Inositol Lipids and Phosphates Part 1 (Molecular Biology)

Myoinositol, a carbohydrate first found in the mid-1800s in muscle, was defined in the 1930s as a growth factor for yeasts and mammals and then as a component of membrane phospholipids (phosphoinositides) (1, 2). In the 1950s, Hokin and Hokin found that secretory stimuli often accelerate phosphoinositide turnover in their target cells (2, 3). This initial observation led ultimately to recognition of inositol lipids and phosphates as crucially important regulatory molecules in eukaryote cells.

1. Myoinositol

Myoinositol is one of nine stereoisomeric hexahydroxycyclo-hexanes (the inositols). Several inositols occur in nature, but only myoinositol is used widely in the headgroups of membrane phospholipids and in water-soluble inositol polyphosphates. When in the preferred "chair" configuration, myoinositol has five equatorial hydroxyl groups (1-6): only the 2-OH is axial (Fig. 1) (1, 2, 4). IUPAC recommendations decree that D- myoinositol 1-phosphate (abbreviated as Ins1P; the same molecule as L-myoinositol 3-phosphate) is the reference molecule for the numbering of biological myoinositol derivatives (4). Inositol is made biosynthetically by cyclization of the central metabolite glucose 6-phosphate (by way of 5-ketoglucose 6-phosphate) to Ins3P, which is then dephosphorylated (1).

Figure 1. The configuration of, and carbon atom numbering (D-configuration) in, myoinositol. The mirror plane ()identifies the plane of symmetry through the 2- and 5-carbons of the inositol ring.


 The configuration of, and carbon atom numbering (D-configuration) in, myoinositol. The mirror plane ()identifies the plane of symmetry through the 2- and 5-carbons of the inositol ring.

It is not clear how evolution "selected" myoinositol (from here on simply termed inositol) to take on multiple biological roles. Maybe inositol’s stereochemistry gives its derivatives some biologically desirable property. Alternatively, evolution may have "needed" a conveniently synthesized and stable polyol, and selected a molecule that comes, by a very short route, from a ubiquitous cell constituent.

The stereochemical versatility of inositol has allowed biology to put it to many uses. Because it has an axis of symmetry through its 2- and 5-carbons (Fig. 1), addition of one substituent to C-1, C-3, C-4, or C-5 immediately renders every carbon in the ring stereochemically unique. For example, Ins1P and Ins3 P are enantiomers, as are the inositol tetrakisphosphates Ins(1,3,4,5)P4 and Ins(3,4,5,6)P4 (L-Ins(1,3,4,5)P4) (1, 4). Thus, the possible variety of stereochemically (and biologically) unique inositol derivatives can be almost endless.

2. Inositol lipids and phosphates: variety and evolution

Inositol seems to be essential to all eukaryotic cells, and some members of both bacterial kingdoms (Eubacteria and Archaebacteria) also contain inositol lipids and phosphates. Many of the functions of the inositol lipids are becoming understood in remarkable detail, but only a few functions have been definitively ascribed to particular inositol polyphosphates.

Before about 1950, cells were thought to contain a single inositol glycerophospholipid, namely phosphatidylinositol (PtdIns; sn-1,2-diacyl-glycero-3-phospho-D-1-myoinositol) (Fig. 2). This is generally the most abundant inositol glycerophospholipid, and it and its phosphorylated derivative often have a 1-arachidonyl, 2-stearoyl acyl fatty acyl pairing in mammalian cells. Seven other glycerophosphoinositides, all of which are phosphorylated derivatives of PtdIns, have been identified since 1949 (Fig. 2). Figure 3 summarizes the likely metabolic and functional interrelationships between these glycerolipids.

Figure 2. The "simple" inositol glycerolipids of eukaryotic cells.

The "simple" inositol glycerolipids of eukaryotic cells.

