Glycosylphosphatidylinositol Anchors for Proteins
and Phosphatidylinositol Mannosides

Glycosylphosphatidylinositols are complex glycophospholipids that are found in all eukaryotic organisms, from fungi to plants and animals, and anchor cell proteins to the outer leaflet of the plasma membrane after covalent attachment via the C-termini as post-translational modifications. These glycosylphosphatidylinositol-anchored proteins display many different and important functions, ranging from enzymatic activity to signalling, cell adhesion, cell wall metabolism and immune responses, and their spatio-temporal organization within defined domains of the plasma membrane is crucial for their efficient operation in cells.

Although there were earlier hints, they were discovered after a novel phospholipase C was obtained from Bacillus cereus in 1976 with the specificity to act upon phosphatidylinositol to generate diacylglycerol and inositol phosphate. When this was tested with tissues a year or two later, it was found to release a variety of proteins including 5’‑nucleotidase and erythrocyte acetylcholinesterase as well as the expected metabolites, and it was apparent that these and many other proteins were attached covalently to phosphatidylinositol located in the cellular membranes. By 1985, detailed evidence was obtained for various components linking phosphatidylinositol to cell surface proteins, especially in relation to acetylcholinesterase in several species and of surface glycoproteins in the parasitic protozoan Trypanosoma brucei (the cause of sleeping sickness), where they were more readily accessible in sufficient quantity for structural analysis (a hundred times greater than in mammalian cells, where there may only be ~105 molecules/cell). By 1988 a complete structure of the protozoal lipid was obtained by Sir Michael Ferguson and colleagues (University of Dundee).

The lipid component of these glycosylphosphatidylinositols linked to proteins is much more complex than in other covalently linked protein-lipid complexes, such as the proteolipids, which are discussed in a separate web page. A further difference between the two lipid-protein classes is that the glycosylphosphatidylinositol-anchored proteins are located on on the external surface of the plasma membrane (or of the cell wall of lower organisms), while other proteolipids are located on the cytosolic face of the plasma membrane.

Phosphatidylinositol mannosides are related lipids but with oligosaccharides attached to phosphatidylinositols, which play a part in the surface antigenicity of protozoal parasites and of some prokaryotic organisms, including pathogenic Mycobacteria, and in view of the structural similarities between the basic lipid components, they are discussed in this web page.

1.   Structure and Occurrence of Glycosylphosphatidylinositol-Anchored Proteins

General formula for a GPI-anchored proteinAs studies were extended to mammalian systems, it soon became apparent that there was a basic general structure for the lipid component of what are now termed the glycosylphosphatidylinositol(GPI)-anchored proteins. Phosphatidylinositol in the external leaflet of the plasma membrane is the lipid anchor that binds a variety of proteins via the α-carboxyl group of the carboxy-terminal amino acid to a phosphoethanolamine unit at the end of a complex glycosyl bridge, consisting of a non-acetylated glucosamine (GlcN) and three mannose (Man) residues connected via glycosidic linkages to inositol. Although some minor modifications to the side chains of these protein-lipid complexes are occasionally seen, the basic structure is a ubiquitous post-translational modification that is conserved in eukaryotic organisms (fungi, protozoans, plants, insects and animals) and in some of the Archaebacteria (but not Eubacteria). In animals, they are found in every type of cell and tissue, and a typical molecule from what is a single family of complex molecules is illustrated schematically.

These complicated glycophospholipid-protein aggregates are abundant in nature, amounting to about 1% of all proteins and up to 20% of membrane proteins (at least 250 different or 150 in humans), which are required for many different purposes; they include hydrolytic enzymes, adhesion molecules, receptors, protease inhibitors and regulatory proteins. Typically, the GPI-protein complexes are believed to be associated with the membrane domains known as rafts and caveolins, which typically harbour cholesterol (and caveolin-1).

