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Biochem. Soc. Symp. 74, 223–246
(Printed in Great Britain)
© 2007 The Biochemical Society
Evolution of the diverse
biological roles of inositols
Robert H. Michell1
School of Biosciences, University of Birmingham, Birmingham B15 2TT, U.K.
Abstract
Several of the nine hexahydroxycylohexanes (inositols) have functions in
Biology, with myo-inositol (Ins) in most of the starring roles; and Ins polyphosphates are amongst the most abundant organic phosphate constituents on Earth.
Many Archaea make Ins and use it as a component of diphytanyl membrane
phospholipids and the thermoprotective solute di-L-Ins-1,1′-phosphate. Few
bacteria make Ins or use it, other than as a carbon source. Those that do include
hyperthermophilic Thermotogales (which also employ di-L-Ins-1,1′-phosphate)
and actinomycetes such as Mycobacterium spp. (which use mycothiol, an
inositol-containing thiol, as an intracellular redox reagent and have characteristic phosphatidylinositol-linked surface oligosaccharides). Bacteria acquired
their Ins3P synthases by lateral gene transfer from Archaea. Many eukaryotes, including stressed plants, insects, deep-sea animals and kidney tubule cells,
adapt to environmental variation by making or accumulating diverse inositol
derivatives as ‘compatible’ solutes. Eukaryotes use phosphatidylinositol derivatives for numerous roles in cell signalling and regulation and in protein anchoring at the cell surface. Remarkably, the diradylglycerol cores of archaeal and
eukaryote/bacterial glycerophospholipids have mirror image configurations:
sn-2,3 and sn-1,2 respectively. Multicellular animals and amoebozoans exhibit
the greatest variety of functions for PtdIns derivatives, including the use of
PtdIns(3,4,5)P3 as a signal. Evolutionarily, it seems likely that (i) early archaeons first made myo-inositol approx. 3500 Ma (million years) ago; (ii) archeons
brought inositol derivatives into early eukaryotes (approx. 2000 Ma?); (iii) soon
thereafter, eukaryotes established ubiquitous functions for phosphoinositides in
membrane trafficking and Ins polyphosphate synthesis; and (iv) since approx.
1000 Ma, further waves of functional diversification in amoebozoans and metazoans have introduced Ins(1,4,5)P3 receptor Ca2⫹ channels and the messenger
role of PtdIns(3,4,5)P3.
1
email [email protected]
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Introduction
Inositols (hexahydroxycyclohexanes) are key components of diverse biological molecules with a remarkable variety of functions. As the contributions to
this Symposium illustrate, important signalling and regulatory events in animals
have mainly dominated research on inositol derivatives. Early work is accessible by reference to reviews [1–5]. Most notably, PtdIns(4,5)P2 stars in two widespread transmembrane signalling mechanisms: formation of the second messengers
sn-1,2-diacylglycerol and Ins(1,4,5)P3 by receptor-controlled PIC (phosphoinositidases C), and synthesis of the membrane-associated messenger PtdIns(3,4,5)P3 by
receptor-controlled PPIn3K-I (Type I phosphoinositide 3-kinases).
Each of the seven known PPIn (polyphosphoinositides), which are phosphorylated derivatives of the sn-1,2-diacyl-glycerol-3-phosphate-based membrane lipid PtdIns, has distinctive roles in regulating cellular processes, including
exocytosis, membrane trafficking and cell movement. PtdIns (or, sometimes a
physically similar inositol sphingolipid) is also the hallmark constituent of the
GPI-(glycosylphosphatidylinositol) or GIPL (glycosylinositolphospholipid)
anchors that tether many external proteins and complex glycans to eukaryote
cells. Eukaryotes make a spectrum of myo-inositol polyphosphates and pyrophosphate derivatives thereof, for most of which functions remain to be found.
These widely studied compounds and processes, which are mainly restricted
to eukaryotes, represent only part of the diverse spectrum of biological inositol
compounds and functions. For example, inositols (and simple derivatives thereof)
are widely distributed as compatible solutes that cells accumulate when their hosts
encounter stresses such as drought, environmental salinity or over-heating. And
myo-, scyllo-, D-chiro- and neo-inositol polyphosphates contribute much of the
organic phosphate of soils and of lake and estuarine sediments [4,6–12], hence the
suggestion that ignorance about the origins and fates of environmental inositol
polyphosphates constitutes “the greatest gap in our understanding of the global
phosphorus cycle” [9]: see also a recent set of meeting abstracts (http://striweb.
si.edu/inositol_conference/PDFs/Abstract_Book_Content.pdf).
The present article has two main aims. The first is to enumerate and briefly
discuss the inositol-containing and/or inositol-related compounds that diverse
organisms make and the astonishing variety of roles they fulfil: Figure 1 depicts
some of these molecules. ‘New’ biological inositol derivatives are regularly
added, and more almost certainly remain to be found. The second is to try to
discover some clues as to how the remarkably versatile biological exploitation
of inositols might have evolved, particularly during the early aeons of evolution
during which the major classes of extant organisms (Bacteria, Archaea, Eukarya
and subsets within each) evolved from their still-obscure progenitors.
The evolutionary context
Organisms that make inositol derivatives occur in all three Kingdoms of Life.
Figure 2 offers a simplified Tree of Life, emphasizing organisms for which information about usage of inositols is available. This tree draws on recent models
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Evolution of the diverse biological roles of inositols
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Figure 1 A variety of the biological inositol derivatives discussed in
this article. (A) The inositols, with myo-inositol and Agranoff’s mnemonic of a
myo-inositol turtle both numbered in accordance with the ‘always D-numbering’
convention that is discussed in the text. (B) Ins3P3'Ins, used as a compatible
solute by some archaea and a few bacteria. (C) Pinitol. (D) Gentobiosylcaldarchaetidylinositol. (E) Archaetidylinositol. (F) Stearoyl,arachidonyl-PtdIns, with
the three hydroxy groups that are phosphorylated in various PPIn highlighted.