Figure 3. Likely pathways involved in eukaryotic glycerophosphoinositide-based signaling. Substrates of signaling path’ in shaded ovals, and proven or probable second messengers are in shaded boxes. Note that PtdIns serves as the common and that PtdIns(4,5)P2 3-kinase signaling pathways and PtdIns(4,5)P2-directed (Type I) and PtdIns-directed (Type III) in functions.

Likely pathways involved in eukaryotic glycerophosphoinositide-based signaling. Substrates of signaling path' in shaded ovals, and proven or probable second messengers are in shaded boxes. Note that PtdIns serves as the common and that PtdIns(4,5)P2 3-kinase signaling pathways and PtdIns(4,5)P2-directed (Type I) and PtdIns-directed (Type III) in functions.

In addition to these relatively simple membrane lipids, the membrane-penetrating lipid anchors of many cell-surface (glyco)proteins and their precursors are PtdIns glycans of varying complexity (see GPI Anchor). Some eukaryotic cells, notably plants and yeasts, also contain complex sphingolipids with inositol-containing headgroups. Although these do not yet have proven functions, their metabolism in yeast is somehow linked to vesicle trafficking (5).

Cells also contain many water-soluble inositol (poly)phosphates. For example, Dictyostelium and mammalian cell lines, such as WRK1 (mammary tumor) and HL60 (myeloid), contain 25 or more different inositol phosphate species (eg, ref. 6). Figure 4 summarizes the metabolic links between many of these inositol phosphates, primarily as in mammalian cells. A variety of inositol phosphate interconversion pathways have been reported from plants and yeasts, including a remarkably direct conversion of Ins(1,4,5)P3 to InsP 6, apparently by a single enzyme (7). Plant seeds store much of the phosphate essential to their successful germination and development as phytate (an insoluble bivalent cation complex of InsP 6), alleged to be the most abundant phosphate ester in nature.

Figure 4. Pathways of inositol polyphosphate interconversion in eukaryote cells. For simplicity, individual inositol monophosphates and bisphosphates on the dephosphorylation pathways have been omitted.

Pathways of inositol polyphosphate interconversion in eukaryote cells. For simplicity, individual inositol monophosphates and bisphosphates on the dephosphorylation pathways have been omitted.

Some families of Eubacteria have additional inositol-containing phospholipids, the best characterized being the PtdIns mannosides of mycobacteria. Archaebacteria, which inhabit some of the most hostile environments on the planet, have glycerophospholipids that are very distinctive, both because the steric configuration of the diradylglycerol backbone of these lipids is opposite to that of the eukaryotic and eubacterial lipids and because they use very different, and chemically very stable, hydrocarbon side chains. Again, however, some of these have inositol headgroups (8). Moreover, hyperthermophilic archaebacteria use inositol in another remarkable way. When they are exposed to temperatures that are even more extreme than usual, they synthesize very high cytosolic concentrations (~0.5M) of the K+ salts of water-soluble inositol phosphate derivatives, such as dimyoinositol 1,1′-(3,3′)-phosphate, as cytoprotective solutes (9).

When the primeval cells from which all later organisms evolved were emerging, a fairly early step was almost certainly enclosure of the newly evolving cellular metabolic machinery within a selectively permeable membrane envelope made of amphiphilic lipids. The fact that myoinositol, an unusually stable cyclic polyol, is a component both of the diether lipids of Archaebacteria and of the (mainly) diacyl-glycerolipids of Eubacteria (some) and eukaryotes suggests that it was recruited into membrane lipids very early. This probably happened before the two-billion-year-old evolutionary radiation that gave rise to the major biological kingdoms, making inositol a very ancient cell component.

Only since the early 1980s, however, has it been recognized how inositol’s stereochemical versatility has let cells employ its derivatives for many different jobs. Throughout this recent period, frequent discoveries of "new" inositol-containing cell constituents have regularly been followed by the definition of "new" functions for inositol derivatives.

Next post:

Previous post: