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Membrane Glycolipids: Functional Heterogeneity: A Review

Membrane Glycolipids: Functional Heterogeneity: A Review Glycolipids are membrane components in species ranging from bacteria to man especially in those organisms which live in unusual harsh environments. The most probable function of glycolipids in membrane is based on their capability to undergo extensive interlipid hydrogen bonding via glycosyl head groups; therefore they impart structural integrity to the membranes of the organisms. Besides, being structural components of the cell membrane, they play an important role in cellular functions such as in cell-cell communication, as receptor components, as anchors for proteins and as regulators of signal transduction. In addition, glycolipids provide a molecular platform for clustering of signal transducers. The tight interactions between cholesterol and glycolipids in the membrane are the driving force that segregates them from phospholipids that remain fluid in nature. organisms and some bacteria [2]. e Th most important and abundant Keywords: Glycolipids; Structural components; Cell-cell interaction of the oligosylceramides is β-D-galactosyl-(1-4)-β-D-glucosyl-(1-1’)- Glycolipids and their Classification ceramide, also called lactosylceramide (LacCer). Glycolipids were discovered and named by Ernst Klenk aer ft their Acidic glycosphingolipids: e Th y are divided into two groups: isolation from brain tissue in 1942. e Th y are ubiquitous membrane • Sulfoglycosphingolipids: e Th y are sometimes called constituents, which are embedded in the cell plasma membrane. “sulfatides” or “sulfatoglycosphingolipids” also. es Th e are Glycolipids are glycosyl derivatives of lipids. e Th y are collectively glycosphingolipids carrying a sulfate ester group attached to a part of a larger family of substances known as glycoconjugates. the carbohydrate moiety. Sulfated is mainly formed of 3-sulfate e Th term glycolipid designates any compound containing one or esters of galactosylcerebrosides (galactosyl-3-sulfate esters). more monosaccharide residues bound by a glycosidic linkage to a e Th y are mainly found in tissues that are very active in sodium hydrophobic moiety such as an acylglycerol, a sphingoid, a ceramide transport such as kidneys, salt glands and gills [3]. (N-acylsphingoid) or a prenyl phosphate. Glycolipids are classified as follows: • Gangliosides: This group of glycosphingolipids consists of molecules composed of ceramide linked by a glycosidic bond Glycoglycerolipids to an oligosaccharide chain containing hexose and sialic acid e Th term glycoglycerolipid is used to designate glycolipids units. es Th e lipids can amount to 6% of the weight of lipids containing mono, di or trisaccharides linked glycosidically to the from brain. One of the common monosialo-gangliosides is hydroxyl group of diglycerides (e.g. monogalacosyldiglycerides, ganglioside GM1. digalacotosyldiglycerides). Monogalactosyldiacylglycerols and Distribution of Glycolipids in the Cell digalactosyldiacylglycerols are the main glycolipid components of the various membranes of chloroplasts and also these are the most Most of the glycolipids are distributed in membranous structures in abundant lipids in all photosynthetic tissues, including those of higher the cell. Two-thirds of the total glycolipids are distributed in intracellular plants, algae and certain bacteria [1]. membranes such as golgi apparatus, endosomes, lysosomes, nuclear membrane, endoplasmic reticulum, and mitochondria [4]. Glycolipids Glycosphingolipids are synthesized in golgi apparatus by the addition of saccharides one by e Th term glycosphingolipid designates lipids containing at least one to the ceramide moiety. Most glycolipids are transported between one monosaccharide residue linked to ceramide moiety. Ceramides membranes as small vesicles maintaining a bilayer structure. However, are amides of fatty acids with long chain di or trihydroxy bases. the first step of the biosynthesis of most glycosphingolipids i.e. transfer e Th acyl group of ceramides is generally a long chain saturated or of a glycosyl residue to ceramide, occurs at the cytosolic surface of cis golgi and the other sugars are transferred at the luminal face of the monounsaturated fatty acids. e Th glycosphingolipids can be subdivided golgi complex [5]. Some glycolipids