(G) A space-filling model of stearoyl,arachidonyl-PtdIns(4,5)P2. (H) Ceramidephospho-1-Ins. (I) InsP6. (J) 5-PP-InsP5. (K) Mycothiol. (L) Axinelloside A, with
the integral scyllo-inositol annotated.
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R.H. Michell
Figure 2 Development of the diverse usage of inositol derivatives
through evolution. The underlying tree is based on recent attempts at
reconstructing the Tree of Life, especially the emerging close relationship
between Metazoa and Amoebozoa (see the text for references).
of the contentious relationships between the various eukaryote groups: these
envisage the metazoan, fungal and amoebozoan clades diverging during much
the same period [13–17].
The context of the discussion that follows is that the Archaea/Bacteria
divergence probably predated the present by approx. 3500 million years (Ma),
the earliest divergences amongst primitive eukaryotes probably occurred before
2000 Ma, and the various phyla within the eukaryote ‘crown group’ probably
diverged during the period 1200–700 Ma.
Annotated onto this simplified tree (Figure 2) are boxes that summarise
which of the various roles currently played by inositols characterize extant
members of each group of organisms. As discussed below, these suggest that
myo-inositol was ‘invented’ very early by Archaea, and that evolution of major
new functions has continued since the separation of the lineages leading to
amoebozoans and metazoans around 1000 Ma ago.
Myo-inositol and other inositols
There are nine isomeric inositols (Figure 1A). Their all-carbon cyclohexane
ring makes them remarkably chemically stable. Myo-inositol is the most widespread and versatile in Biology, but several others (including scyllo-inositol,
neo-inositol, D-chiro-inositol, epi-inositol and muco-inositol), are found in
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diverse places or organisms and in multiple forms. Later mentions simply of
‘inositol’ refer only to myo-inositol: other isomers are always named.
Cells probably make inositol isomers other than myo-inositol mainly by
inverting the hydroxy group configuration around one or more of the ring carbons of myo-inositol [18–20], but there may be other routes at least to some
isomers [21]. We are largely ignorant about the origins and functions of biological compounds containing ‘other’ inositols, and this should be fertile ground for
future research.
Inositol biosynthesis
All organisms that make inositol use evolutionarily related Ins3P synthases
(inositol monophosphate synthases; often termed MIPS), of which Ino1p of
Saccharomyces cerevisiae is the prototype [22–28]. These mainly cytosolic [29]
Ins3P synthases are NADH-dependent cycloaldolases that convert D-glucose6-phosphate, via bound intermediates, into L-Ins1P.
L-Ins1P is also known as D-myo-inositol 3-phosphate, or, simply and conveniently, as inositol 3-phosphate (abbreviated to Ins3P, with Ins meaning
‘myo-inositol with the numbering of the 1D configuration’). This convention of
numbering all biological myo-inositol (Ins) derivatives in relation to 1D-myoinositol was introduced to obviate the difficulties that otherwise arise when
rigid adherence to standard stereochemical numbering rules demands confusing
switches between 1D- and 1L- numbering midway through metabolic pathways
(see http://www.chem.qmul.ac.uk/iupac/cyclitol/myo.html).
Inositol in Archaea and Bacteria
The majority of archaeal genomes encode an Ins3P synthase, and many archaeons incorporate the resulting inositol into their characteristic sn-1-phosphoryl-2,
3-diether-based membrane glycerolipids (discussed later). A subset of hyperthermophilic Archaea accumulates a di-myo-inositol phosphodiester when they
are exposed to temperatures higher than their normal growth conditions (see the
section on compatible solutes). There have been indications, yet to be validated,
that some archaeal surface proteins may be attached through eukaryote-like
GPI-anchors [30 –32].
By contrast, most bacterial genomes have no Ins3P synthase gene. Those that
do are mostly in the actinobacterial clade (e.g. Mycobacterium spp.) or are obligate hyperthermophiles (e.g. members of the related Thermotoga and Aquifex
clades). Bacteria of the Thermotoga/Aquifex grouping are genetically extraordinary, in that almost one-quarter of their genes have been imported from Archaea
[33]. Closely related Ins3P synthases have also been noted sporadically in a few
other bacteria and in the cyanobacterium Synechocystis PCC 6803 [25,34,35].
Sequence comparisons reveal that all bacterial Ins3P synthases are more closely
related to archaeal than to eukaryal Ins3P synthases [34,36]. This suggests that
the ‘standard’ bacterial enzyme toolkit lacks an Ins3P synthase, and that bacteria
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have through the ages acquired their Ins3P synthases (Streptomyces coelicolor
has three!) by lateral gene transfer from co-existing Archaea [34].
A few gram-negative bacteria contain small amounts of PtdIns (see below),
but most have none. I once made a total acid hydrolysate of approx. 5 g of
Escherichia coli, trimethylsilylated the dried residue, subjected it to GLC and
was disappointed to find no sign of trimethylsilyl Ins [3]. I thus realized that
Ins is not a universal ingredient of living cells, as both Posternak [2] and I had
imagined it to be!
So Ins is a core component of many Archaea, but not of most bacteria. A few
bacteria have recruited Ins for particular purposes (see also the later comments
on compatible solutes and on actinomycetes). For example, some ice+ gramnegative bacteria have an inherited propensity to act as ice nucleators, with consequent damage to plants that they colonize. This ability is primarily conferred
by ice-nucleating proteins, but some of the most effective ice nucleators have
the highest, albeit small, PtdIns content [37]. Whether this might be achieved
by ice-nucleating proteins being GPI-anchored on the bacterial surface remains
uncertain [38,39]. A complex chiro-inositol-containing polysaccharide from
Bifidobacterium bifidum is an enigmatic bacterial material [40].