The aliphatic residues are embedded in the membrane, and their chemical composition is dependent on the organism and the stage in its life cycle, but commonly position sn-1 is occupied by a long chain (C18 or C24) ether-linked alkyl moiety and position sn-2 by a saturated fatty acid (12:0 to 26:0) although forms are known with simple fatty acid compositions, such as two myristic acid residues (14:0). Some GPI anchors contain an additional fatty acid, often 16:0, attached to position 2 of the inositol ring, and this has the property of inhibiting the action of the bacterial cleavage enzyme phospholipase C. In mammalian GPIs, the sn-2-linked fatty acid is usually 18:0 (occasionally polyunsaturated), while the sn-1-linked alkyl chain is C18 or C16, sometimes with one double bond, but there are many exceptions, including lysoacyl-PI and alkenylacyl-PI. It is worth noting that phosphatidylinositol per se in animals is very different in that it contains trace amounts only of 1-alkyl-2-acyl forms and the 2-acyl group is predominantly arachidonic acid.

Although the core glycan Man(α1-2)Man(α1-6)Man(α1-4)GlcN(α1-6)-myo-inositol is conserved, it can be substituted in a species-specific manner with side-chains such as ethanolamine phosphate. A distinctive feature in comparison with other complex glycolipids is that the glucosamine residues are only rarely acetylated. As an example, the GPI anchor for acetylcholinesterase from human erythrocytes is illustrated. It has either an 18:0 or an 18:1 alkyl group attached to position sn-1 of the phosphatidylinositol moiety with a 22:4, 22:5 or 22:6 acyl group linked to position sn‑2 and a 16:0 fatty acid linked to position 2 of inositol.

Formula of the GPI anchor for acetylcholinesterase from human erythrocytes

In type-1 GPIs, there are two ethanolamine phosphate residues attached to the glycan core, and the protein is linked to the ethanolamine phosphate on the third mannose. A few proteins are linked to an ethanolamine phosphate on the second mannose, although this is usually removed during biosynthesis. In other types, there can be an oligosaccharide side chain attached to the first mannose, e.g., N‑acetylgalactosamine-galactose-sialic acid. Certain protozoa and trypanosomatid parasites contain type-2 and hybrid GPIs, which differ at one of the hexose linkage points and in having one fewer ethanolamine phosphate residue than the mammalian form. The phospholipid moiety is variable among protozoan species and includes diacylglycerol, alkylacylglycerol and ceramide forms with differing fatty acid constituents. In Leishmania, the GPI-anchor is dominated by phosphoglycosylated glycans, which are related to the lipophosphoglycans and phosphatidylinositol mannosides discussed below.

The protein components can be released from the membrane by enzymic cleavage of the protein-lipid bond. Free or non-protein-bound glycosyl phosphatidylinositols are present on the external surface of the plasma membrane of some cells both in animals and protozoa (see below), but not in yeasts. Normally, they are present at low levels, but the parasitic protozoan Babesia bovis contains substantial amounts.

Yeasts and plants: Yeasts are distinctive in that they contain both GPI-anchored proteins with a characteristic C26 fatty acid component and ceramide phosphorylinositol(CPI)-anchored proteins in which ceramide replaces the diacylglycerol unit; the GPI-anchor is found in both the plasma membrane and cell wall, while the CPI-anchor is primarily in the cell wall. With the latter, the ceramide moiety is incorporated by an exchange reaction that occurs after the addition of the GPI precursor to proteins and during transfer to the cell wall with the aid of a protein Cwh43p. Phytosphingosine is the sphingoid base in this instance together with 26:0 fatty acid.

Approximately 1% of plant proteins are believed to be GPI-linked (~300 in Arabidopsis), and they are located mainly at the interface of the plasma membrane and cell wall with some having ceramide replacing diacylglycerols as the lipid component as in yeasts. Perhaps surprisingly, these plant molecules are not well characterized as yet, and the glycan core in the only species to have been examined in detail is a relatively simple structure devoid of phosphoethanolamine side chains and with a plant-specific β-linked galactose side chain attached to the first mannose.

