INOSITOL POLYPHOSPHATE 5-PHOSPHATASE

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. 

The Li+-induced inhibition of IMPase also results in increases in the levels of the other monophosphates, Ins(3)P, and Ins(4)P, although the increase is less than for Ins(l)P in the brain. Increases in the levels of the bisphosphates are also observed and these increases are believed to be related to the Li+-induced inhibition of another enzyme in this cycle, inositol polyphosphate 1-phosphatase [92], which dephosphorylates both Ins(l,3,4)P3 and Ins(l,4)P2, producing Ins(3,4)P2 and Ins(4)P, re-... 

Inositol Monophosphate Phosphatase and Inositol Polyphosphate 1 -Phosphatase... 

Figure 6. Schematic representation of inositol monophosphate phosphatase (left) and inositol polyphosphate 1-phosphatase (right), showing the helical (green cylinders) and (3-sheet (yellow arrows) regions. The monophosphatase is complexed with lns(1)P (solid spheres) and Gd3+ (orange sphere) in the binding cleft and the polyphosphatase has two Mg2+ (lilac spheres) ions. (The coordinates were obtained from the Brookhaven Protein Data Bank).

Inositol polyphosphate 1-phosphatase Another enzyme in inositol recycling inhibited by lithium, resulting in depletion of substrate for IP3 production (Figure 29-4)... 

In humans, Li+ therapy is used in the clinical treatment of certain bipolar disorders (e.g., manic depression), where its action is presumed to be inhibition of abnormal PI signaling, due to a decrease in inositol substrate availability (Lachman and Papolos, 1989). More recent studies have indicated the presence of other Li+-sensitive enzymes in animals that may also function as in vivo targets for Li+ action in animal development. These include the inositol polyphosphate-1 phosphatase (IPPase) (York et al., 1995) and glycogen synthase kinase-3(3 (Klein and Melton, 1996). However, why inositol would rescue the phenotypes putatively caused by the inhibition of such enzymes remains unclear thus, this area is still ripe for experimentation that could reconcile these issues. 

York, J.D., and Majerus, P.W., 1990, Isolation and heterologous expression of a cDNA encoding bovine inositol polyphosphate 1-phosphatase. I roc. Natl. Acad. Sci. 87 9548-9552. 

Acharya, J.K., Labarca, P., Delgado, R., Jalink, K., and Zuker, C.S., 1998, Synaptic defects and compensatory regulation of inositol metabolism in inositol polyphosphate 1-phosphatase mutants. Neuron 20 1219-1229. 

Xiong, L., Lee, B., Ishitani, M., Lee, H., Zhang, C., and Zhu, J.-K., 2001, Fiery 1 encoding an inositol polyphosphate 1-phosphatase is a negative regulator of abscisic acid and stress signaling in Arabidopsis. Genes Devel. 15 1971-1984. 

In general there are three phosphatase families alkaline, acid, and protein phosphatases. Alkaline phosphatases are typically dimers that contain three metal ions per subunit and have a pH optimum pH above 8. Acid phosphatases exhibit an optimum pH<7 and are usually divided into three classes low molecular weight acid phosphatases (<20 kDa), high molecular weight acid phosphatases (50-60 kDa), and purple acid phosphatases (which contain an Fe-Fe or Fe-Zn center at the active site). Phosphatases specific for I-l-P appear to be most similar (in kinetic characteristics but not in mechanism) to the alkaline phosphatases, but their structures define a superfamily that also includes inositol polyphosphate 1-phosphatase, fructose 1, 6-bisphosphatase, and Hal2. The members of this superfamily share a common structural core of 5 a-helices and 11 (3-strands. Many are Li+-sensitive (York et al., 1995), and more recent structures of archaeal IMPase proteins suggest the Li+ -sensitivity is related to the disposition of a flexible loop near the active site (Stieglitz et al., 2002). 

Quintero, F.J., Garciadeblas, B., and Rodriguez-Navarro, A., 1996 The SAL1 gene of Arabidopsis, encoding an enzyme with 3 (2 ),5 -bisphosphate nucleotidase and inositol polyphosphate 1-phosphatase activities, increases salt tolerance in yeast. Plant Cell 8 529-537. 

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.

The crystal structure of recombinant bovine inositol polyphosphate 1-phosphatase (1-ptase) was determined in the presence of Mg + at 2.3-A resolution (York et al., 1994). The fold of 1-ptase is similar to that of two other metaI-dependent/Li+-sensitive phosphatases, inositol monophosphate phosphatase and fructose 1,6-biphosphatase. Comparison of the active-site pockets of these proteins will likely provide insight into substrate binding, the mechanisms of metal-dependent catalysis, and Li+ inhibition. 

Patel S, Yenush L, Rodriguez PL, Serrano R and Blundell TL (2002) Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3 -phosphoadenosine-5 -phosphate phosphatase activities a novel target of lithium therapy. J Mol Biol 315 677—685. 

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