are also distributed in cytosol. e Th as follows: Neutral glycosphingolipids: es Th e glycolipids contain one or more glycosyl moieties linked to ceramide e.g. cerebrosides: Cerebrosides are *Corresponding author: Renuka Malhotra, Department of Biotechnology, monoglycosylceramides in which glucose or galactose sugar residue DAV College, Jalandhar-144008, India, Tel: +91-0181-2255641-43; E-mail: is attached by O-ester linkage to the primary alcohol of the ceramide. m_renu@yahoo.com Galactosylceramides are found in all nervous tissues, but they can Received November 23, 2011; Accepted January 17, 2012; Published January amount to 2% of the dry weight of grey matter and 12% of white matter 21, 2012 [2]. Glucosylceramide (Glcß1-1’Cer) is found at low levels in animal Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A tissues, such as spleen and erythrocytes, as well as in nervous tissues. Review. Biochem Anal Biochem 1:108. doi:10.4172/2161-1009.1000108 Copyright: © 2012 Malhotra R. This is an open-access article distributed under Oligoglycosylceramides: Glycosphingolipids containing more the terms of the Creative Commons Attribution License, which permits unrestricted than one sugar moiety belongs to the oligoglycosylceramide group. use, distribution, and reproduction in any medium, provided the original author and e Th y are vital components of cellular membranes of most eukaryotic source are credited. Biochem Anal Biochem Volume 1 • Issue 2 • 1000108 ISSN:2161-1009 Biochem, an open access journal B Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A Review. Biochem Anal Biochem 1:108. doi:10.4172/2161- 1009.1000108 Page 2 of 5 soluble fraction of brain contains 5% of the total gangliosides and their evidence for carbohydrate-carbohydrate interaction came from the composition is similar to that of the membrane fraction. Glycolipids studies of liposomes containing highly purified glycosphingolipids. are distributed prudentially into exofacial leaflets of plasma membrane Glycosphingolipids bind to the complementary glycosphingolipids and the luminal side of organelles [6]. In polarized epithelial cells, through interaction between their carbohydrate moieties [15]. glycosphingolipid are enriched on apical side of the cells while cells Cell surface carbohydrates play a major role in cell-cell or cell- with polarity, e.g. epithelial cells in intestine and kidney glycolipid substrate recognition. e Th y suggested that melanoma cell adhesion to composition differ at the apical and basolateral side. endothelial cells was based on GM3/LacCer interaction, which initiates Simons and Toomre [7] observed that in plasma membrane, metastatic deposition, and may trigger a series of “cascade” reactions glycosphingolipids along with cholesterol form clusters, called rafts. leading to activation of endothelial cells and expression of Ig family or This region had relatively less phospholipids than other areas of plasma selectin receptors, thereby promoting adhesion and migration of tumor membrane. Approximately 70% of total cellular glycolipids are found cells, hence demonstrated dramatic changes in surface carbohydrates in rafts. Rafts are lateral assemblies of sphingolipids and cholesterol during oncogenesis. that form tight hydrophobic interactions between these molecules. Boggs et al. [16] suggested that galactosyl ceramide and cerebroside Brown and London [8] reported that sphingolipids associate laterally sulfate present in high concentrations in multilayered myelin sheath with one another through weak interactions between the carbohydrates was involved in carbohydrate- carbohydrate interactions between lipid heads of the glycosphingolipids and the hydrophobic interactions head groups. e Th interaction resulted in dehydration of the sulfate, between their saturated side chains and any void between associated changes in the intermolecular hydrogen bonding, interactions of the glycosphingolipids were filled by cholesterol molecules which interact sugar and other oxygens, decreased intermolecular hydrogen bonding with hydrophobic portions of glycolipids. e Th tight interactions between of the amide C=O of GalC and dehydration of the amide region of one cholesterol and glycolipids in the membrane are the driving force that or both of the lipids, and disordering of the hydrocarbon chains of segregates them from phospholipids that remain fluid