Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism
Chapter XIX1l-myo-Inositol-1-phosphate synthase
Section snippets
Discovery
The inositol containing phospholipids have been shown to play a diversity of roles in eukaryotic cells. Much of the attention in recent years has focussed upon the role of inositol phosphates, produced by regulated hydrolysis of the multiple phosphorylated forms of phosphatidylinositol (PtdIns), in signal transduction pathways in cells of higher eukaryotes [1]. PtdIns is synthesized from CDP-diacylglycerol and myo-inositol. The phospholipid precursor, myo-inositol, is derived by
Purification, characterization, and localization
I1-P synthase has been observed in virtually all eukaryotic organisms which have been investigated as well as in several prokaryotes and in the chloroplasts of plants (Table 1). It is found in the tissues of higher animals and plants, and in algae, protozoa, and fungi (Table 1). However, the well-studied fission yeast, Schizosaccharomyces pombe, is a natural inositol auxotroph apparently lacking I1-P synthase, despite the fact that it synthesizes inositol containing phospholipids [25]. As
Genetics of inositol biosynthesis
Eukaryotic microorganisms provide an opportunity for genetic analysis of the inositol biosynthetic pathway and its regulation. Indeed, inositol auxotrophs of Neurospora crassa were among the mutants studied by Beadle and Tatum 46, 47. Shatkin and Tatum [48]showed that inositol is required for growth in Neurospora and in its absence, inositol auxotrophs of Neurospora undergo inositol-less death, a phenomenon later described in other fungi including bakerÕs yeast, S. cerevisiae [49]. An extensive
I1-P synthase regulation
Hasegawa and Eisenberg [58]studied expression of I1-P synthase in rats following surgical removal of various hormonally-active organs. After hypophysectomy in male rats, I1-P synthase activity decreased in the reproductive organs and liver. Thyroidectomized male rats showed a decrease in I1-P synthase activity in liver, but not in the reproductive organs. These decreases were reversed by hormonal treatments. The results of Hasegawa and Eisenberg suggest that there may be considerable regulation
Evolution and molecular biology of I1-P synthase
The availability of the ino1 mutants of S. cerevisiae permitted the cloning [70]and sequencing [71]of the INO1 gene encoding the yeast I1-P synthase subunit. Homologous genes have been isolated and characterized from a number of other organisms, notably higher plants and eukaryotic microorganisms (Fig. 1, Table 2).
Alignment of the amino acid sequences deduced from the DNA sequence of the genes encoding I1-P synthase reveals remarkable evolutionary conservation of the primary structure (Fig. 1).
Conclusions
I1-P synthase catalyzes an essential step in phospholipid biosynthesis. The enzyme is found in diverse organisms, both eukaryotic and prokaryotic, suggesting that the pathway for the synthesis of myo-inositol from d-glucose arose early in the evolution of life. In those organisms from which the structural gene has been isolated, a high degree of transcriptional regulation has been observed. Unfortunately, this regulation has not yet been studied on the molecular level in higher animals.
Acknowledgements
The authors are indebted to Frank and Mary Loewus for their many contributions to our understanding of inositol metabolism, as well as for their generosity in critically reading this manuscript. We thank them for their invaluable help in evaluating the early literature on the subject of I1-P synthase, as well as their insightful discussion of current issues. We also wish to acknowledge Frank Loewus for pointing out to us the absence of an INO1 homolog in the genome of Methanococcus jannaschii.
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