2.   Biosynthesis and Function of GPI-Protein Complexes

Biosynthesis: Considerable progress has been made towards an understanding of the biosynthesis of GPI-protein complexes, and it is apparent that both the biosynthesis of GPI precursors and post-translational modification of proteins with GPI take place in the endoplasmic reticulum (ER) and Golgi. The process is highly complex, and briefly, it starts on the cytoplasmic side of endoplasmic reticulum and is completed on the lumenal side, so the intermediate glycophospholipid must be flipped across the membrane. In brief, the GPI precursor is synthesised in the ER before attachment to a newly synthesized protein in the ER lumen with concomitant cleavage of a carboxy-terminal GPI-addition signal peptide, followed by lipid remodelling and/or carbohydrate side-chain modifications in the ER and after transport to the Golgi.

In mammalian cells, the lipid precursor is a phosphatidylinositol molecule with 1,2-diacyl moieties, which is first attached via inositol to an N‑acetylglucosamine residue. This is de-acetylated before the molecule is translocated to the other side of the membrane by a flippase, i.e., an integral membrane protein with eight putative transmembrane domains and designated CLPTM1L (cleft lip and palate transmembrane protein 1‑like). Then, a saturated fatty acid (usually palmitate) is attached to the inositol residue in an acyltransferase reaction using acyl-CoA as donor in yeast (but not T. brucei) and GlcN-PI as acceptor, and the resulting GlcN-(acyl)PI is subjected to a process of lipid remodelling, in which the diacyl PI moiety is exchanged for a mixture of 1-alkyl-2-acyl-PI, the main form, and disaturated diacyl-PI by enzymes that have still to be characterized. As with other ether lipids, 1-alkyl-2-acyl-PI must be synthesised in the peroxisomes. This is followed by a sequence of reactions in which two mannose residues are linked to the glucosamine moiety by dolichol phosphate mannose synthase (also important for the synthesis of glycoproteins - see the web page on dolichol phosphates) before attachment of the first ethanolamine phosphate moiety (derived from phosphatidylethanolamine) to mannose I. After a further mannose unit and then ethanolamine phosphate residues are added to mannose II and III, the protein component can be attached to the ethanolamine phosphate on the third mannose.

Biosynthesis of GPI-anchored proteins

In some instances, the first mannose unit is decorated by the addition of a short oligosaccharide sequence, starting with N‑acetylgalactosamine. While detailed discussion is best left to carbohydrate experts, an interesting feature is that galactose is then added by the action of a GM1 ganglioside synthase requiring the presence of lactosylceramide, i.e., a link between glycerolipid and sphingolipid metabolism.

The GPI proteins all contain a characteristic carboxyl-terminal signal peptide with a hydrophobic tail, which is split off before the protein with a new carboxyl-terminal is combined with the amino group of the ethanolamine residue on mannose III of the GPI moiety. A GPI-transamidase complex catalyses the overall process of cleavage and GPI attachment. The palmitate attached to inositol and the ethanolamine phosphate on mannose II may then be removed before the GPI-anchored proteins are transported to the Golgi. Here, the unsaturated fatty acid in position sn-2 of the glycerol moiety is removed by the action of phospholipase A2 to form a lyso-GPI-protein, and this is re-acylated with a saturated acid (mainly 18:0 in mammalian cells). In yeast, the lipid remodelling event (addition of 26:0) occurs in the ER and is necessary for the efficient transport of GPI-APs from the ER to the Golgi apparatus. Remodelling of the glycan side chain by removal of an ethanolamine phosphate residue and addition of an N-acetylgalactosamine unit can occur, and in yeast, this happens when the molecule is transferred from the plasma membrane to the cell wall.

