Inositol phosphate phosphatases

Norris, F., Wilson, M., Walhs, T., Galyov, E., Majerus, P. SopB, a protein required for virulence of Salmonella dublin, is an inositol phosphate phosphatase. Proc Natl Acad Sci USA 95 (1998) 14057-14059. 

In plants, inositol is biosynthesized from glucose 1-phosphate via inosose 1-phosphate, which is reduced into ID-inositol 3-phosphate (INOl pathway). After dephosphorylation by inositol phosphate monophosphatase, myo-inositol is fed into biosynthesis of inositol phospholipids via a Kennedy-like sequence. In mammalian organisms, inositol is acquired from the diet and is also biosynthesized via INOl. The latter pathway, rather than the inositol phosphate phosphatase, seems to be a more promising target of antipsychotic drugs (17, 18) (see Fig. 2). 

Irving, G.C.j. and Cosgrove, D.J. (1971) Inositol phosphate phosphatases of microbiological origin observations on the nature of this active centre of a bacterial (Pseudomonas sp.) phytase. Australian Journal of Biological Science 24, 559-554. 

The inositol polyphosphate 5-phosphatases belong to a family of enzymes that terminate the signals generated by inositol lipid kinases and PLC. To date, two major types of 5-phosphatase have been identified, both of which share a common 5-phosphatase domain of approximately 300 amino acids, with several highly conserved motifs. Type-I enzymes are 43-65 kDa and preferentially hydrolyze 1(1,4,5)P3 and 1(1,3,4,5)P4, with the attendant formation of I(1,4)P2 and 1(1,3,4)P3, but have little or no activity towards membrane-bound phosphoinositides. The pro-totypic form of a type-15-phosphatase is a 43 kDa protein that is post-translationally modified by farnesylation of the carboxyl terminus CAAX motif this modification juxtaposes the enzyme with the membrane. Type-II enzymes are larger (75-160 kDa) and will hydrolyze both water-soluble inositol phosphates and lipids that... 

FIGURE 20-7 Pathways of inositol phosphate metabolism. Note that the metabolism of the second messenger I(1,4,5)P3 is shown to the left of the dashed line, while the interconversions of the higher inositol phosphates are shown to the right of the dashed line. Only the quantitatively major established pathways are depicted. Li+ is known to block the dephosphorylation reactions indicated by the (black) bars. Numbers refer to the following enzymes 1, inositol polyphosphate 5-phosphatase (I) 2, inositol polyphosphate 1-phosphatase 3,I(1,4,5)P3 3-kinase 4, inositol polyphosphate 4-phosphatase 5, inositol polyphosphate 3-phosphatase 6, inositol monophosphate phosphatase 7, I(1,3,4)P3 6-kinase/I(3,4,5,6)P4 1-kinase 8, Ipmk 9, DIPP 10, IP6 kinase 11, Ipk 1 12, MIPP 13, PP-IP5 kinase. 

Figure 6.9. Pathways of inositol phosphate metabolism. Ins 1,4,5-P3, generated via the hydrolysis of phosphatidyl 4,5-bisphosphate by phospholipase C, can be metabolised by a kinase (to generate Ins 1,3,4,5-P4) or via a phosphatase (to yield Ins 1,4-P2). These products can be metabolised further to produce inositol, which itself may be sequentially phosphory-lated to regenerate phosphatidylinositol 4,5-bisphosphate.

GLYCOGEN PHOSPHORYLASE HISTIDINOL-PHOSPHATE PHOSPHATASE myo-INOSITOL 1-MONOPHOSPHATASE... 

Ins(l,4,5)P3 is subject to rapid degradation to compounds without any regulatory activity, due to the effects of phosphatases. In addition, there are many other inositol phosphate derivatives (see Berridge Irvine, 1989). Thus, further phosphorylation of Ins(l,4,5)P3 may take place. Of the more highly phosphorylated inositol compounds, Ins(l,4,5,6)P4 in particular is attributed a regulatory function. 

Recently, an additional IP3 isomer, inositol 1,3,4-trisphosphate (1,3,4-IP3), which is ineffective in releasing calcium from the ER, has been identified. Unlike 1,4,5-IP3, 1,3,4-IP3 is thought not to be a product of the direct hydrolysis of an isomer of PIP2, but rather a result of the action of a 5-phosphatase on a more polar inositol phosphate, inositol 1,3,4,5-tetrakisphosphate (IP4) [34], At this time neither 1,3,4-IP3 nor its precursor IP4, which is formed as a result of a 3-kinase-catalysed phosphorylation of 1,4,5-IP3, has a clear physiological role, although IP4 has been implicated in the regulation of plasma membrane calcium influx (see Rasmussen and Barrett, Chapter 4). 