in nature [9]. both lipids. e Th interaction between these two lipids could be either a lateral cis interaction in the same bilayer or a trans interaction between Carbohydrate-Carbohydrate Interaction of Glycolipids apposed bilayers and may be involved in stabilization of the myelin Cell-cell interactions play an important role in the development, sheath. maintenance, and host-pathogen interaction. e Th y are highly dynamic Schnaar [17] observed that human leukocytes were recognized by processes, which include migration, recognition, signaling, adhesion, E-selectins present on vascular endothelium during inflammation. e Th and finally attachment. Carbohydrates moieties of glycolipids, the recruitment of neutrophils to sites of inflammation was mediated by most prominently exposed structures on the surface of living cells, endothelial leukocytes adhesion molecule-1(ELAM-1) expressed on with flexible chains and many potential binding sites are ideal to serve activated endothelial cells of blood vessels walls. ELAM-1 is a member as important players in these events. Molecular interactions where of the selectin family of adhesion molecules that contain a lectin motif carbohydrates are involved are usually considered as weak interactions, thought to recognize carbohydrate ligands. e Th y observed that cell and therefore, there is biological relevance of carbohydrate-carbohydrate adhesion by ELAM-1 was mediated by a carbohydrate ligand, sialyl- and carbohydrate-protein interactions [10]. Lewis X (SLex; NeuAc alpha 2,3Gal beta 1,4(Fuc alpha 1,3)-GlcNAc-), Glycolipid-glycolipid interaction is a rapid process, as compared a terminal structure found on cell-surface glycoprotein and glycolipid with protein-protein interaction, although the strength of the carbohydrate groups of neutrophils. e Th sialyl Lewis A and sialyl Lewis interaction is weaker than that of protein-protein interaction [10]. A X, the carbohydrate determinants which are frequently expressed synergistic effect between cell adhesion based on glycosphingolipids- on human cancer cells, serve as ligands for a cell adhesion molecule glycosphingolipids interactions and adhesion based on integrins was of the selectin family, E-selectin, which is expressed on vascular observed by Bucior et al. [11]. e Th y postulated that glycosphingolipid- endothelial cells. es Th e carbohydrate determinants are involved in the glycosphingolipid interaction may define the initial specificity and adhesion of cancer cells to vascular endothelium and thus contribute direction of the cell recognition and regulate the adhesion process. to hematogenous metastasis of cancer by triggering the activation of integrin molecules through the action of several cytokines leading to One of the important properties of the bilayer is the ability to extravasation of cancer cells. orient and cluster glycolipid species in such a way so that interactions in the biological systems are maximized. e Th lipid moiety of Overall, it can be stated that carbohydrate-carbohydrate interactions glycolipids is generally buried in the cell membrane bilayer, leaving the play an important role in recognition and signaling events in a variety oligosaccharide moieties exposed but in close proximity to the bilayer of biological phenomena. surface [12]. This represents a unique environment for carbohydrate interactions with other molecules. Glycolipids cause two types of Biological Functions of Membrane Glycolipids interactions. e Th y interact side by side within the same membrane Membrane glycolipids perform a number of functions in biological to form clusters and by trans interactions in which two interfacing system. Glycolipids have roles in response to cell contact, as receptor membrane interact through their surface carbohydrates [13]. e Th y components, as anchors for proteins and as markers for tumor further reported that trans interactions between the glycolipids progression and cell differentiation [18]. provides the basis for glycosphingolipids-dependent cell to cell adhesion, which takes place through specific complementary structures Glycolipids as signal transducers catalyzed in many cases by calcium ions. er Th efore, cell surface complex Glycolipids have been known to be modulators of signal carbohydrate has emerged as key recognition molecules, mediating transduction. Glycosphingolipids and sphingomyelin in animal