erbstatin and oxanosine

Topics: Bacteria; Fungi; Furans; GTP-Binding Proteins; Hydroquinones; Lovastatin; Monophenol Monooxygenase; Oncogene Proteins; Phenols; Phosphatidylinositols; Plants; Ribonucleosides

We investigated for the first time the effect of lipopolysaccharide and the signal transduction pathway on the biosynthesis of tetrahydrobiopterin [(6R-L-erythro-1',2'-dihydroxypropyl) -2-amino-4-hydroxy-5,6,7,8-tetrahydropteridine], the cofactor for the enzymatic hydroxylation of the aromatic amino acids, in the murine neuroblastoma cell line N1E-115, which synthesizes tetrahydrobiopterin constitutively. Activation of N1E-115 cells with 1 microgram/ml lipopolysaccharide resulted in statistically significant increases in both intracellular tetrahydrobiopterin contents and the activity (Vmax) of GTP cyclohydrolase I, a rate-limiting enzyme in tetrahydrobiopterin de novo biosynthesis. Following simultaneous addition of the inhibitors of protein tyrosine kinases and GTP-binding proteins into serum-free culture media with lipopolysaccharide, we analyzed the transduction pathway of lipopolysaccharide signal toward the tetrahydrobiopterin biosynthetic system in N1E-115 cells. Our data indicate the following conclusions: (a) Protein tyrosine kinase systems are involved in mediating lipopoly-saccharide signal to tetrahydrobiopterin production, and (b) there may be a cross-talk between GTP-binding protein and the protein tyrosine kinase system in mediating lipopolysaccharide signal. These observations suggest that a neuronal cell such as N1E-115, which barely expresses CD14 on its cell surface, responds to lipopolysaccharide like macrophages and monocytes in the absence of soluble CD14.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Benzoquinones; Biopterins; Dose-Response Relationship, Drug; Enzyme Inhibitors; GTP Cyclohydrolase; Hydroquinones; Lactams, Macrocyclic; Lipopolysaccharides; Mice; Neuroblastoma; Quinones; Ribonucleosides; Rifabutin; Signal Transduction; Tumor Cells, Cultured

Streptomyces and other microorganisms produce antibiotics, and enzyme inhibitors as secondary metabolites. Thus, they could be said as a treasury of organic compounds which have various structures and biological functions. Since oncogene theory has been extensively developed, we have screened oncogene function inhibitors from microorganisms as a new group of microbial secondary metabolites. Erbstatin is an inhibitor of epidermal growth factor (EGF) receptor and p60v-src-associated tyrosine kinase. Its inhibitory pattern vs. peptide is competitive. In cell culture it inhibited both EGF receptor autophosphorylation and internalization. Recently, we have isolated lavendustin A, an extremely potent inhibitor of tyrosine kinase, from Streptomyces. Lavendustin A is a novel compound and about 50 times stronger than erbstatin in inhibiting tyrosine kinase. Oxanosine is an inhibitor of ras oncogene product activity. It induces normal phenotypes in temperature-sensitive Kirsten sarcoma virus-infected rat kidney cells, lowering the intracellular levels of guanine nucleotides. Many oncogenes including src, ras, sis, fms and erbB are known to activate cellular phosphatidylinositol (PI) turnover. Therefore we have screened inhibitors of PI turnover and isolated psi-tectorigenine and pendolmycin from Nocardiopsis and inostamycin from Streptomyces. PI kinase is an enzyme involved in PI turnover pathways. We have isolated 2, 3-dihydroxybenzoic acid from Streptomyces as an inhibitor of PI kinase. These oncogene function inhibitors from microorganisms will be useful for the mechanistic study of oncogene product activities.

Topics: 1-Phosphatidylinositol 4-Kinase; Benzaldehydes; Benzoates; Benzoic Acid; Genes, ras; Genistein; Hydroquinones; Isoflavones; Oncogene Proteins; Phenols; Phosphotransferases; Protein-Tyrosine Kinases; Ribonucleosides