Ceramide synthase pathway

Inhibition of ceramide synthase could cause symptoms by depletion of ceramide and ceramide derivatives or by toxic increases in sphinganine and its derivatives. The effects of these phytotoxins are so rapid, that it is unlikely that depletion of ceramides is responsible for cellular death. Others have invoked induction of apoptosis in the mode of action of these compounds [e.g., 6] however, treatment of plant tissues with phytoshingosine and sphinganine causes symptoms very similar to those caused by inhibition of ceramide synthase [7]. Very low levels of AAL-toxin tuid other ceramide synthase inhibitiors may cause apoptosis, but the rapidity of plasma membrtme damage at one micromolar and higher concentrations makes it unlikely that it is involved in the main phytotoxic effect. Attempts have been made to find a ceramide synthase inhibitor with good phytotoxicity, but little mammalitm toxicity [e.g., 8]. However, even inhibitors with little structural similarity to the fumonisins such as australifimgin [9], have relatively little difference between mammalian and plant toxicity. Nevertheless, these studies demonstrate that the ceramide synthase pathway is a viable site for herbicides, provided an inhibitor can be found that is plant specific. This topic is considered in more detail in a recent review [10]. 

The ceramide synthase pathway is clearly a viable site for herbicides, provided an inhibitor can be found that is plant specific. We have been unsuccessfiil in finding a ceramide synthase inhibitor with high phytotoxicity, but low mammalian toxicity (e.g., 11). Even inhibitors widi little structural similarity to the fumonisins, such as australifungin 12), have relatively little difference between mammalian and plant toxicity. This topic is considered in more detail in a recent review 13). 

It is important to note that these reverse activities of CDases are distinct from the major CoA-dependent ceramide synthase activity that is present in the ER and is thought to be responsible for de novo synthesis of Cer. Further, this reverse activity of CDases, may emerge as a new pathway of Cer formation, different from the known de novo or sphingomyelinases pathways. 

Constable, P. D., Smith, G. W., Rottinghaus, G. E., Tumbleson, M. E., and Haschek, W. M. (2003). Fumonisin-induced blockade of ceramide synthase in sphingolipid biosynthetic pathway alters aortic input impedance spectrum of pigs. Am. J. Phusiol. Heart Circ. Physiol. 284(6), H2034 2044. 

Using inhibitors of serine palmitoyltransferase and ceramide synthase together, one can not only establish a role for de novo synthesis of ceramide, but also distinguish the de novo pathway from salvage pathways. For example. 

FIGURE 3.10 Biosynthetic pathway of ceramide. SPT, serine palmitoyltransferase 3-KSR, 3-ketosphinganine reductase Cer-Synthase, ceramide synthase. In fact, the reaction catalyzed by ceramide synthase leads to dihydroceramide. Ceramide is obtained by the secondary action of a desaturase that creates a trans double bond between carbons C4 and C5 of the sphingosine moiety (A). 

Recently, it has been shown that cell-permeable cerantides dramatically inhibited the synthesis of the two major membrane phospholipids, PC and PE (Bladergroen et al, 1999b Allan, 2000). The inhibition of phospholipid synthesis was rapid, within 2 h, and resulted in massive apoptosis after 16-24 h. The mechanism by which short-chain cerantides exert their effect on phospholipid synthesis is possibly cell type dependent. In baby-hamster kidney (BHK) fibroblasts rc synthesis was reduced at the level of CT, the putative rate-determining enzyme in the CDP-choline pathway (Allan, 2000). This conclusion was based solely on radio-label studies in combination with an earlier published observation (Wieder et al, 1995) showing that C2-SM (the SM generated from C2-ceramide by SM synthase, which was actively synthesized in the BHK-cells) inhibited CT activity in vitro. On the other hand, data obtained from studies with rat-2 fibroblasts clearly showed that short-chain cerantides regulate the synthesis of PC and PE mainly at the final step of the CDP-pathways. This conclusion was based on the following observations (a) incorporation of [ H]-choline into PC and... 

Additionally, small molecule inhibitors of the sphingolipid pathway to induce the accumulation of ceramide have been used in some cancers. For example, B13, an inhibitor of acid CDase was used in a metastatic colon cancer mouse model and a prostate cancer xenograph model (Selzner et al., 2001 Samsel et al., 2004). In both cases, BI3 caused the accumulation of ceramide and resulted in prevention of tumor growth. Another effective approach to increase ceramide accumulation in cancer cells has been to inhibit SM synthase, or acid CDase (Meng et al., 2004 Saad et al., 2007). 

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