Overall, this remodelling process converts the GPI anchor into a transport signal that promotes the sorting and export of GPI-proteins from the ER by a vesicular mechanism to the Golgi apparatus, from where they are transferred to their active site at the outer leaflet of the plasma membrane. This export system is driven by the cytosolic coat complex COPII, which forms vesicles at ER exit sites for transport of secretory cargo to the Golgi apparatus. GPI-anchored proteins use a specialized form of this machinery for assembly and selective export from the ER, and their processing and maturation may regulate COPII.

Function: The flexible carbohydrate linkage provides GPI-proteins with a much higher degree of rotational freedom than is available to most other membrane proteins, enabling them to act more easily as signal receptors and host-recognition molecules. They are utilized in the interaction of cells with their external environment to enable the receipt of signals and the response to challenges as well as to mediate adhesion of extracellular compounds to the cell surface. GPI-proteins with two long hydrocarbon chains are in a stable association with the lipid bilayer, and those with three fatty acid/alkyl chains are held even more strongly, but Leishmania GPI-proteins with a single C24:0 alkyl chain has a half-life of only minutes at the cell surface and are secreted intact into the medium.

Scottish thistleGPI-anchored proteins have a diverse range of activities, but many are hydrolytic enzymes (including peptidases) or serve as receptors, cell surface antigens or cell adhesion molecules, complement regulatory proteins, receptors, protozoan coat proteins, and prion proteins, and most can be identified from proteomic analysis or DNA analysis of the appropriate genes by the presence of characteristic N- and C-terminal signal peptides. The main purpose of the GPI anchor is to act as a stable anchoring device that resists the action of most extracellular proteases and lipases. It targets its protein/enzyme component to a particular membrane, where it is required for some purpose, although some further movement is possible and transfer between membranes and even between cells can take place. Some of these can also exist as transmembrane and/or soluble forms.

GPI-anchored proteins can act as signalling molecules to mediate cell-cell communication, and the GPI-anchor may be a sorting signal for transport of GPI-anchored proteins in the secretory and endocytic pathways, facilitated by the remodelling processes that occur in the Golgi. They ensure the fertility of mouse sperm and egg and coordinate growth during embryonic development. As an example, high-density lipoprotein-binding protein 1 (GPIHBP1) is a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells that picks up lipoprotein lipase, a key enzyme in plasma triacylglycerol metabolism, from the interstitial spaces and transports it across endothelial cells to the capillary lumen where it can operate. In the brain, GPI-anchored proteins are required for the dynamic control of axon and synapse function and local signal transduction within raft domains, as they are synapse organizers that help to determine the properties of various types of synapses and circuits. GPI-anchored glycoproteins of the immunoglobulin superfamily mediate interactions between neurons, and between neurons and other cells in the nervous system, and so they play a part in the regulation of neuronal development and many other aspects of brain metabolism.

The nature of the hydrophobic moiety with its saturated fatty acid components resembling that of a ceramide ensures that the GPI anchor is readily incorporated into those regions of the apical plasma membrane enriched in sphingolipids and cholesterol and termed ‘rafts’, where the glycan core may aid lateral mobility. Both saturated acyl/alkyl moieties in the GPI anchor ensble raft association to occur, but the anchored proteins may also affect microdomain formation by forming transient homodimers. There seems to be a need for an interaction with phosphatidylserine in the inner leaflet of the plasma membrane and with the underlying actin cytoskeleton.

Release of GPI-anchored proteins: GPI-linked proteins are not as tightly anchored to the membrane as transmembrane proteins and so can migrate from one cell to another enabling cell communication. Thus, GPI proteins attached to their GPI anchors are released from the plasma membrane into the intercellular medium, sometimes via membrane vesicles, and they are found in serum and other body fluids. These can be re-inserted spontaneously into cell membranes and so participate in cell-cell interactions enabling control over the behaviour of neighbouring cells.

