SIP lyase

SIP is formed from sphingosine by sphingosine kinases (SphKs). Degradation of SIP occurs either reversibly by lipid phosphate phosphohydrolases (LPPs) and SIP phosphatases (SPPs), or irreversibly by SIP lyase (SPL) (Fig. 1). The localization of SIP production is highly important since SIP plays a role both as extracellular mediator and as intracellular... 

The intracellular concentrations of sphingosine and SIP are governed by the activities of enzymes that catalyse their synthesis and removal. These include ceramidase, sphingosine kinase (SPHK), SIP phosphatase and SIP lyase (Figure 1). Several of these enzymes have only recently been cloned and knowledge of their respective roles and regulation is incomplete. 

SIP lyase, a pyridoxal 5 -phosphate dependent enzyme that has a potential role in controlling cell fate and stress responses (96, 97), cleaves SIP between C-2 and C-3 to produce an a,P-unsaturated fatty aldehyde and phosphoethanolamine. Pyridoxal 5 -phosphate forms a Schiff base with the amino group of SIP. SIP lyase plays a role in determining the balance between the intracellular levels of SIP and ceramide. 

A caramel food colorant and component of coffee, 2-acetyl-4-tetrahydroxybutylimidazole (THl, Fig. 7), inhibits SIP lyase, which causes SIP to accumulate in the lymph nodes (110). 

Inhibition of dihydroceramide desaturase. The last enzyme in the de novo biosynthesis of ceramide is inhibited by GT-11, but at high concentrations this compound also inhibited SIP lyase and SPTase (147, 148). Fenretinide (4-HPR, Fig. 12) also inhibited dihydroceramide desaturase (147, 148). This synthetic retinoid and its analogs have apoptogenic activity, which elevates intracellular ceramide levels and induces cell death in a variety of cell types in vitro and in vivo by multiple mechanisms (117, 149, 150). 

Inhibition of SIP lyase. SIP lyase is inhibited by sulfhydryl reagents, FTY720 (151), and by racemic 2-vinyldihydrosphingosine 1-phosphate (152) (Fig. 12). When SIP lyase is overexpressed, ceramide levels are increased and apoptosis is induced (153). 

Schwab, S. R., Pereira, J. P., Matloubian, M., Xu, Y., Huang, Y., Cyster, J. G. Lymphocyte sequestration through SIP lyase inhibition and disruption of SIP gradients. Science 309... 

SPL expression was seen to be downregulated in colon carcinoma (Oskouian et ah, 2006), but upregulated in ovarian cancer (Hibbs et ah, 2004) and atopic dermatitis (Seo et ah, 2006). Most importantly, SPL knockout mice feature postnatal mortality due to multiple congenital abnormalities, in particular of the vasculature (Schmahl et ah, 2007). Whether these findings would limit the usefulness of SIP lyase inhibitors as immunomodulatory drugs remains to be explored. 

If SIP is not secreted or dephosphorylated by specific SIP phosphatases, as well as by more general lipid phosphatases, it is cleaved irreversibly to ethanolamine phosphate and rrans-2-hexadecenal by SIP lyase (J. Zhou, 1998 P.P. Van Veldhoven, 20(X)). As shown first in the 1970s by W. Stoffel and coworkers, the phosphoethanolamine can be utilized for the synthesis of phosphatidylethanolamine (Chapter 8), and fran5-2-hexadecenal can be reduced to the alcohol and incorporated into alkyl ether lipids. Under certain conditions, degradation of sphingoid bases can account for as much as one-third of the ethanolamine in phosphatidylethanolamine (E.R. Smith, 1995). It is interesting that both the first enzyme of sphingoid base metabolism (SPT) and the last enzyme, the lyase, are pyridoxal 5 -phosphate-dependent. 

SIP lyase expression is significantly down-regulated in human colon cancer tissues (as are SIP phosphatases), which should increase the stability of SIP that might contribute to carcinogenesis (B. Oskouian, 2006). 

The concentration of SIP in cells is low and is tightly controlled due to regulation of the enzymes that catalyse its synthesis and removal (Figure 1). These include sphingosine kinase, SIP lyase and SIP phosphatase (Figure 1). These enzymes have only recently been cloned, and full knowledge of their roles and regulation remains to be fully defined. 

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