Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several species of protozoa belonging to the genus Leishmania are pathogenic for humans, causing visceral and cutaneous diseases. They are transmitted by phlebotomine sandflies as flagellated promastigotes to mammals hosts, where they live as aflagellated amastigotes mainly within macrophages. Studies performed on mice infected with Leishmania major demonstrated that host defence against this infection depends on the interleukin-12-driven expansion of the T helper 1 cell subset, with production of cytokines such as interferon-gamma, which activate macrophages for parasite killing through the release of nitric oxide. The parasitocidal role of this radical is now emerging also in the human and canine model. Healing or progression of the infection is related to the genetic and immune status of the host, and to the virulence of different species and strains of Leishmania. The parasite survival ultimately depends on the ability to evade the host immune response by several mechanisms. Among them, inhibition of the signal transduction pathway of the host cells is particularly important. In fact, promastigotes inhibit protein kinase C activation, cause Ca++ influx into the host cell and decrease the levels of myristoylated alanine-rich C kinase substrate-related proteins, which are substrates for PKC. In addition, Leishmania infection blocks IFN-gamma-induced tyrosine kinase phosphorylation, with consequent impairment of signalling for IL-12 and nitric oxide production. Finally, Leishmania activates protein phosphotyrosine phosphatases, which down-regulate mitogen-activated protein kinase signalling and c-fos and nitric oxide synthase expression. New pharmacological applications, including protein tyrosine phosphatase and protein farnesyltransferase inhibitors, are being evaluated against leishmaniosis in vitro and in vivo in the murine model.
 ...
PMID:Interactions between Leishmania parasites and host cells. 1168 76

As the most frequently mutated oncogene in human cancers, the small GTPase Ras is a logical target for anticancer drug development. Ras proteins serve as molecular switches regulating many key signaling processes, including growth-promoting pathways critical for normal cell functions that go awry in cancer. How to interfere selectively and successfully in oncogenic Ras function has proved to be surprisingly vexing. The complexity and importance of controlling correct subcellular localization supports the development of inhibitors that disrupt specific aspects of Ras membrane binding. Here, we concentrate on assays and compounds relevant to inhibiting enzymes responsible for post-translational modifications required for full processing and correct localization of Ras proteins or their targets. Common modifications include farnesylation (by farnesyltransferase, FTase) or geranylgeranylation (GGTase I), proteolysis (Rce1) and carboxymethylation (Icmt), as well as palmitoylation (PATs) and phosphorylation (PKC). We discuss history, current status and prospects of inhibitors designed to block these steps of prenyl and post-prenyl processing of Ras itself, or that appear to compete with oncogenic Ras (farnesyl-S-thiosalicylic acid, FTS) for key membrane binding sites that dictate its ability to transduce specific oncogenic signals. Recent patents focusing on GGTIs, Icmt and PATs, and on novel approaches to Ras inhibition, are emphasized.
 ...
PMID:Inhibitors of chronically active ras: potential for treatment of human malignancies. 1828 22