The most parsimonious evolutionary interpretation of these observations
is that Archaea invented Ins synthesis from glucose-6-phosphate and adopted
Ins as a widespread membrane phospholipid headgroup early in their evolution, may be as long as 2500 Ma ago, and lateral gene transfer quite soon passed
this ability to other organisms. Ins was probably first made, therefore, by some
early, and relatively simple, primeval archaeon living in an environment over
which it had little control. It seems that development of this ability to redirect
a minor flux of carbon along a very short side pathway from central energy
metabolism into a small and chemically very stable polar entity with versatile
properties must have been a beneficial evolutionary stratagem.
Inositol in eukaryotes
Eukaryotes, with rare exceptions, always have an Ins3P synthase gene. All
eukaryotes exploit inositol derivatives for numerous cellular roles (Table 1 and
Figure 2), most notably as components of membrane phospholipids and protein anchors, and as polar hydrophilic solutes involved in cellular adjustment to
environmental challenges (see below).
Even the few eukaryotes that cannot make their own Ins need it
(e.g. Schizosaccharomyces pombe). They often live in Ins polyphosphate-rich
environments from which Ins can readily be obtained [41]: an appropriate secreted
phosphatase (phytase) and a transporter with which to pump Ins into the cell
are all that they need. Few tissues in metazoans, the most complex eukaryotes,
make their own Ins, notably the brain and testis in mammals [42,43]. Despite
this universal requirement, it is hard to establish Ins deficiency in experimental
mammals. Except in gerbils, this tends to become manifest only when animals
are prevented from obtaining Ins from their food or from micro-organisms in
their gut contents, or during lactation-driven nutrient stress [2,44–53].
© 2007 The Biochemical Society
[80,259]
[24,79,81,83,259]
Buckwheat (Fagopyrum spp.): levels respond to desiccation stress.
Legumes, Grasses, Proteacea, Crucifers, etc.; galactosyl donor to raffinose saccharides.
Sweet Pea
Lathyritol α[D-galactosyl-(1>3)-bornesitol]
[269]
[90]
[56,91,255]
[57,85 – 89,93,94,96,
256 –258]
[63,64,254]
Sequoyitol (1D-5-O-methyl-myo-inositol)
(−)Bornesitol (1D-1-O-methyl-myo-inositol)
Viscumitol (1D-1,2-O-dimethyl-muco-inositol)
Liriodendritol (1D-1,4-di-O-methyl myo-inositol)
Pinpollitol (D-1,4-di-O-methyl-chiro-inositol)
(+)Quercitol (1L-1,3,4/2,5-cyclohexane-pentol)
Fagopyritols (pinitol, mono-, di- or trigalactosylated on 1 and/or 3 positions)
Galactinol [1-α-D galactosyl (1>3)-myo-inositol]
(+)Ononitol (1D-4-O-methyl-myo-inositol)
Chiro-inositol
L-Quebrachitol [1L-(−)-2-O-methyl-chiro-inositol]
D-Pinitol (1D-3-O-methyl-chiro-inositol)
Scyllo-inositol and myo-inositol
Scyllo-inositol
Myo-inositol
Ins3P3´Ins & Man-2-β-O-Ins3P3´Ins-O-2-β-Man
Ins3P3´Ins
[55,58,60,62,253]
References
[2,68]
[2,69,76]
[2,24,66,67,69,71,
72,74,259]
[2,24,65,70,78,260,
261]
[262–264]
[2,69]
[265,266]
[2]
[267,268]
[72,75,76]
Organisms, effects and behaviours
Archaea
Many hyperthermophilic archaea. Accumulate when temperature raised further, and in stationary phase.
Bacteria
Hyperthermophilic Thermotoga spp., accumulate with raised temperature or salt.
Animals
More in the tissues of echinoderms, gastropods and polychaetes that live in marine abyssal deeps.
Renomedullary cells
Dehydrated collembolans (springtails)
Hibernating beetles
Hibernating spiders.
Plants
Numerous species.
Oaks; rubber (Hevea brasiliensis) latex; maple (Acer saccharum) sap; some Proteacea
Some eucalyptes; Limonium gmelini; Mesambryanthemum crystallina (ice-plant); some Proteacea;
soybean (Glycine max).
Ice-plant (Mesembryanthemum crystallinum); transgenic tobacco; legumes, including rice bean
(Vigna umbellata), chickpea (Cicer arietanium); etc.
Soybean; Aristolochia gigantean; can be epimerised to pinitol.
Some Proteacea and legumes. Enantiomer in rubber latex
Mistletoe (Viscum alba)
Liriodendron tulipiifera (tulip tree)
All gymnosperms
Various plants, including sugar maple and many eucalyptes.
Compound
Table 1 Cyclitol-based compatible solutes
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R.H. Michell
Inositol derivatives as stress-adaptive compatible solutes
Many organisms make or accumulate substantial intracellular concentrations of small and polar, and often uncharged, cytosolic solutes, often termed
compatible solutes, to protect themselves against environmental stresses such
as extremes of heat, salt exposure, hydrostatic pressure or exposure to reactive
oxygen species [24,54–59]. Compatible solutes include various polyols (glycerol, sorbitol, disaccharides such as trehalose etc.), methylamines [e.g. TMAO
(trimethylamine N-oxide)], glycerophosphocholine, taurine and betaine, and
also proline, glycine, β-alanine and other amino acids. The physically benign
properties of these molecules allow cells to accumulate them to high concentrations and to tolerate large changes of concentration without major adverse
effects on cell function. Their protective effects include protein stabilization,
osmotic compensation and supercooling of tissue water [56].
Numerous organisms throughout Biology employ inositols and simple
derivatives thereof, under the generic term cyclitols, as compatible solutes: these
are listed in Table 1.
