Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1. Sphk1 null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in most Sphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from the Sphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs of Sphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.
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PMID:Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. 1545 1

In the search for bioactive sphingosine 1-phosphate (S1P) receptor ligands, a series of 2-amino-2-heterocyclic-propanols were synthesized. These molecules were discovered to be substrates of human-sphingosine kinases 1 and 2 (SPHK1 and SPHK2). When phosphorylated, the resultant phosphates showed varied activities at the five sphingosine-1-phosphate (S1P) receptors (S1P(1-5)). Agonism at S1P(1) was displayed in vivo by induction of lymphopenia. A stereochemical preference of the quaternary carbon was crucial for phosphorylation by the kinases and alters binding affinities at the S1P receptors. Oxazole and oxadiazole compounds are superior kinase substrates to FTY720, the prototypical prodrug immunomodulator, fingolimod (FTY720). The oxazole-derived structure was the most active for human SPHK2. Imidazole analogues were less active substrates for SPHKs, but more potent and selective agonists of the S1P(1) receptor; additionally, the imidazole class of compounds rendered mice lymphopenic.
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PMID:Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs. 1963 23

The lipid mediator sphingosine-1-phosphate (S1P) is generated within cells from sphingosine by two sphingosine kinases (SPHK1 and SPHK2). Intracellularly synthesized S1P is released into the extracellular fluid by S1P transporters, including SPNS2. Released S1P binds specifically to the G protein-coupled S1P receptors (S1PR1/S1P(1)-S1PR5/S1P(5)), which activate a diverse range of downstream signalling pathways. Recent studies have proposed that one of the central physiological functions of intercellular S1P signalling is in lymphocyte trafficking in vivo because genetic disruption of SPHK1/2, SPNS2 or S1PR1/S1P(1) in mice induces a lymphopenia phenotype. In this review, we discuss the current understanding of intercellular S1P signalling in the context of immunity.
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PMID:The functional roles of S1P in immunity. 2292 32