Scottish thistleAlternatively, the lipid anchor can be removed by phospholipases, such as phosphatidylinositol-specific phospholipases C and D, by a process termed ‘shedding’, which frees selected proteins, perhaps as part of a regulatory mechanism. A mammalian GPI-specific phospholipase D, GPLD1, which is a soluble protein abundant in serum, hydrolyses a set of GPI anchors that have acylated inositol, in contrast to those GPI anchors cleaved by phosphatidylinositol-phospholipase C and GPI-phospholipase C. PGAP6, a GPI-specific phospholipase A2, has narrow substrate requirement for certain GPI-anchored proteins involved in embryonic development, and by removing one of the fatty acids, it releases the proteins from the membranes.

Free (unlinked) glycosylphosphatidylinositols have been detected on the surfaces of several mammalian cell types in studies with monoclonal antibodies, and they may be normal membrane components in some tissues at least. These are not hydrolysis products but are formed in the same way as the GPI-anchored forms at the endoplasmic reticulum and transported as such to the plasma membrane. In this process, they undergo fatty acid remodelling, inositol deacylation, removal of the ethanolamine phosphate from the second mannose, and modification with N-acetylgalactosamine side chains with or without elongation by galactose. Eventually, circulating GPI-anchored proteins and their components are subjected to endocytosis and degradation.

GPI-anchored proteins and health: There is little doubt that GPI anchoring is essential for mammalian embryogenesis, development, neurogenesis, fertility and the immune system. When defects occur at any stage in the biosynthetic process, there are serious metabolic consequences and many human genetic disorders due to faulty GPI synthesis are known, and animals with major defects in the biosynthesis of GPI anchors do not survive beyond the embryo stage. They stimulate the immune system in mammalian host tissues by activating macrophages and promoting the release of different proinflammatory cytokines and chemokines, such as tumour necrosis factor-alpha, interleukin-1 and nitric oxide. Defects in the regulatory mechanisms involving GPI-anchored proteins may underlie various brain disorders and cancer, while some inherited GPI deficiencies are known in humans.

GPI-anchored proteins are factors in several other diseases, and when associated with lipid rafts, they can be incorporated into the lipid envelopes of viruses, where they may promote viral replication. In T. brucei and many other protozoan parasites, GPI-anchored proteins, such as a glycoprotein termed the ‘promastigote surface protease’, accompanied by lipophosphoglycans (see below) form a dense layer or glycocalyx as a protective barrier around the organism. This protects against the host defence systems and is a virulence factor that has been implicated in "hijacking" proteins concerned with host innate immunity. A further example is the prion protein responsible for ‘mad cow’ disease where the GPI-anchor may have a role in its pathogenicity; loss of the N‑acetylgalactosamine side chain exacerbates the disease by impairing bone formation and brain metabolism. In the same way, certain bacterial toxins bind to GPI-anchors to exert their pathological effects. Synthetic GPI analogues are under investigation as potential vaccines against such intractable parasitic diseases as malaria among other biomedical applications, while the phospholipase GPLD1 could be therapeutic target for chronic diseases.

Other eukaryotic species: While the synthesis and structure of GPI-anchored proteins are well conserved within eukaryotes, there are striking diversities in their cellular functions, and some variations are built into the biosynthetic pathway. In yeast and fungi, GPI-anchored proteins participate in the structural integrity of the cell wall through covalent linkages to polysaccharides and so ensure the viability and survival of the organisms. Thus, the developing GPI-anchored proteins tend to be heavily glycosylated by both N- and O-glycosylations in the endoplasmic reticulum and Golgi during their transit to the plasma membrane and thence to the cell wall, where they form further glycosidic linkages with other mannoproteins with the result that a complex mannoprotein lattice is presented to the external environment. In yeast, the lipid moieties of mature GPI-anchors contain a modified diacylglycerol with a 26:0 fatty acid in position sn-2, that is introduced in the Golgi apparatus and not in the endoplasmic reticulum.

