Phosphatidylinositols synthesis

The phosphatidylinositol pathway is completed by regeneration of the phospholipid from IP3 and DG. It is remarkable that IP3 is successively dephosphorylated to mositol. The last step of this sequence is inhibited by Li ions, which block phosphatidylinositol synthesis. Li salts are used to control the symptoms of manic-depressive illness, an affective mental disorder (see section 3.5.4), and it is thus tempting to implicate the last reaction of the PI pathway in the etiology of this disorder. 

There are few commercial fungicides that have glycerophospholipid biosynthesis inhibition as their mode of action. The validated targets are phosphatidylcholine synthesis and phosphatidylinositol synthesis. 

Phosphatidylinositol Synthesis. The symptoms of inositol depletion include a decreased hyphal extension rate, increased branching and cell lysis. Other changes occur in protein, carbohydrate and nucleic acid metabolism, and reduced activity levels of membrane-bound wall biosynthetic enzymes.7... 

Zhu, X., and Eichberg, J., 1990, A myo-inositol pool utilized for phosphatidylinositol synthesis is depleted in sciatic nerve from rats with streptozotocin-induced diabetes. Proc. Natl. Acad. Sci. U.S.A. 87 9818-9822. 

Norman, R.A., McAlister, M.S., Murray-Rust, J., Movahedzadeh, E, Stoker, N.G., and McDonald, N.Q., 2002, Crystal structure of inositol 1-phosphate synthase from Mycobacterium tuberculosis, a key enzyme in phosphatidylinositol synthesis. Structure 10 393 102. 

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. 

Berridge MJ, Fain JN. Inhibition of phosphatidylinositol synthesis and the inactivation of calcium entry after prolonged exposure of the blowfly salivary gland to 5-hydroxytryptamine. Biochem. J. 1979 178 59-69. 

The mechanism of action and antitumor activity of 38a was studied [153]. Piericidin B1 N-oxide decreased EGF-stimulated phosphatidylinositol synthesis in a concentration dependent manner. It did not inhibit phosphatidic acid synthesis, phosphatidylinositol-4-kinasc, phospholipase C, protein kinase C, EGF receptor tyrosine kinase, EGF-induced inositol phosphate formation, DNA synthesis, RNA synthesis, or protein synthesis at concentrations which caused inhibition of phosphatidylinositol synthesis [153]. 

A. Masayama, T. Takahashi, K. Tsukada, S. Nishikawa, R. Takahashi, M. Adachi, K. Koga, A. Suzuki, T. Yamane, H. Nakano, and Y. Iwasaki Streptomyces phospholipase D mutants with altered substrate specificity capable of phosphatidylinositol synthesis. Chembiochem 9 (2008) 974-981. 

These groups were designed for use in the synthesis of phosphatidylinositol phosphates, where it was desirable to be able to cleave a benzoate without cleaving a glyceryl ester. 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

Cheatham, B., Vlahos, C. J., Cheatham, L., Wang, L., Blenis, J., and Kahn, C. R. (1994). Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol. Cell. Biol. 14, 4902-4911. 

Zaikova, T. (2001). Synthesis of fluorogenic substrates for continuous assay of phosphatidylinositol-specific phospholipase C. Bioconjug. Chem. 12, 307-313. 

Figure 1. Control of mitochondrial biogenesis by the nuclear genome. Most mitochondrial proteins, including cytochrome c, are nuclear gene products which are subsequently imported into mitochondria. Similarly, most enzymes involved in synthesis of mitochondrial phosphoplipids are encoded in the nuclear genome. Being located in the endoplasmatic reticulum, they synthesize phosphatidylcholine (PtdCho), phosphatidylserine (PtdSer), phosphatidylglycerol (PG) and phosphatidylinositol (Ptdins). The phospholipids are transferred to the outer membrane. The imported lipids then move into the inner membrane at contact sites. Mitochondria then diversify phospholipids. They decarboxylate phosphatidylserine to phosphatidylethanolamine (PtdEtN), but the main reaction is the conversion of imported phosphatidylglycerol to cardiolipin (CL). Cardiolipins localize mainly in the outer leaflet of the inner membrane.

A recent report suggests that inhibition of PC synthesis constitutes one of the primary events by which C2-ceramide triggers apoptosis (Ramos et al, 2000). Treatment of cerebral granule neurons with C2-ceramide resulted in a rapid (within 1 hour) reduction in PC biosynthesis, whereas only 6 h after exposure to the agonists the first significant drop in cell viability was observed. The authors further showed that addition of exogenous PC resulted in a dose-dependent full prevention of neuronal death. This was specific for PC, because addition of other glycerohpids Uke, PE, PS, phosphatidylinositol and phosphatidic acid had no effect on C2-ceramide-induced apoptosis. 

Figure 11.21 Outline of synthesis of phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine. Note in the synthesis of phosphatidylinositol, the free base, inositol, is used directly. Inositol is produced in the phosphatase reactions that hydrolyse and inactivate the messenger molecule, inositol trisphosphate (IP3). This pathway recycles inositol, so that it is unlikely to be limiting for the formation of phosphatidylinositol bisphosphate (PIP )- This is important since inhibition of recycling is used to treat bipolar disease (mania) (Chapter 12, Figure 12.9). Full details of the pathway are presented in Appendix 11.5. Inositol, along with choline, is classified as a possible vitamin (Table 15.3).

PHOSPHATIDYLINOSITOL SYNTHASE 1-Phosphatidyl-1 D-myo-inositol 4,5-bisphos-phate synthesis,... 

Akaterpin (372) is an inhibitor of phosphatidylinositol-specific phospholipase C from a Callyspongia sp. [326]. The relative stereochemistry of the ring junction in the upper decalin moiety of akaterpin was shown to be cis by synthesis of model compounds [327]. 

Chakravorty, A. Joslyn, M.L Davis, J.S. Characterization of insulin and insulin-like growth factor-I actions in the bovine luteal cell Regulation of receptor tyrosine kinase activity, phosphatidylinositol 3-kinase, and deoxyribonucleic acid synthesis. Endocrinology, 133, 1331-1340 (1993)... 

In eukaryotes, phosphatidylglycerol, cardiolipin, and the phosphatidylinositols (all anionic phospholipids see Fig. 10-8) are synthesized by the same strategy used for phospholipid synthesis in bacteria. Phosphatidylglycerol is made exactly as in bacteria. Cardiolipin synthesis in eukaryotes differs slightly phosphatidylglycerol condenses with CDP-diacylglycerol (Fig. 21-26), not another molecule of phosphatidylglycerol as in E. coli (Fig. 21-25). 

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