Sphingolipid Metabolism Inhibitors and Cell Function

Abstract

It has been widely shown that ceramide, ceramide phosphate, sphingosine and sphingosine-1-phosphate are molecules involved in cell proliferation, differentiation and apoptosis. The regulation of the enzymes that control their metabolism has an important role for cellular fate. Many studies in the field have shed light on sphingolipid metabolism inhibition and on its role in cell processes such as gene expression, DNA duplication and RNA transcription. The aim of this review is to collect, in a systematic way, the recent advances in the field of sphingolipid metabolism inhibitors, with special emphasis on their effects on cell function. The name sphingolipid was born at the end of the XIX century on the basis of the molecule structure similar to the riddle of the sphinx. These molecules are complex lipids, localized in animal and plant membranes and in some forms of lower life, which contain sphingoid bases and have a very complex metabolism. The sphingolipid biosynthetic pathway initiates with the condensation of the serine with palmitoyl-CoA to form 3- ketodihydrosphingosine or 3-ketosphinganine, a serine pal- mitoyl transferase (SPT) catalyzed reaction. 3-ketodihy- drosphingosine is reduced to dehydrosphingosine or sphin- ganine by a NADPH dependent 3-ketosphinganine reduc- tase. An acylation in the presence of acyl-CoA produces di- hydroceramide by ceramide synthase (CerS). Dihydrocera- mide is then converted to ceramide through the introduction of the double bond trans-4,-5 by dihydroceramide desatu- rase. The ceramide can be transformed to sphingomyelin (SM) by two different ways: the first one involves the reaction with CDP-choline catalyzed by ceramide choline phos- photransferase and the second, described subsequently, con- sists in phosphocholine transfer from lecithin to ceramide by phosphatidylcholine: ceramide phosphocholine transferase or sphingomyelin synthase (SM-synthase). The synthesized SM can be used as source of phosphocholine to form phosphati- dylcholine in the presence of diacylglycerol by reverse- sphingomyelin-synthase (RSM-synthase) freeing ceramide, or can be degraded to ceramide and phosphocholine by acid or neutral sphingomyelinase (aSMase or N-SMase). The new-produced ceramide can be deacylated by acid or neutral ceramidase (AC or NC) to form sphingosine, which can be phosphorylated by a sphingosine kinase 1 (SphK1) or by sphingosine kinase 2 (SphK2) to sphingosine phosphate, can be phosphorylated by ceramide kinase (CerK) or can be