating factor (PAF), and phosphatidylinositol 3,4,5-trisphosphate (PIP3) being produced by phosphatidylinositol 3-kinase (PI3-K) and supposed to activate enzymes like Akt/protein kinase B (PKB), phosphoinositide-dependent kinase (PDK), PKC-εand PKC-ζ.More recently, another class of membrane lipids was discovered asimportant signaling molecules: the sphingolipids. They are derivatives of long-chain bases and display a great structural diversity and complexity. In glycolipids on mammalian cell surfaces, the carbohydrate residues are attached to a sphingolipid-based membrane anchor.The first isolation and characterization of this class of natural substances was performed by the German practitioner Tudichum. By using fractional crystallization of ethanolic brain extracts, he isolated a substance that contained sugar residues, a fatty acid and an organic base in one molecule, and he dubbed the molecules'sphingosine', referring to the Greek Sphinx to indicate the enigmatic structure.To date, at least 300 mammalian sphingolipid species have been identified. Their potential function, their metabolism, and especially the diseases associated with their impaired degradation have been investigated in detail. Later on, the discovery from Yusuf.A Hannun that PKC was inhibited by the sphingolipid breakdown product sphingosine, triggered a exponentially growing research interest in sphingolipids as bioactive molecules. Besides the involvement of sphingolipids in signaling processes, their metabolism, as well as enzymological, topological and pathobiochemical problems associated with it, are current areas of research.Most notable of these bioactive molecules are the sphingoid bases, ceramide, and sphingosine 1-phosphate (S1P); other emerging bioactive sphingolipids include sphingosylphosphorylcholine, psychosine, lactosylceramide, and cerebroside.Much attention in the last decade has focused on ceramide metabolism and function because of the increased appreciation of the involvement of pathways involving this lipid in regulating key biologic responses such as stress responses, cell senescence, and apoptosis.Ceramidases are the most important enzymes in degrading ceramides. They catalyze the hydrolysis of ceramide to the free sphingoid base and fatty acid, and thus, their interplay with the SMases crucially regulates the available pool of the signaling molecule ceramide. Different forms ofceramidase activity have been identified, including an acid, alkaline and neutral one. Once sphingosine is generated, it is converted to sphingosine-1-phosphate by sphingosine kinase (SPHK), an ubiquitously expressed cytosolic enzyme. It has been suggested that SPP may also function as an intracellular second messenge...
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