Certain archaeons, notably those that live in very hot environments such
as volcanic springs, have evolved adaptations by which they survive transient
exposure to even more extreme temperatures than those at which they normally
grow. One such is accumulation of di-L-myo-inositol-1,1′-phosphate (sometimes abbreviated as DIP; Figure 1B) [60]. Using the all-D numbering, this compound can be systematically abbreviated as Ins3P3′ Ins. It is probably made by
the transfer of Ins3P from Ins3P-CMP to C-3 of a free Ins molecule [61].
The estimated intracellular concentration of Ins3P3′ Ins increases from
approx. 60 mM to approx. 200 mM after Thermococcus celer is shifted from
its normal growth temperature of 88°C to 94°C [62]. The concentrations of
other archaeal compatible solutes, such as mannosyglycerate, often rise when
cells are exposed to thermal, hyperosmotic or salt stress, but the protective
action of Ins3P3′ Ins seems to be fairly specific to heat stress [54,62], a notion
supported by the ability of Ins3P3′ Ins to protect isolated Pyrococcus woesei
glyceraldehyde-phosphate dehydrogenase against thermal inactivation [60].
Ins3P3′ Ins also accumulates during stationary phase [62].
As with Ins3P synthase (see above), the hyperthermophilic bacteria Thermotoga
maritima and Thermotoga neapolitana make Ins3P3′Ins (plus the related stereoisomer Ins3P1′Ins and the dimannosylated derivative Man-2-β-O-Ins3P3′InsO-2-β-Man [63,64]), this time in response to both salt and heat stress. Given the
remarkable genetics of these bacteria (see above), their ability to make Ins3P3′Ins is
likely to be a result of lateral gene transfer from a hyperthermophilic archaeon.
The best understood inositol-based compatible solutes are diverse molecules that accumulate in stressed (or stress-tolerant) eukaryotes, particularly
plants. These include methyl-inositol and deoxy-inositol derivatives, sometimes
with one or more attached sugars [2,24,65–73]. For example, pinitol (Figure 1C)
is synthesized thus:
myo-Ins → 3-O-methyl-myo-Ins (ononitol) →
3-O-methyl-D-chiro-Ins (pinitol)
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The accumulated cyclitols are often studied in leguminous plants, in which
some are abundant. Changes in cytosolic concentrations of various methylinositols, especially pinitol, correlate with adaptation to arid or saline conditions. For example, soybean (Glycine max) cultivars from semi-arid regions of
China constitutively make more pinitol than those from regions with higher
rainfall, and water restriction of soybean plants promotes a graded accumulation
of pinitol in their stems and leaves [71,74]. The cyclohexane-pentol quercitol is
the predominant cyclitol in eucalypts from arid environments [72,75], and quebrachitol and/or bornesitol are the most abundant cyclitols in many Proteaceae
[69]. Quebrachitol is, after sucrose, the dominant polyol of the winter sap of
sugar maple (Acer saccharum) and of maple syrup [76].
Not only do some salt-tolerant plants accumulate cyclitols when
saline-stressed [68], but the Ins3P synthases that support cyclitol accumulation may be optimized for activity in high salt conditions [26]. Transfer of the
stress-regulated Ins methyltransferase of the ice-plant Mesembryanthemum
crystallinum [77], a facultative halophyte that makes ononitol from myo-inositol,
into tobacco plants that normally lack this activity makes the tobacco plants
more tolerant of drought and salt stress, at least partly because of stress-induced
myo-inositol and ononitol accumulation [78].
The raffinose series of sucrose-based oligosaccharides, which includes raffinose (trisaccharide), stachyose (tetrasaccharide) and verbascose (pentasaccharide), and the fagopyritols (galactosylated derivatives of pinitol) are structurally
and functionally related. These soluble oligosaccharides accumulate in diverse
plants as carbohydrate stores during seed development and they sometimes also
confer stress-resistance [24,79–84] (See Table 1). Galactinol (1α-D-galactosyl(1>3)-myo-inositol), made from myo-inositol and UDG-galactose by a family
of stress-inducible galactinol synthases, is the galactose donor for their synthesis,
but only some of them retain a cyclitol in their final structure. For example:
UDP-Gal ⫹ myo-Ins → Galactinol ⫹ UDP
Galactinol ⫹ Sucrose → Raffinose ⫹ myo-Ins
Galactinol ⫹ Raffinose → Stachyose ⫹ myo-Ins
Less is known about the protective effects of cyclitols in animals, in which
internal tissues are generally protected from osmotic or other stresses (but see
the next paragraph). However, some eudaphic collembolans (springtails), small
insects with permeable cuticles that live mainly in the water-saturated spaces
between soil particles, lack this environmental security. Any substantial drying of the soil subjects them to extreme dehydration stress, and they respond
with biosynthetic accumulation of remarkable amounts of myo-inositol and
other polyols. This dramatically increases the osmotic potential of their body
fluids, so that they become capable of rehydrating themselves by adsorbing
atmospheric moisture [85–87]. Some beetles that must tolerate subzero temperatures during hibernation accumulate myo-inositol in the haemolymph as
an antifreeze [88,89], and hibernating spiders accumulate myo-inositol and
scyllo-inositol [90]. In a quite different setting, the concentrations of several
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solutes, notably scyllo-inositol, escalate with increasing depth and pressure in
some marine animals [56,91].
