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RESEARCH PRODUCT

Modulation of protein phosphorylation by natural products

subject

description

Studies carried out to determine the influence of phosphorylation and dephosphorylation of proteins in a variety of physiological events are of increasing interest. The activity of kinases and phosphatases and their respective inhibition by endogenous mediators and by pharmacological agents regulates a huge number of biochemical pathways involved in cellular proliferation, apoptosis, inflammation, hormonal activity, and gene transcription, amongother processes. This article focuses on the recently described natural products able to interfere negatively with the activity of serine/threonine and tyrosine kinases. These agents are classified, according to theirbiosynthetic origin and chemical properties in phenolics, terpenoids, alkaloids and miscellaneous substances. The nucleus of the review is preceded by a general overview on kinase activity, followed by a chapter devoted to naturally occurring kinase activators. Finally, a section concerning the advances in phosphatase inhibition research is included. The main sources of novel phenolic kinase inhibitors are tannins, coumarins, polycyclic isopentenyl isoflavonoids, and phloroglucinols. Other phenolics like flavonols or simple isoflavones are also reported, together with some reputed plant active principles such as curcumin, hypericin or resveratrol. Amongthe terpenoids, the effects of wortmannin, and thoseof certain triterpenoids like ginsenoside Rb1 or Rh1 should be mentioned. The alkaloids comprise two main groups of inhibitors: the indole alkaloids, headed by staurosporine and its derivatives, which are potent, selective inhibitors of protein kinase C, and the isoquinoline alkaloids, subdivided into aporphines, benzophenanthridines and naphtylisoquinolines. The scientific panorama regarding the inhibition of phosphatases is dominated by the polyether and cyclic polypeptide environmental toxins, although some new agents such as indole and isoquinoline alkaloids have been described.