cells are physiological interactions between cells. Typically glycans on one cell clustered and organized as membrane microdomains closely associated surface engaged by complementary carbohydrate binding proteins on opposing cells, initiate a cellular responses [14]. e Th preliminary with various signal transducer molecules such as cSrc, Src family Biochem Anal Biochem Volume 1 • Issue 2 • 1000108 ISSN:2161-1009 Biochem, an open access journal Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A Review. Biochem Anal Biochem 1:108. doi:10.4172/2161- 1009.1000108 Page 3 of 5 kinases, small G-proteins (e.g. RhoA, Ras), and focal adhesion kinase. on cholera toxin binding to the lipid-based receptor ganglioside GM1 Glycosphingolipid clustering in such microdomain causes adhesion to and association with detergent-insoluble membrane microdomains. complementary glycosphingolipids on the surface of counterpart cells Cholera toxin action depends on the stable formation of the cholera through carbohydrate-carbohydrate interaction. Glycosphingolipids toxin B-subunit- GM1 complex. dependent cell adhesion in microdomain causes activation of the signal Bock et al. [26] studied that enterohaemorrhagic E. coli bind to transducers, leading to cell phenotypic changes [19,20] neutral glycosphingolipids having an alpha-1,4 galabiose moieties in Glycosphingolipid microdomains mediate signal response either by the sugar chain, such as galabioside (Ga2Cer) and ceramide trihexoside associating with GPI-anchored proteins or Immuno and growth factor (Gb3Cer).They suggested that E. coli bind to glycosphingolipid by receptors. Kasahara et al. [20] reported that GPI anchored proteins recognizing not only the terminal sequence but also the internal and acylated proteins like src-family tyrosine kinases and trimeric-G sequence of the sugar chain. Propionibacterium, which causes skin proteins are known to associate with glycosphingolipid microdomains. disease, recognizes the lactosyl moiety of glycosphingolipids as a GPI-anchored proteins having saturated acyl chains were likely to insert binding epitope. es Th e bacteria bind strongly to lactosylceramide and preferentially into glycosphingolipid microdomains. e Th y observed also bind to isoreceptors such as asialo GM1 (GA1) and asialo GM2 that antibody (or ligand)-mediated crosslinking of GPI-anchored (GA2). This bacterium could not bind to any glycosphingolipids proteins induces activation of src-family kinases and transient increase composed of a dihydroxy base and nonhydroxy fatty acid in ceramide, in tyrosine phosphorylation of several substrates. Reports showed even though they contain a lactosylmoiety. that enzymatic removal of the carbohydrate moiety from cell-surface Glycolipids in modulation of cell proliferation glycosphingolipids impairs the activation of the src-family kinase by antibody-mediated crosslinking of GPI-anchored protein. Several observations underline the role of the glycolipids in regulation of cell growth by interacting through growth factor receptors Glycosphingolipid microdomains are also involved in signaling [22]. Auge et al. [27] observed that intracellularly produced ceramide, by immunoreceptors and growth factor receptors [21]. Efficient T-cell Lac Cer stimulated DNA synthesis in endothelial smooth muscle cells. activation requires one signal from a T-cell antigen receptor and a e Th y also potentiated the mitogenesis induced by various growth second signal from the co-stimulatory molecule. e Th co-stimulation factors including platelet-derived growth factor. e Th lactosylceramide leads to the recruitment of glycosphingolipid microdomains to the site (LacCer, Galβ4Glcβ1Cer) activates NADPH oxidase to modulate the of cell-cell contact between the T cell and antigen-presenting cell. intercellular adhesion molecule-1 expression on human umbilical Iwabuchi et al. [22] reported that adhesion process is based vein endothelial cells and to induce the proliferation of human aortic essentially on a glycosphingolipid-enriched microdomain (GEM) at smooth muscle cells. Reports showed that decrease in ceramide content the B16 cell surface. More than 90% of GM3 present in the original cells via increased activity of ceramidase, sphingomyelin synthase or GlcCer were found in GEM. GEM is also enriched in several signal transducer synthase correlated with proliferative response of smooth