The renomedullary cells that line the mammalian kidney tubule do regularly
encounter such environmental challenges. When the salt concentration in the
glomerular filtrate rises, they face an hyperosmotic challenge to which they must
adapt if they are to continue to function normally. They do so by increasing their
intracellular concentrations of compatible solutes such as sorbitol and inositol
[57,92]. Ins accumulation is achieved as a result of increased expression of two
Na⫹/Ins co-transporters. These are the sodium-dependent myo-inositol transporters SMIT1 and SMIT2 [92–97]. The regulatory region of the SMIT1 gene
includes an osmotic response element and also responds to prostanoids produced
by COX-2 (cyclooxygenase-2) [98,99]. If SMIT-catalysed Ins uptake is inhibited, blunting osmotic adaptation, the outer medullary cells suffer severe injury
and acute renal failure follows [100]. Cerebral cortical astrocytes show a similar SMIT-dependent Ins accumulation when they are hyperosmotically stressed
[101], and this protein is one candidate target for anti-bipolar drugs [102].
The protective value of the compatible solutes made by mammalian cells is
illustrated by the fact that some of them, including myo-inositol, potentiate the
capacity of the mutant form of CFTR, the cAMP-regulated Na⫹ channel that
has impaired function in cystic fibrosis, to mature and function correctly in the
membranes of cultured epithelial cells [103].
How high concentrations of these cyclitols and other compatible solutes fulfil their presumed protective roles, serving as antifreezes, osmolytes, protection
against reactive oxygen metabolites etc. is not clear. A key argument, summarized by Yancey, is that the manner in which they participate in water–solute–
macromolecule interactions tends to stabilize proteins and membranes. Binding
of destabilizers such as some salt ions and urea to proteins tends to expose groups
that undergo thermodynamically favourable binding with the destabilizer, and
pushes the proteins towards unfolding. By contrast, many compatible solutes
do not bind to proteins and tend to be excluded from the hydration layer adjacent to a protein’s surface. Termed the ‘osmophobic’ effect, this exclusion arises
from an apparent repulsion between stabilizers and the peptide backbone. This
reduced exposure of the peptide backbone to thermodynamically unfavourable
interactions with solutes allows the proteins to fold more compactly [56,104].
Inositol in membrane phospholipids:
sn-2,3-diphytanylglycero-1-phosphorylinositol
(archaetidylinositol) and related lipids in Archaea
Many Archaea contain the Ins-containing membrane glycerophospholipid ArcIns (archaetidylinositol; Figure 1E) and/or a glycosylated derivative
thereof. As in all archaeal glycerolipids, the membrane-embedded hydrophobic
chains of ArcIns (typically C20 or C25 polyisopranoid chains) are ether-linked
to the 2- and 3-hydroxy groups of glycerol [105–107] (see Figure 1). This sn-2,
3-diradylglycerol-1-phosphoryl (archaetidyl) structure is the mirror image
of the configuration of glycerol in the sn-1,2-diacylglycerol-3-phosphoryl
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(phosphatidyl) glycerolipids of Eukarya and Bacteria (e.g. Figures 1F and 1G).
Despite this difference, the Ins headgroups of ArcIns and of PtdIns are linked
to the diradylglycerol-phosphate backbones through the same D-1-hydroxy
group [108].
G1PDH (glycerol-1-phosphate dehydrogenases), make the sn-glycerol1-phosphate core of archaeal lipids from DHAP (dihydroxyacetone phosphate). These are mainly found in Archaea, and bacterial G1PDHs again look
like consequences of early lateral gene transfer [109]. The archaeal G1PDHs
and the G3PDHs (glycerol-3-phosphate dehydrogenases) that convert DHAP
into the sn-glycerol-3-phosphate of bacterial and eukaryal glycerolipids have
evolved independently as near-basal members of two different dehydrogenase
subfamilies [109–114].
In some archaeal phospholipids, the ω-termini of the polyisopranoid chains
from the two membrane leaflets are covalently joined to form the even more
remarkable caldarchaetidyl lipids [106,115,116]. Each bipolar caldarchaetidyl
glycerolipid, of which Figure 1(D) shows an example, spans the membrane bilayer
and unsymmetrically displays two headgroups, one on each side of the membrane. Strikingly, the orientation in archaeal membranes of this tetraether lipid
with Ins and gentobiose headgroups, and also of the archaetidyl (diether) lipids
that correspond to the two halves of this tetraether, mimics that of Ins lipids and
glycolipids in eukaryotic plasma membranes: Ins headgroups face the cytosol
and sugar headgroups are exposed to the external environment [117].
Some Archaea, particularly extreme halophiles (e.g. Halobacterium halobium), lack both Ins3P synthase and Ins-containing phospholipids. This is
apparently because bilayer membranes dominated by archaeal lipids with polyol
headgroups (e.g. ArcIns and archaetidyglycerol) are unstable at very high salt
concentrations. Instead, the membranes of extreme halophiles are dominated
by archaetidyglycerol–methylphosphate, which is apparently specialized for
bilayer formation in a high salt environment [118].
Inositol(s) in membrane phospholipids:
sn-1,2-diacylglycero-3-phosphoryl-1-inositol
(phosphatidylinositol) and related lipids of Eukaryotes
and Bacteria
Inositol’s most studied cellular function is as an ubiquitous headgroup of
eukaryotic membrane glycerophospholipids, in which an sn-1,2-diacylglycerol1-phosphoryl (phosphatidyl) core, which is characteristic of most bacterial and
eukaryal glycerophospholipids, is linked to the axial 1-D hydroxy group of Ins
(Figure 1F). PtdIns occurs in all Eukaryotes, as do at least some of its seven
phosphorylated derivatives (Figures 1F and 1G).
As noted above, PtdIns is present, and occasionally essential, in a few
bacteria, notably actinomycetes (Mycobacterium spp., Corynebacterium spp.,
Streptomyces spp., etc; see below). These complex bacteria use autonomously
synthesized Ins to make substantial amounts of PtdIns, and this serves as
the precursor for a spectrum of PtdIns polymannosides and of GPI-linked
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lipomannans: the latter display extended oligosaccharide structures that
contribute to the diverse and characteristic mix of cell surface macromolecules
on these cells [119–122] (see also Chapter 13).
