Inositol phosphatase

Damen, J.E., Liu, L, Ware, M.D., Ermolaeva, M., Majerus, P.W., and Krystal, G., 1998, Multiple forms ofthe SH2-containing inositol phosphatase, SHIP, are generated by C-terminal truncation. Blood, 92 1199-1205. 

Harmer, S.L., and DeFranco, A.L., 1999, The Sre homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with She and Grb2 in antigen receptor stimulated B lymphocytes. J. Biol. Chem. 274 12183-12191. 

Ishihara, H., Sasaoka, T, Hori, H., Wada, T., Hirai, H., Harata, T, Langjois, W.J., and Kohayashi, M., 1999, Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin siganhng. Biochim. Biophys. Res. 

Mikhalap, S.W., Shlapatska L.M., Berdova, A.G., Law, C.-L., Clark, E.A, and Sidorenko, S.P., 1999, CDwl50assodates with Src-homology 2-containinng inositol phosphatase and modulates CD95-mediated apoptosis. J. Immunol. 162 5719-5727. 

Ono, M., BoUand, S., Tempst, P., and Ravetch, J.V., 1996, Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcyRIIB. Nature, 383 263-266. 

WadaT, SasaokaT, Funaki M, Hoii H, Murakami S, Ishiki M, HarutaT, Asano T, Ogawa W, Ishihara H, Kobayashi M. 2001, Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5 -phosphatase catalytic activity. Mol. Cell. Biol. 21 1633-1646. 

Tricklebank MD, Singh L, Jackson A, et al Evidence that a proconvulsant action of lithium is mediated by inhibition of myo-inositol phosphatase in mouse brain. Brain Res 558 145-148, 1991... 

Berdy, S.E., Kudla, J., Gruissem, W. and Gillaspy, G.E., 2001, Molecular characterization of At5PTasel, an inositol phosphatase capable of terminating inositol trisphosphate signaling. Plant Physiol. 126 801-810. 

Cdt is related to a eukaryotic cytosolic enzyme, phosphatidyl inositol-3,4,5, triphosphate 5-phosphatase which removes the 5-phosphate group from phosphatidyl inositol-3,4,5, triphosphate. This activity is part of an intracellular signaling cascade induced by a ligand binding to a nearby receptor. Phosphatidyl inositol-3,4,5-triphosphate 5-phosphatase possesses an Src Homology 2 (SH2) domain in addition to its Inositol Phosphatase activity (SHIP). 

There are multiple phospholipase C s (PLCs) that are linked via G-proteins to neurotransmitter receptors. PLCs split the link between the Sn3 carbon and the phosphorus, thus generating two molecules the headgroup phosphate and diacylglycerol (DAG). PLCs particularly act on inositol phospholipids, generating inositol phosphates and DAG. As in the PLA2 cycle, both of these products are active signal transduction molecules. Again, the cycle must be terminated as shown in Fig. 2, by means of inositol phosphatases and DAG kinases. 

Prior to the recent work by Chang and Rapoport. the most widely accepted hypothesis of the mechanism of action of lithium was that it interfered with the PLC-inositol cycle by blocking inositol phosphatase and thus preventing the completion of the cycle by the regeneration of phosphatidyl-inositol. This effect undoubtedly occurs, but doubt has been cast on its relevance because it only does so at concentrations that are considerably higher than those required to inhibit CPLA2. 

In addition to these well-characterized routes, further transformations of inositol phosphates and phosphatidyl-inositol phosphates are known which lead to the formation of nearly 30 inositol-containing compounds with potential messenger function. These reactions include phosphorylation to inositol polyphosphates as well as specific dephosphorylation by inositol phosphatases. However, for only some of these compounds the biochemical attack points are known and specific in vivo functions could be demonstrated (review Irvine and Schell, 2001). 

From these data it appears that through the action of specific inositol phosphatases both IP3 and IP4 are sequentially dephosphorylated to free inositol (cf. Fig. 2). The dephosphorylation of IP3 requires Mg2+ and physiological concentrations of Ca +. The inositol phosphate phosphomonoesterase is inhibited by Li+, but the IP3 5 -phosphomonoesterase is not inhibited (Carsten and Miller, 1990). Interestingly, soluble and particulate extracts from porcine skeletal muscle also metabolize IP3 and IP4 to inositol in a stepwise fashion (Foster et al., 1994). Apparently, smooth and skeletal muscles have the same set of inositol polyphosphate phosphatases, although their functional role in skeletal muscle is not known. 

Several 9-(phosphonoalkyl)- and 9-(difluoroalkyl)-guanine derivatives (12, X = H or F) have been studied as potential inhibitors of guanylate kinase. The most pronounced effect was observed with n - 5 Phenoxymethylene bisphosphonates (13, where R R and R represent a variety of substituents) were prepared and found to act as inositol phosphatase inhibitors and antimanic agents some inhibited the enzyme with IC50 < 50 pmol 4-(Phosphonomethylphenoxy)-l-carbamoylazetidine-2-ones (14) inhibited human leukocyte elastase for 14 (R R = OEt = 1.2 x 10 moL s (ref. 38). 

Lad C, Williams H, Wolfenden, R. The rate of hydrolysis of phosphomonoester dianions and the exceptional catalytic proficiencies of protein and inositol phosphatases. Proc Natl Acad Sci U S A 2003 100 5607-5610. 

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