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Review
. 2009 Aug;13(8):1013-25.
doi: 10.1517/14728220903039722.

Lyase to live by: sphingosine phosphate lyase as a therapeutic target

Ashok Kumar  1 , Julie D Saba
Affiliations
Review

Lyase to live by: sphingosine phosphate lyase as a therapeutic target

Ashok Kumar et al. Expert Opin Ther Targets. 2009 Aug.

Abstract

Background: Sphingosine 1-phosphate (S1P) is a bioactive lipid that regulates cell proliferation, survival and migration and plays an essential role in angiogenesis and lymphocyte trafficking. S1P levels in the circulation and tissues are tightly regulated for proper cell functioning, and dysregulation of this system may contribute to the pathophysiology of certain human diseases. Sphingosine phosphate lyase (SPL) irreversibly degrades S1P and thereby acts as a gatekeeper that regulates S1P signaling by modulating intracellular S1P levels and the chemical S1P gradient that exists between lymphoid organs and circulating blood and lymph. However, SPL also generates biochemical products that may be relevant in human disease. SPL has been directly implicated in various physiological and pathological processes, including cell stress responses, cancer, immunity, hematopoietic function, muscle homeostasis, inflammation and development.

Objective/methods: This review summarizes the current know-ledge of SPL structure, function and regulation, its involvement in various disease states and currently available small molecules known to modulate SPL activity.

Results/conclusion: This review provides evidence that SPL is a potential target for pharmacological manipulation for the treatment of malignant, autoimmune, inflammatory and other diseases.

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Figures

Figure 1
Figure 1
Autocrine and paracrine actions of S1P and its degradation by SPL. S1P is cleaved by SPL to yield phosphoethanolamine and hexadecenal. S1P can exert its effects through autocrine (intracellular), paracrine (receptor-dependent) or through formation of its products. Hexadecenal is unstable and rapidly converted to fatty acid and fatty alcohol. Physiological importance of phosphoethanolamine and hexadecenal produced in the SPL reaction in mammalian system is not known.
Figure 2
Figure 2
Potential role of SPL in human diseases. Sphingosine (So) is phosphorylated by sphingosine kinase (SK), yielding S1P. S1P can be recycled back to sphingosine by S1P phosphatase (SPP). Alternatively, S1P can be irreversibly degraded by SPL yielding phosphoethanolamine (EP) and hexadecenal (Hex). SPL has been implicated in various human diseases such as cancer, autoimmune, neurodegenerative, cardiovascular and infectious diseases. Inhibition of SPL activity by THI or novel inhibitor LX2931 prevents lymphocyte egress from thymus and secondary lymphoid organs, indicating SPL can serve as a potential drug target for immunomodulatrory drug.
See this image and copyright information in PMC

References

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