muscle cells. molecules, e.g. c-Src, Ras, Rho, and focal adhesion kinase. Sphingolipid breakdown products, sphingosine and e Th general function of glycosphingolipid microdomains in signal lysosphingolipids, inhibit protein kinase C, an important enzyme in cell transduction may be to concentrate receptors and effectors on both regulation and signal transduction. Sphingolipids and lysosphingolipids sides of the membrane, thus speeding up binding during signaling and ae ff ct significant cellular responses and exhibit antitumor promoter preventing inappropriate crosstalk between pathways. activities in various mammalian cells. es Th e molecules may function as endogenous modulators of cell function and possibly as second Glycolipids as receptors of bacteria and bacterial toxins messengers [28]. Ceramides in turn activate the serine-theronine Binding of pathogenic bacteria and bacterial toxins to host cell protein phosphatases PP1 and PP2A. Ceramide activated protein surfaces is an essential step in establishing infection in tissues and phosphates leads either to cell cycle arrest or to apoptosis [18] producing toxic effect. Glycolipids on cell surfaces are receptors for Some gangliosides are apoptotic inducers. Ceramide is a mediator binding to cells. Many pathogenic bacteria bind to glycolipids of host of programmed cell death signaling in lymphoid cells. GD3 is potent cell surface for colonization and infection. mediator of cell death. De Maria [29] reported that the apoptotic signal triggered by CD 95 in lymphoid and myeloid tumor cells increases the Rodighiero et al. [23] reported that many bacterial toxins bind to ceramide levels, which is followed by an increase in ganglioside GD3 gangliosides as the receptors on cell surface and invade host cells. e Th synthesis. Addition to cells in culture damaged mitochondria with best known of these is the cholera toxin, an enterotoxin produced by Vibrio cholerae, and its specific cell surface receptor was identified as consequent dissipation of mitochondrial transmembrane potential ganglioside GM1. e Th entry of cholera toxin into target epithelial cells and caused DNA fragmentation in HuT78 cell. Glycosphingolipids are abundant components of external leaflet of the plasma membrane of and the induction of toxicity depend on the cholera toxin binding to cancer cells. Addition of anti-ganglioside GD2 monoclonal antibodies ligand-based receptor GM1 and association with the glycosphingolipid into cell medium results in apoptosis in GD2 expressing human lung microdomain [24]. Cholera toxin consists of a pentameric B subunit that binds to GM1 and an A subunit with direct toxic activity. e Th cancer cells. binding of B subunit to membrane GM1 induces a conformational Glycolipids as biosurfactant change in the toxin, resulting in the entry of the A subunit into the cell. Wolf et al. [25] observed that to induce toxicity cholera toxin must bind Biosurfactants are amphiphilic compounds containing hydrophobic ganglioside GM1 at plasma membrane, enter the cell by endocytosis and hydrophilic moieties that reduce surface tension and interfacial and then retrograde into endoplasmic reticulum. e Th y proposed that tensions between individual molecules at the cell surface and interface GM1provides the sorting motif necessary to retrograde trafficking into respectively. Glycolipids are the most common types of biosurfactants. biosynthetic, secreatory pathway of host cells. e Th entry of cholera e Th polar moiety is a carbohydrate and the nonpolar moiety is a long toxin into target epithelial cells and the inductions of toxicity depend carbon chain fatty acid. Mannosylethritol lipids (MELs) are microbial Biochem Anal Biochem Volume 1 • Issue 2 • 1000108 ISSN:2161-1009 Biochem, an open access journal Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A Review. Biochem Anal Biochem 1:108. doi:10.4172/2161- 1009.1000108 Page 4 of 5 interaction provides adhesion force and specificity for cellular recognition. J extracellular glycolipids composed of mannosylethritol and fatty acids Cell Biol 165: 529-537. as hydrophilic and lipophilic moieties, respectively. e Th y are produced by Schizonella melanograma, Candida antarctica T-34 [30] and Ustilago 12. Marrow MR, Singh D, Lu D, Grant CW (1995) Glycosphingolipid fatty acid arrangement in phospholipid bilayer: Cholesterol effects. Biophys J 68: 179- maydis [31]. MEL