Remarkably, it seems that a few bacteria can make membrane-spanning
tetraether lipids with a superficial similarity to the caldarchaetidyl lipids of
archaeons (see above). However these are based on the bacterial sn-1,2-diradyl
configuration [123], and whether these ever include Ins is yet to be determined.
Approx. 2–30% of the phospholipid complement of most eukaryotic cells
is PtdIns, which is, as has been shown in the plasma membranes of animal cells,
mainly confined to the cytoplasmic leaflets of membrane lipid bilayers. Since early
experiments on scyllo-inositol-rich tissues [124] it has generally been assumed
that myo-inositol is the only inositol that is incorporated into phospholipids, but
a few studies suggest that plant and animal cells may occasionally contain some
phosphatidyl-scyllo-inositol or phosphatidyl-chiro-inositol [19,125–129].
PPIn
The seven phosphorylated derivatives of PtdIns (phosphoinositides, abbreviated as PPIn) have 1–3 monoester phosphate groups on some combination
of the 3-, 4- and 5-hydroxy groups of PtdIns (shaded in Figure 1F). PPIn seem
to be present only in eukaryotes. PtdIns4P and PtdIns(4,5)P2 are present in the
plasma membranes [3] and several other compartments [130] of all eukaryotic cells [3,131,132]; and PtdIns3P and PtdIns(3,5)P2 are found in intracellular
membranes of almost all nucleated eukaryotic cells [133–135]. By contrast, only
metazoa and Dictyostelium (and other amoebozoans?) make PtdIns(3,4,5)P3 by
the ‘standard’ PPIn3K-I route [136–139]. How many species employ PtdIns5P
and PtdIns(3,4)P2, and with what functions, is little understood as yet [140–142]
(see Chapter 11).
PtdIns4P and PtdIns(4,5)P2, ubiquitous players in eukaryotes
PtdIns(4,5)P2 (Figure 1G) is the substrate for activated PICs and plays
several other roles in cells, for example, in exocytotic events and in cytoskeletal
homoeostasis.
The ultimate origin of eukaryotic PICs, which have evolved into at least six
subfamilies, is something of an enigma. PICδs constitute the only near-ubiquitous
PIC subfamily, so they might be structurally and/or functionally most similar to
the common ancestor of all extant PICs [143,144]. Despite much effort, however,
we still do not understand at all clearly either the functions of PICδs or how
they are regulated. What is established is that the Ins(1,4,5)P3 that is liberated
when Plc1p, a yeast PICδ-like PIC, is activated does not hang around as a Ca2⫹
-mobilizing second messenger. It is immediately converted into InsP6, and some
of it thence to pyrophosphorylated derivatives of InsP6 [145]. Moreover, fungi
and plants have no Ins(1,4,5)P3 receptors, the intracellular Ca2⫹-mobilizing
targets of classical Ins(1,4,5)P3 signalling [146].
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The biological functions of the other PICs, the β, γ, ε, ζ and η families;
which are all restricted to metazoans, are much better understood [143] (and see
Chapter 3).
Structural comparisons of bacterial PtdIns-specific PLCs and of eukaryotic
PtdIns(4,5)P2-selective PICs have revealed common features in their catalytic
mechanisms [147–149]. This suggests evolution from a common ancestor, most
likely a bacterial phospholipase, that became incorporated into a primitive
ur-eukaryote [132].
PtdIns3P and PtdIns(3,5)P2 in membrane trafficking
PtdIns3P and PtdIns(3,5)P2, which play central roles in regulating membrane
traffic within the endomembrane system of (all?) eukaryote cells, are discussed
in detail in recent reviews [135,150,151] and elsewhere in this symposium (see
Chapters 8,9 and 12).
PtdIns(3,4,5)P3 as a membrane-bound second messenger
Conversion of PtdIns(4,5)P2 into the plasma membrane-located messenger PtdIns(3,4,5)P3 by PPIn3K-I, in response to activation of receptor tyrosine
kinases or G protein-coupled receptors or to activated Ras, seems to be confined
to metazoans and amoebozoans (exemplified by Dictyostelium, see above; see
Chapters 5 and 6). The trace of PtdIns(3,4,5)P3 that is present in yeast seems to be
formed by a different pathway and its function is not yet known [152,153].
Inositol polyphosphates and polyphosphate diphosphates
Phytate, a mixed cation salt of myo-inositol hexakisphosphate (phytic acid:
InsP6; Figure 1I), was recognized as a major phospho-organic component of
plant seeds more than a century ago: the crop seeds and fruit that are harvested
each year contain more than 50 million metric tonnes of phytate [154].
InsP6 is an almost universal constituent of eukaryote cells, from plants and
mammals to free-living (Dictyostelium) and parasitic (Entamoeba) amoebae
[155,156]. There are multiple biosynthetic pathways to InsP6, both directly from
free Ins [157] and from the Ins(1,4,5)P3 liberated by PICs [158–161]. Remarkably
little is known about the distribution or functions of InsP6 and related Ins polyphosphates within cells [155,156,162], but recent work has raised the possibility of a variety of unanticipated roles, especially in the nucleus [163–166] (see
Chapters 16 and 18).
Not surprisingly, inositol polyphosphates are abundant in the environment, for
example in soils and in freshwater and marine sediments. However, we do not know
which organisms make these, and substantial and varying proportions are based on
the ‘unconventional’ scyllo-, D-chiro- and neo-inositol isomers [4,7–11,167–169].
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At present, the only organisms known to make inositol polyphosphates
other than InsP6 are the parasitic amoeba Entamoeba histolytica and the freeliving amoeba Phreatamoeba balamuthi, both of which make neo-inositol and
scyllo-inositol polyphosphates by undefined routes [170]. Perhaps unwisely,
most studies make the assumption that any inositol polyphosphates that are biosynthetically labelled from [3H]myo-inositol contain myo-inositol rather than
other inositol isomer(s); might these ‘unconventional’ inositol polyphosphates
be more common than the published information suggests?
