Tautomycin

Abstract: Publisher Summary Tumor promotion by the okadaic acid class of compounds binds to the okadaic acid receptors protein phosphatases 1 and 2A (PP-1 and PP-2A), which inhibit their activities. It results in an increase of phosphorylation of proteins in the cells. This chapter reviews the okadaic acid class of tumor promoters and discusses the significance of inhibition of PP-1 and PP-2A—the okadaic acid pathway—in the study of tumor promotion. Two-stage carcinogenesis experiments with the okadaic acid class of compounds established a general mechanism of tumor promotion for various organs. Okadaic acid was subjected to screening system for 12- O- tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which consist of three successive tests. Okadaic acid responded differently from TPA in the three tests. Thirty okadaic acid class compounds include four structurally different types—namely, okadaic acid, calyculin, microcystin, and tautomycin. The tumor promotion on mouse skin, rat glandular stomach, and the treatment of okadaic acid with teleocidin or TPA are also discussed in the chapter. Okadaic acid and teleocidin showed about the same potencies for production of papillomas and carcinomas during tumor promotion. The structure, distribution, gene expression, and biochemical effects of okadaic acid class compounds are also summarized.

Abstract: Reversible phosphorylation is a key mechanism for regulating the biological activity of many human proteins that affect a diverse array of cellular processes, including protein-protein interactions, gene transcription, cell-cycle progression and apoptosis. Once viewed as simple house keeping enzymes, recent studies have made it eminently clear that, like their kinase counterparts, protein phosphatases are dynamic and highly regulated enzymes. Therefore, the development of compounds that alter the activity of specific phosphatases is rapidly emerging as an important area in drug discovery. Because >98% of protein phosphorylation occurs on serine and threonine residues, the identification of agents that alter the activity of specific serine/threonine phosphatases seems especially promising for drug development in the future. This review is focused on the enzymes encoded by the PPP-gene family, which includes PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7. The structure/functions of human phosphatases will be addressed briefly, as will the natural product inhibitors of PP1-PP6 (e.g. okadaic acid, microcystins, nodularin, cantharidin, calyculin A, tautomycin, and fostriecin). The development of chimeric antisense oligonucleotides that support RNAase H mediated degradation of the targeted mRNA has resulted in compounds capable of specifically suppressing the expression of PP5 (ISIS 15534) and PP1gamma 1 (ISIS 14435) in human cells. Such compounds have already proven useful for the validation of drug targets, and if difficulties associated with systemic delivery of antisense oligonucleotides can be overcome, antisense is poised to have a major impact on the clinical management of many human disorders.