glycolipids produced by Candida antarctica T-34 showed excellent surface and interfacial tension lowering actions and exhibited antimicrobial activity particularly against Gram-positive 13. Hakomori SI, Handa K (2002) Glycosphingolipid-dependent cross-talk between glycosynapses interfacing tumor cells with their host cells: essential basis to bacteria, thereby suggesting a strong potential for their industrial use. define tumor malignancy. FEBS Letts 531: 88-92. e Th excellent surface tension reducing and emulsifying characteristics of MELs glycolipids and its stability over a wide range of temperature 14. Evans IV, Roger MC (1999) Characterization of protein-glycolipid recognition at and pHs, made MELs important for commercial application. MELs the membrane bilayer. J Mol Recognit 12: 155-168. glycolipids were potent inducers of apoptosis and differentiation in 15. Kojima N, Hakomori S (1991) Cell adhesion, spreading, and motility of GM3- mouse melanoma cells. expressing cells based on glycolipid-glycolipid interaction. J Biol Chem 266: 17552-17558. Role of glycolipids in calcium homeostasis 16. Boggs JM, Menikh A, Rangaraj G (2000) Trans interaction between galactosyl e Th association of calcium ions with glycolipids especially ceramide and cerebroside sulphate across opposed bilayers. Biophys J 78: 874-885. gangliosides were involved in neuronal function. Gangliosides micelles bind calcium ions with high affinity. This may have some 17. Schnaar RL (2004) Glycolipid-mediated cell-cell recognition in inflammation significance in the process of synaptic transmission. Levade et al. [31] and nerve regeneration. Arch Biochem Biophys 426: 163-172. reported that sphingosine and ceramide mediated a profound release 18. Hannun YA (1996) Review: Functions of ceramide in coordinating cellular of calcium ions from intracellular stores. Gangliosides function in responses to stress. Science 274: 1855-1859. calcium homeostasis and signaling. He observed that gangliosides 19. Kasahara K, Sanai Y (2000) Functional roles of glycosphingolipids in signal induced changes in cellular calcium, which was accomplished through transduction via lipid rafts. Glycoconj J 17: 153-162. modulation of calcium influx channels, calcium exchange proteins 20. Hakamori SI (2000) Cell adhesion, recognition and signal transduction through and various calcium dependent enzymes that were altered through the glycosphingolipid microdomain. Glycoconj J 17: 143-151. association with the gangliosides. Lloyd-Evans et al. [32] demonstrated 21. Jordan S, Rodgers W (2003) T-cell glycolipid-enriched membrane domains that elevation of intracellular glucosylceramide (GlcCer) levels results 2+ are constitutively assembled as membrane phases that translocate to immune in increased functional Ca stores in cultured rat neurons. Surface synapses. J Immunol 171: 78-87. 2+ glycolipid galactocerebroside participate in the opening of the Ca channels in oligodendrocytes cells. 22. Iwabuchi K, Yamamura S, Prinetti A, Handa K, Hakomori SI (1998) GM3- enriched microdomain involved in cell adhesion and signal transduction through carbohydrate-carbohydrate interaction in mouse melanoma B16 cells. Conclusion J Biol Chem 273: 9130-9138. Overall, it can be stated that glycolipids in the cell membranes play 23. Rodighiero C, Fujinaga Y, Hirst TR, Lencer WI (2001) A cholera toxin B-subunit an important role in recognition and signaling events in a variety of variant that binds ganglioside G(M1) but fails to induce toxicity. J Biol Chem biological phenomena, are potent inducers of apoptosis and differtiation 27: 36939-36945. in melanoma cells, regulating cell growth by interacting through 24. Zhang RG, Scott DL, Westbrook ML, Nance S, Spangler BD, et al. (1995) The growth factor receptors, concentrated receptors and effectors on both three-dimensional crystal structure of cholera toxin. J Mol Biol 251: 563-573. sides of the membrane, thus speeding up binding during signaling and 25. Wolf AA, Fujinaga Y, Lencer WI (2002) Uncoupling of cholera toxin-G(MI) preventing inappropriate crosstalk between pathways. ganglioside receptor complex from endocytosis, retrograde golgi trafficking and References downstream signal transduction by depletion of membrane cholesterol. J Biol Chem 277: 16249-16256. 1. Heinz E, Christie WW (1996) Plant glycolipids: structure, isolation and analysis. In: Advances in Lipid Methodology. Volume 3, Oily press, Dundee. 