One of the most exciting advances of the last decade has been recognition
that InsP6, and at least some isomers of InsP5 and maybe InsP4, can undergo the
addition of yet more phosphate groups, yielding inositol polyphosphates with
one or two pyrophosphate groupings [164,171–175]: see, for example, Figure 1J.
These compounds seem likely to be ubiquitous in eukaryotes. They are certainly
present in metazoans, amoebozoans and fungi [175]; suggestive HPLC peaks in
labelled barley and duckweed [176–178], and genomic prediction of an appropriate inositol phosphate multikinase in rice (Oryza sativa) and flax (Linum
usitatissimum) points to their presence in plants [175]; and Irvine mentions a
related putative kinase in Giardia [179]. Evolutionarily, these diphosphates
must have appeared later than the monoesterified Ins polyphosphates. Their
functions are yet to become clear (see [175]).
Sphingolipids containing inositol
It was realized long ago that many eukaryotes, notably fungi, plants and
various protists, contain sphingolipids that have an InsPCer (Ins1P-ceramide;
Figure 1H) moiety at their core [2,180–192]. The best characterized are the
InsPCer-mannosides and InsPCer-anchored oligosaccharides that are displayed on the external surface of the plasma membrane in S. cerevisiae and
other fungi [184,191,193,194]. The Ins-containing plant sphingolipids, typified by Carter’s ‘phytoglycolipid’, are complex and structurally less well characterized [180,188,195,196]. Although animals have generally been assumed
to lack InsPCer-based lipids, there are recent reports of their presence in a
feather star (Comanthus japonica), a helminth (Ascaris suum) and a polychaete
(Tylorrhynchus heterochetus) [197–201].
Sphingolipids are mainly regarded as molecules of eukaryotes, but they
also occur in a few, mainly or exclusively anaerobic, bacteria (Sphingomonads,
Flectobacillus): there have so far been no reports of inositol-containing bacterial
sphingolipids [193].
Phosphoinositide-anchored proteins and oligosaccharides
at cell surfaces
Cells display molecules on their cell surfaces in a variety of ways, including
through attachment to PtdIns-based anchors. The first hint of these structures
came when exposure of kidney or bone cells to bacterial PtdIns-PLCs
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(PtdIns-specific phospholipase Cs) caused the release of soluble alkaline phosphatase [202]. Later studies showed similar effects in many cells and with
many proteins, and established that a substantial proportion of the externally
displayed proteins, and oligosaccharides, on eukaryote cells are C-terminally
linked (through a complex oligosaccharide and phosphoethanolamine) to a
phosphoinositide molecule that is embedded in the external lipid leaflet of the
plasma membrane [203–205].
Assembly of these structures, known either as GPI-anchors or GIPLanchors, is a complex process that occurs in endoplasmic reticulum, Golgi
complex and secretory membrane elements. It has been reported that chiroinositol or scyllo-inositol sometimes replaces myo-inositol in the GIPL anchors
of some cell surface proteins [129,206], but it is possible that isomerization of
myo-inositol to chiro-inositol will make this attribution artefactual [207].
Remarkably, there is substantial overlap between the last two groups of
molecules that have been discussed, the inositol sphingolipids and GPI/GIPLanchors, in that the cores of some of the membrane anchors of GIPL- anchored
cell surface proteins and oligosaccharides are based on InsPCer rather than
GroPIns. The InsPCer structures are in the majority in yeasts (see Chapter 17).
It seems likely that all GIPL anchors are initially made with a diradylGroPIns
(sn-1,2-diradylglycerophosphoinositol) core, though with a remarkable variety
of different acyl and ether hydrophobic chains in different organisms. But then,
at least in non-mammalian eukaryotes (including plants, fungi, trypanosomes
and Dictyostelium), the phosphoinositol plus its linked glycans and/or proteins
are transferred as a unit from the original diradylglycerol to ceramide, yielding an
InsPCer-anchored structure [194,208–215]. Confusingly, these InsPCer-anchored
and membrane-embedded molecules are often still referred to as GPI-anchored.
Chiro-inositol, pinitol and diabetes
Some years back, several groups observed that insulin-treated cells liberate mediator molecules that mimic, to varying degrees, the effects of insulin
on cells. No definitive structures have been reported, but at least one of the
active molecules seems to include a chiro-inositol glycoside structure, possibly
derived from a cell surface glycophospholipid or from the GIPL anchors of cell
surface proteins [216–221]. These observations were followed by indications of
substantial changes in the metabolic handling of chiro-inositol in diabetic people
and animals [20,222–227]. Most recently, several studies have indicated that
dietary intake of myo-inositol, chiro-inositol or pinitol has therapeutic potential
as a treatment for improving insulin-mediated glycaemic control, particularly
in Type I diabetes [221,228–234], and the same molecules have beneficial effects
on endothelial function in diabetics [235]. These observations have been accruing in parallel with recent major discoveries on the phosphoinositide 3-kinase/
PtdIns(3,4,5)P3-mediated actions of insulin, so they have received relatively little attention. They seem to offer the potential to illuminate one important aspect
of how animals employ chiro-inositol.
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Actinobacterial metabolites: mycothiol, antibiotics etc.
Many actinomycetes, including pathogenic and other mycobacteria, use the
inositol containing sulfydryl peptide mycothiol [1 D-myo-inositoyl-3-(N-acetylysteinyl)amido-α-D-glucopyranoside; Figure 1K] as their major intracellular
redox buffer [236–239]. Moreover, mycobacterial pathogens appear to use mycothiol both as a protectant against electrophilic compounds and for the detoxification of reactive oxygen and nitrogen species. For example, Mycobacterium
tuberculosis uses mycothiol to conjugate and detoxify antimycobacterial drugs
(e.g. rifamycin S) in a manner similar to the formation of mercapturic acid derivatives in glutathione-based detoxification mechanisms. Mycothiol synthesis has
therefore become a target for anti-mycobacterial drug development. It has also
long been known that actinomycetes synthesize streptidine (a guanido derivative of scyllo-inositol) and other myo-inositol-derived cyclitol derivatives as
precursors of aminoglycoside antibiotics such as streptomycin [240–242].
