Tetrahydrobiopterin is a required cofactor for nitric oxide synthesis and for the three aromatic amino acid hydroxylases that hydroxylate phenylalanine, tyrosine and tryptophan,producing precursors of biogenic amine neurotransmitters. Tissue levels of tetrahydrobiopterin are regulated mainly by the activity of the first enzyme on the de novo biosynthetic pathway, GTP cyclohydrolase I (GTPCH). Sphingolipid metabolites, ceramide, sphingosine, and sphingosine-1-phosphate, play important signaling roles in many biological processes, including cell growth, death, and differentiation. We previously showed that although ceramide plays a role in TNF-alpha induction of nitric oxide synthase and nitric oxide production in glial cells, TNF-alpha stimulates GTP cyclohydrolase activity and tetrahydrobiopterin synthesis by a ceramide independent mechanism. We have now found that activation of sphingosine kinase and generation of intracellular sphingosine-1-phosphate, a metabolite of ceramide, regulates GTPCH expression and tetrahydrobiopterin synthesis. Moreover, intracellularly produced sphingosine-1-phosphate protects neuronal cells from apoptosis induced by trophic factor withdrawal by inhibiting activation of caspases and of the MAP kinases, JNK and p38. In a continuing and highly successful collaboration on sphingolipid signaling with Spiegel?s lab at Georgetown University, now at Virginia Commonwealth University, we have pioneered studies showing that sphingosine-1-phosphate generation is essential for growth factor induced cell motility, characterized a specific sphingosine-1-phosphate phosphatase that regulates cellular levels of this sphingolipid metabolite, cloned a sphingosine kinase interacting protein that regulates its activity, and discovered new roles for sphingosine-1-phosphate in asthma and allergic responses. These discoveries were recognized by invitations to write reviews on our work from several prestigious journals.
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