26. Bock K, Breimer ME, Brignole A, Hansson GC, Karlsson KA, et al. (1985) Specificity of binding of a strain of uropathogenic Escherichia coli to Gal1--- rd 2. Christie WW (2003) Lipid Analysis. (3 edn), Oily Press, Bridgwater. 4Gal-containing glycosphingolipids. J Biol Chem 260: 8545-8551. 3. Ishizuka I (1997) Chemistry and functional distribution of sulfolipids. Prog Lipid 27. 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Bucior I, Scheuring S, Engel A, Burger MM (2004) Carbohydrate-carbohydrate Biochem Anal Biochem Volume 1 • Issue 2 • 1000108 ISSN:2161-1009 Biochem, an open access journal Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A Review. Biochem Anal Biochem 1:108. doi:10.4172/2161- 1009.1000108 Page 5 of 5 33. Levade T, Auge N, Veldman RJ, Cuvillier O, Salvayre AN, et al. (2001) 34. Zhao X, Wakamatsu Y, Shibahara M, Nomura N, Gettinger C, et al. (1999) Mannosyl erythritol lipid is potent inducers of apoptosis and differentiation of Sphingolipid mediators in cardiovascular Cell Biology and Pathology. Cir Res mouse melanoma cells is culture. Cancer Res 59: 482-486. 89: 957-968. Biochem Anal Biochem Volume 1 • Issue 2 • 1000108 ISSN:2161-1009 Biochem, an open access journal http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biochemistry & Analytical Biochemistry Unpaywall

Membrane Glycolipids: Functional Heterogeneity: A Review

Biochemistry & Analytical BiochemistryJan 1, 2012

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Abstract

Glycolipids are membrane components in species ranging from bacteria to man especially in those organisms which live in unusual harsh environments. The most probable function of glycolipids in membrane is based on their capability to undergo extensive interlipid hydrogen bonding via glycosyl head groups; therefore they impart structural integrity to the membranes of the organisms. Besides, being structural components of the cell membrane, they play an important role in cellular functions such as in cell-cell communication, as receptor components, as anchors for proteins and as regulators of signal transduction. In addition, glycolipids provide a molecular platform for clustering of signal transducers. The tight interactions between cholesterol and glycolipids in the membrane are the driving force that segregates them from phospholipids that remain fluid in nature. organisms and some bacteria [2]. e Th most important and abundant Keywords: Glycolipids; Structural components; Cell-cell interaction of the oligosylceramides is β-D-galactosyl-(1-4)-β-D-glucosyl-(1-1’)- Glycolipids and their Classification ceramide, also called lactosylceramide (LacCer). Glycolipids were discovered and named by Ernst Klenk aer ft their Acidic glycosphingolipids: e Th y are divided into two groups: isolation from brain tissue in 1942. e Th y are ubiquitous membrane • Sulfoglycosphingolipids: e Th y are sometimes called constituents, which are embedded in the cell plasma membrane. “sulfatides” or “sulfatoglycosphingolipids” also. es Th e are Glycolipids are glycosyl derivatives of lipids. e Th y are collectively glycosphingolipids carrying a sulfate ester group attached to a part of a larger family of substances known as glycoconjugates. the carbohydrate moiety. Sulfated is mainly formed of 3-sulfate e Th term glycolipid designates any compound containing one or esters of galactosylcerebrosides (galactosyl-3-sulfate esters). more monosaccharide residues bound by a glycosidic linkage to a e Th y are mainly found in tissues that are very active in sodium hydrophobic moiety such as an acylglycerol, a sphingoid, a ceramide transport such as kidneys, salt glands and gills [3]. (N-acylsphingoid) or a prenyl phosphate. Glycolipids are classified as follows: • Gangliosides: This group of glycosphingolipids consists of molecules composed of ceramide linked by a glycosidic bond Glycoglycerolipids to an oligosaccharide chain containing hexose and sialic acid e Th term glycoglycerolipid is used to designate glycolipids units. es Th e lipids can amount to 6% of the weight of lipids containing mono, di or trisaccharides linked glycosidically to the from brain. One of the common monosialo-gangliosides is hydroxyl group of diglycerides (e.g. monogalacosyldiglycerides, ganglioside GM1. digalacotosyldiglycerides). Monogalactosyldiacylglycerols and Distribution