Other complex biological products containing inositol
Another complex biological product containing inositol is axinelloside
A, a telomerase inhibitor, isolated from a marine sponge: this is a complex,
highly sulfated, lipopolysaccharide containing scyllo-inositol lipopolysaccharide (Figure 1L) [243].
Can we now start to reconstruct early stages of the
complex evolutionary progression that has led to the
current multiplicity of functions for inositol-containing
molecules in metazoans and other eukaryotes?
There have been recent attempts to reconstruct the evolutionary histories
of kinase and phosphatase families involved in PPIn and inositol polyphosphate
metabolism and function [e.g. 179], but little attention has yet been paid to the
deeper history of the biology of inositols, particularly the transition from primeval Archaea and Bacteria to the ancestors of extant Eukarya.
Once Ins3P synthase had evolved in an early archaeon, the next major step
will have been the incorporation of D-1-linked Ins into ArcIns by a still unidentified CMP-ArcOH (CMP-archaetidate) inositol transferase. This enzyme will
likely be a member of the CMP-ArcOH alcohol transferase family, candidates
for which have recently been identified in several ArcIns-containing archaeons
[27], but we still await functional studies.
The passage of this type of biosynthetic pathway into eukaryotes, ultimately to make PtdIns rather than ArcIns, is likely to have required a series of
developments. First, the synthesis of phosphatidate (sn-1,2-diacylglycerophosphate; PtdOH) by G3PDH and glycerophosphate acyltransferases, is likely to
be achieved by enzymes with bacterial ancestry. Secondly, formation of CMPPtdOH will have needed a cytosolic-type synthase, which may have evolved
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either from a bacterial progenitor or from an archaeal CMP-ArcOH synthase.
And finally, transfer of the resulting phosphatidyl grouping to the D-1 hydroxy
group of inositol may be catalysed by a CMP-PtdOH inositol transferase that
is a descended from an archaeal CMP-ArcOH inositol transferase? When the
archaeal CMP ArcOH synthetase and CMP-ArcOH inositol transferase just
mentioned are biochemically examined, it will be particularly interesting to
learn whether they exhibit any, even slight, activity against sn-2,3-diradylglycerophosphate precursors, particularly of diacyl types.
The difficult problem of how the archaeal and bacterial progenitors of
eukaryotes brought together and blended the activities needed for synthesis of
two stereochemically incompatible sets of lipids, and settled on the sn-1,2-diradyl
configuration while retaining archaeal constituents such as inositol, remains to
be solved. Various models are nicely discussed in a recent review [109].
Bacterial PtdIns-specific PLC and eukaryotic PICs, which are substratepromiscuous but PtdIns(4,5)P2-selective, have probably evolved from a common
bacterial ancestor (see above). Hydrolysis by both proceeds either directly to
Ins(1:2-cyclic)P [244] or to Ins1P via Ins(1:2-cyclic)P [or a phosphorylated
Ins(1:2-cyclic)P derivative] as an intermediate [245–250]. A key difference lies
in the preference by eukaryotic PICs for the phosphorylated forms of PtdIns.
This property is, so far as we know, characteristic only of eukaryotic PICs.
Intriguingly, however, a PIC from trypanosomes not only hydrolyses both
PtdIns(4,5)P2 and PtdIns but also efficiently hydrolyses InsPCer in vitro [251].
When the first PPIn were made, and in what organisms, are amongst the
next key questions: PtdIns4P synthesis, my PhD thesis topic [252], is likely
to have been an early eukaryotic innovation. And when did PLC first become
capable of hydrolysing PPIn possessing a 4-phosphate group? Hints might
come from carefully targetted examinations of extant phospholipases C and
PtdIns 4-kinases.
Note added in proof (received 2 October 2006)
Porteresia coarctata is a salt-resistant wild relative of rice, which has an
Ins3P synthase that remains fully active even in 0.5 M NaCl. In a remarkable
recent paper [75], the gene encoding this enzyme was introgressed into E. coli
(which normally contains no inositol), into S. pombe (which requires inositol
but cannot make its own), into a standard salt-sensitive rice cultivar and into
Indian mustard plants (Brassica juncea). This genetic modification had the same
effects on all four organisms. Each made substantial amounts of intracellular
myo-inositol even when salt-stressed, and each became able to survive and to
grow in the presence of normally toxic amounts of salt. As the authors pointed
out, an ability to make crop plants salt-tolerant simply by permitting them to
sustain myo-inostiol synthesis from glucose 6-phosphate in the face of salt stress
is a very exciting prospect.
I am grateful to all who have, since the early 1960s, helped me to learn about the
functions of inositol derivatives. In particular: my early mentors and supporters (Tim
Hawthorne, Hal Coore, the late Georg Hübscher and Manfred Karnovsky); those
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with whom I have shared the running of my research group through various periods
(the late Roger Coleman and Bryan Finean, and then Chris Kirk and Steve Dove);
and those who joined me in the hunt for the functions of inositol lipids in the early
days when this was still unfashionable [Eduardo Lapetina, David Allan, Lynne Jones,
Shamshad Cockcroft (formerly Jafferji), Martin Low, Motassim Billah, Peter Downes,
Mike Hanley, Phill Hawkins and Len Stephens]. The MRC (Medical Research Council)
has supported my research almost continuously since 1972, and to have held a Royal
Society Professorship for almost two decades has been a great privilege.
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