In plants, GPI-anchored proteins are required as structural components of the cell wall, to organize cellulose microfibrils at the cell surface, for morphogenesis and pollen tube development, while at the interface of the plasma membrane and cell wall, they affect plasmodesmatal transport and the response to plant pathogens. They have the potential to transfer signals into the protoplast and thus stimulate signalling pathways, and they are believed to be essential for many aspects of sexual plant reproduction, including the fertility of the male and female gametophytes and in the interactions between pollen/pollen tube and pistil tissues during pollination. As in animals, a GPI shedding system cleaves and releases the GPI-anchored proteins from the plasma membrane but into the cell wall.

3.   Lipophosphoglycans and Phosphatidylinositol Mannosides

Lipophosphoglycans: Aside from the GPI-anchor molecules, carbohydrates attached to phosphatidylinositols play a part in the surface antigenicity both of certain protozoal parasites, such as the Trypanosomatid family, and of prokaryotic organisms, such as Actinomycetes or coryneform bacteria. In protozoal parasites, lipophosphoglycans are present in a glycocalyx that covers the external cell surface, where they are intimately involved in host-pathogen interactions. All the surface-bound molecules of the Trypanosomatid family have a common structural feature in that they contain a highly conserved GPI-anchor motif that differs significantly from those in mammalian cells, and those of Leishmania species, the causative agent of leishmaniases and an intracellular parasite of macrophages transmitted to humans via the bite of its sand fly vector, have received most study.

In most trypanosomatids, the glycocalyx is composed mainly of GPI-anchored glycoproteins, but in that of the Leishmania promastigote stage, GPI-anchored phosphoglycosylated glycans predominate. They are based on a type-2 GPI core, Manα1-3Manα1-4GlcNα1-6PI, as part of a conserved hexaglycosyl unit, which is attached to a long phosphodisaccharide-repeat domain (15 to 40 units) that carries species-specific side chain modifications and is completed by a neutral oligosaccharide consisting of 2, 3 or 4 galactose and/or mannose units. The lipid component is a monoalkyl-lysophosphatidylinositol with saturated C24 to C26 alkyl groups. These lipophosphoglycans are essential for successful invasion of the host animal, and the galactofuranose unit (Galf), which does not occur in mammalian cells, is believed to play a part in the pathogenicity.

Structure of the lipophosphoglycans from Leishmania species

In these organisms, low-molecular-weight (free) glycosylinositol phospholipids occur also with a glycan core that is similar structurally to that of the glycan core of the lipophosphoglycan or to that of the GPI-anchored glycoprotein, and in particular, the protozoan parasite Toxoplasma gondii expresses non-protein-linked GPIs, which are highly immunogenic. Analogous lipophosphoglycans with the lipid backbone consisting of a ceramide, i.e., ceramide phosphorylinositol, rather than a diacylglycerol, are found in plants, yeasts and other fungi.

Formula of a phosphatidylinositol dimannosidePhosphatidylinositol mannosides: These are related lipids with the first mannose residue attached to the 2‑hydroxyl group and the second to the 6-hydroxyl of myo-inositol that are found uniquely in the cell walls of the bacterial suborder Corynebacterineae, which include Mycobacteria and related species, many of which are important pathogens. In Mycobacteria sp., phosphatidylinositol and phosphatidylinositol mannosides amount to 56% of all phospholipids in the cell wall and 37% in the cytoplasmic membrane. Phosphatidylinositol mannosides range in structure from simple mono-mannosides in some Streptomyces and Mycobacterium species and in Propionibacteria to molecules with 80 or more hexose units. They are crucial structural components of membranes necessary for cell wall integrity, permeability and division. For a more extensive discussion of the cell wall structure and lipid composition of M. tuberculosis, see our web page on mycolic acids, which contains links to web pages on many other unique lipids from this organism.