From the evidence accumulated so far, it seems likely that the cAMP signal transduction pathway will be a major effector of a stimulatory signal to the pars tuberalis, which can be regulated by melatonin [115]. The effect of aluminum as AlF41 has been studied on inositol phosphate accumulation, calcium mobilization, and cyclic AMP production in ovine pars tuberalis cells [116]. In the presence of 10 mmol L-1 LiCl, AlF41 stimulated the net accumulation of inositol phosphates over a 40-min incubation. Lithium is a known inhibitor of phosphatases in the inositol phosphate-recycling pathway. The results show the existence of a lithium-sensitive phosphoinositide signaling. 

The de novo biosynthesis of all inositols follows a common pathway from glucose 6-phosphate (Loewus and Kelly, 1962 Majumder et al., 1997). In the first step, glucose 6-phosphate is converted to myo-inositol 1-phosphate (MIP) by wvo-inositol 1-phosphate synthase, (EC 5.5.1.4 MIPS), and in the second step, MIP is dephosphorylated by myo-inositol 1-phosphate phosphatase to yield myo-inositol (Chen and Charalampous, 1965 Eisenberg, 1967). The... 

Figure 1. Schematic representation of the brain inositol signaling system. The quantities of IMPase isoenzymes and IPPase are increased by chronic lithium treatment occurring at either the gene or protein levels. Inositol in this diagram indicates the myo-inositol isomer. Calbindin -calcium binding protein DAG- diacyl glycerol Gq-GTP binding protein IMPase 1 — inositol mono phosphatase 1 IPPase- inositol polyphosphate 1-phosphatase Ins(l)P, Ins(3)P, Ins(4)P-inos-itol monophosphates Ins(l,3)P2 - inositol 1,3-bisphosphate Ins( 1,4)/ 2 - inositol 1,4-bisphos-phate Ins(3,4)/)2- inositol 3,4-bisphosphate Ins (1,4,5)P3 - inositol 1,4,5-trisphosphate Ins( 1,3,4)/ 3 - inositol 1,3,4-trisphosphate Li+-lithium PA - phosphatidic acid PI- phosphatidyl inositol PIP- phosphatidyl inositol 4-phosphate PIP2- phosphatidyl inositol 4,5-bisphosphate PIP3- phosphatidyl inositol 3,4,5 trisphosphate PLC - phospholipase-C, VPA-valproate.

Plant foods contain relatively large amounts of inositol phosphates, including the hexaphosphate, phytic acid. Phytate chelates minerals, such as calcium, zinc, and magnesium, forming insoluble complexes that are not absorbed. However, both intestinal phosphatases and endogenous phosphatases (phytase) in many foods dephosphorylate a significant proportion of dietary phytate. The inositol released can be absorbed and utilized for phosphatidylinositol synthesis. 

Lithium selectively interferes with the inositol lipid cycle (100) and this is the basis for a proposal of a unifying hypothesis for lithium actions (96). Administration of lithium to rats (10 mmol/kg) resulted in a reduction in brain myoinositol and an increase in the reaction substrate inositol-l-phosphate (101). The magnesium-dependent enzyme inositol monophosphate phosphatase, which catalyzes the conversion of inositol monophosphates to inositol, was totally inhibited in rat mammary gland by high concentrations of lithium (250 mM) and partially inhibited by lower concentrations (2 mAf) (102). At clinically relevant concentrations lithium has been shown to inhibit inositol monophosphate phosphatase in bovine brain (K, = 0.8 mM) by substi-... 

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. 

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). 

The products of the PI3-kinase reaction are different phosphoinositide derivatives phosphorylated at the 3 position, of which PtdIns(3,4,5)P3 has the greatest regulatory importance. PtIns(3,4,5)P3, like cAMP, has the function of a messenger substance that activates effector molecules in the sequence for further signal conduction. In contrast to cAMP, PtdIns(3,4,5)P3 is localized in the cell membrane and performs its function in close association with processes at the cell membrane. The concentration of PtdIns(3,4,5)P3 in the cell depends both on the rates of synthesis by PI3-kinases and the rates of hydrolysis of its phosphate residues. Several inositol polyphosphate phosphatases have been identified that remove the phosphates at position 3 or 5 of the inositol moiety. Among the inositol polyphosphate phosphatases with specificity for the 3-position, the PTEN phosphatase has been identified as a tumor supressor protein (see below). 

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