Phosphatidyl inositol-4-monophosphate

A further intriguing aspect of the biological chemistry of cyclic inositol phosphates lies in the fact that they are not only detected as products of hydrolysis of PIPj catalysed by phospholipase C, but they may also be intermediates in this enzyme-catalysed reaction. The water-soluble products of the breakdown of PIPj catalysed by phospholipase C were hydrolysed in 0-labelled water in the presence of acid (Wilson et al., 1985a,b). The resulting trisphosphates after work-up were analysed by mass spectrometry-gas chromatography. Since only reactive cyclic phosphates are hydrolysed (with label incorporation) in dilute acid, Majerus and coworkers were able to use this technique to quantify the initial cyclic phosphate product of the phospholipase C reaction. Similar experiments were performed with phosphatidyl inositol 4-monophosphate (PIP) and phosphatidyl inositol (PI) as substrates and the results confirmed by hplc ananlysis. 

The inositol monophosphate could then receive a phosphatidyl group from CDP-diglyceride to form phosphatidyl inositol monophosphate by a reaction analogous to Reaction 27 leading to the formation of phosphatidyl inositol ... 

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.

Lithium decreases production of adenosine 3c,5c-cyclic monophosphate (cAMP), and inhibits the recycling of phosphatidyl inositol phosphate to inositol, resulting in a decrease in inositol triphosphate (IP3). Lithium also affects the permeability of membranes to sodium and potassium. 

Fourteen years previously, Dawson et al. (1971) had observed cyclic inositol monophosphate (cIP) to be the major water-soluble product in enzyme-catalysed phosphatidyl inositol breakdown. Dawson observed that cIP and inositol 1-monophosphate (IP) were released from the enzyme simultaneously and surmised that the enzyme (PLC) was primarily a transferase, hydrolysing PI and PIPj by a mechanism similar to that of adenylate cyclase. The observation of 1,2-cyclic phosphate products does suggest that reaction proceeds via a cyclic phosphate intermediate, but an analogy is better drawn with the postulated mechanism of ribonuclease. In such a mechanism, the function of the 2-hydroxyl of phosphatidyl inositol (the only axial ring substituent) is similar to that of the 2 -hydroxyl of RNA in the reaction catalysed by ribonuclease (Scheme 47). Thus enzyme-catalysed phosphatidyl inositol breakdown can be seen as a two-step process, with cyclization (or transphosphorylation) followed by a hydrolysis... 

The different varieties of orthophosphoric monoesters and diesters which are present in all living species are exceedingly numerous. Biologically important monoesters include the mononucleotides such as, for example, adenylic acid (adenosine monophosphate, AMP), inosinic acid, vitamin Bg and many phosphorylated proteins, for example, milk caseins. Biologically important diesters include the phospholipids (e.g. lecithin and phosphatidyl inositol), plasmalogens, sphingomyelins, cyclic nucleotide monophosphates (e.g. cyclic AMP), some teichoic acids, vitamin Bj2 and of course the immensely important nucleic acids (polynucleotides) (Chapters 10 and 11). The great stability of diesters is an essential feature of the chemistry of polynucleotides. 

Phytic acid will form pyrophosphate complexes (10.36c). Phosphates of myo-inositol containing less than 6 ester OP(0)(OH)2 gronps have been obtained from plants and detected in soils. Mixtures of these lower phosphates are known to be produced by enzyme-catalysed hydrolysis of phytic add, and inositol monophosphate is a degradation product from phosphatidyl inositol (Chapter 11.3). Some varieties have been laboratory synthesised [50-52]. 

It is known that inositol monophosphate occurs in mammalian tissues (H.vb-SCHER and Hawthorne 1957) and in fish liver (Tsuyuki and Idler 1961). After the administration of myoinositol-C, the specific radioactivity of inositol monophosphate is such that it cannot be derived from the hydrolysis of phosphatidyl inositol (Tsuyuki and Idler 1961, Galliard and Hawthorne 1963). Although... 

A second enzyme active towards phosphatidyl inositol is present in ox pancreas (Dawson 1959) and rat fiver (Kemp et al. 1961). With this enzyme the lipid is broken down into diglyceride and inositol monophosphate by a reaction analogous to the hydrolysis of lecithin by phospholipase C (Reaction 37). The enzjmae does not hydrolyse lecithin. 

This enzyme [EC 2.7.1.68], also known as diphosphoinos-itide kinase, catalyzes the reaction of ATP with 1-phosphatidyl-lo-myo-inositol 4-monophosphate to produce ADP and 1-phosphatidyl-lD-myo-inositol 4,5-bisphos-phate. 

The activated phosphatidyl unit then reacts with the hydroxyl group of an alcohol to form a phosphodiester linkage. If the alcohol is inositol, the products are pkosphatidylinositol and cytidine monophosphate (CMP). 

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