The phosphatidylinositol dimannoside from M. tuberculosis, M. phlei and M. smegmatis illustrated has been characterized as 1‑phosphatidyl-L-myo-inositol 2,6-di-O-α-D-mannopyranoside and is the basic structure from which additional phosphatidylinositol mannosides are produced. With two further acylations with palmitate (designated Ac2PIM2), it is the main lipid component of the inner leaflet of the inner membrane, but forms with up to four further mannose units are present, and a hexamannoside (Ac2PIM6) is often a major component of the outer leaflet of the inner membrane. The main fatty acid constituents are palmitic and 10‑methyl-stearic (tuberculostearic) acids, and they can have one to four fatty acyl groups in total, with the further fatty acyl substituents linked to position 3 of the inositol moiety and/or position 6 of one of the inner mannose units. Phosphatidylinositol mannosides can be grouped into lower- and higher-order species depending on their number of mannoses, one to four mannoses in the former and five to six mannoses in the latter (linked to the non-acylated mannose); all lower-order species have a terminal α1,6-mannose, while those of a higher order have a terminal α1,2-mannose.

Biosynthesis of such complex lipids involves many reactions, and it is apparent that the first two mannosylation steps of the pathway occur on the cytoplasmic face of the plasma membrane by the action of two distinct phosphatidylinositol mannosyltransferases, which are essential for the viability of the organism and are seen as potential drug targets. After synthesis of the dimannoside, the additional acylations occur at this membrane and are catalysed by an integral membrane enzyme PatA, which transfers a palmitoyl moiety from palmitoyl-CoA in the cytosol to the 6-position of the mannose ring in PIM1 or PIM2. Further mannosylations require first a transfer to the periplasmic side of the membrane and then the action of integral membrane-bound glycosyltransferases, but many of these enzymes have still to be identified.

Acylation of inositol moieties in response to stress is believed to enable mycobacterial cells to resist membrane fluidization. It is evident that these lipids modulate the inflammatory and immune system responses in host animals in many ways during tuberculosis or leprosy.

Lipomannans from Mycobacteria sp. have a longer chain of mannose units, comprising a backbone of an α1,6-mannose residue attached to phosphatidylinositol, and there can be up to two further fatty acid components linked to position 6 of the Manp unit and position 3 of the myo-inositol. An α1,2-mannose side chain (mannan - 20 to 25 linear α-(1,6)-linked Manp residues with α-(1,2)-monomannose side chains) is joined to the inositol unit, and finally an arabinan (arabinose polysaccharide) branch is attached to the mannan to produce the highly complex lipoarabinomannans. For example, in M. tuberculosis, the arabinan component contains a linear polymer of ~70 residues of D‑arabinofuranose in α1,5-linkage and modified with α1,3-branch points, while the nonreducing terminal arabinan can have succinate, lactate, hydroxybutyrate or acetate substituents. The phosphatidylinositol tetramannosides Ac1PIM4 and Ac2PIM4 appear to be the intermediates at the branch point in the biosynthesis of the phosphatidylinositol hexamannosides and of lipomannans and lipoarabinomannans.

Formula of the core lipid structure of lipoarabinomannans

Such molecules are believed be required for the structural integrity of the cell walls of the organisms, a function similar to that of the lipoteichoic acids. Like the phosphatidylinositol mannosides, these lipopolysaccharides have been implicated in host–pathogen interactions in tuberculosis and leprosy, and in infected animals, they can insert into T cell membranes and interact with different receptors to repress the host innate immune system. In particular, lipoarabinomannan binding to lactosylceramide in lipid rafts is necessary for the phagocytosis of mycobacteria by human neutrophils. It is hoped that knowledge of the biosynthetic enzymes may lead to improved drug therapies.

Related Lipids: Bacteria of the genus Thermomicrobia contain unusual long-chain 1,2-diol-containing phosphoinositides and inositolmannosides in which the stereochemistry of the diol unit is the same as the corresponding positions in sn-glycerol-3-phosphate. C17 to C23 Straight-and branched-chain saturated fatty acids are linked to position 2 of the diol.

1,2-Diol-containing-phosphoinositide from Thermomicrobia

Recommended Reading

Lipid listings © Author: William W. Christie LipidWeb icon
Contact/credits/disclaimer Updated: March 27th, 2024