of Glycolipids in the Cell digalactosyldiacylglycerols are the main glycolipid components of the various membranes of chloroplasts and also these are the most Most of the glycolipids are distributed in membranous structures in abundant lipids in all photosynthetic tissues, including those of higher the cell. Two-thirds of the total glycolipids are distributed in intracellular plants, algae and certain bacteria [1]. membranes such as golgi apparatus, endosomes, lysosomes, nuclear membrane, endoplasmic reticulum, and mitochondria [4]. Glycolipids Glycosphingolipids are synthesized in golgi apparatus by the addition of saccharides one by e Th term glycosphingolipid designates lipids containing at least one to the ceramide moiety. Most glycolipids are transported between one monosaccharide residue linked to ceramide moiety. Ceramides membranes as small vesicles maintaining a bilayer structure. However, are amides of fatty acids with long chain di or trihydroxy bases. the first step of the biosynthesis of most glycosphingolipids i.e. transfer e Th acyl group of ceramides is generally a long chain saturated or of a glycosyl residue to ceramide, occurs at the cytosolic surface of cis golgi and the other sugars are transferred at the luminal face of the monounsaturated fatty acids. e Th glycosphingolipids can be subdivided golgi complex [5]. Some glycolipids are also distributed in cytosol. e Th as follows: Neutral glycosphingolipids: es Th e glycolipids contain one or more glycosyl moieties linked to ceramide e.g. cerebrosides: Cerebrosides are *Corresponding author: Renuka Malhotra, Department of Biotechnology, monoglycosylceramides in which glucose or galactose sugar residue DAV College, Jalandhar-144008, India, Tel: +91-0181-2255641-43; E-mail: is attached by O-ester linkage to the primary alcohol of the ceramide. m_renu@yahoo.com Galactosylceramides are found in all nervous tissues, but they can Received November 23, 2011; Accepted January 17, 2012; Published January amount to 2% of the dry weight of grey matter and 12% of white matter 21, 2012 [2]. Glucosylceramide (Glcß1-1’Cer) is found at low levels in animal Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A tissues, such as spleen and erythrocytes, as well as in nervous tissues. Review. Biochem Anal Biochem 1:108. doi:10.4172/2161-1009.1000108 Copyright: © 2012 Malhotra R. This is an open-access article distributed under Oligoglycosylceramides: Glycosphingolipids containing more the terms of the Creative Commons Attribution License, which permits unrestricted than one sugar moiety belongs to the oligoglycosylceramide group. use, distribution, and reproduction in any medium, provided the original author and e Th y are vital components of cellular membranes of most eukaryotic source are credited. Biochem Anal Biochem Volume 1 • Issue 2 • 1000108 ISSN:2161-1009 Biochem, an open access journal B Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A Review. Biochem Anal Biochem 1:108. doi:10.4172/2161- 1009.1000108 Page 2 of 5 soluble fraction of brain contains 5% of the total gangliosides and their evidence for carbohydrate-carbohydrate interaction came from the composition is similar to that of the membrane fraction. Glycolipids studies of liposomes containing highly purified glycosphingolipids. are distributed prudentially into exofacial leaflets of plasma membrane Glycosphingolipids bind to the complementary glycosphingolipids and the luminal side of organelles [6]. In polarized epithelial cells, through interaction between their carbohydrate moieties [15]. glycosphingolipid are enriched on apical side of the cells while cells Cell surface carbohydrates play a major role in cell-cell or cell- with polarity, e.g. epithelial cells in intestine and kidney glycolipid substrate recognition. e Th y suggested that melanoma cell adhesion to composition differ at the apical and basolateral side. endothelial cells was based on GM3/LacCer interaction, which initiates Simons and Toomre [7] observed that in plasma membrane, metastatic deposition, and may trigger a series of “cascade” reactions glycosphingolipids along with cholesterol form clusters, called rafts. leading to activation of endothelial cells and expression of Ig family or This region had relatively less phospholipids than other areas of plasma selectin receptors, thereby promoting adhesion and migration of tumor membrane. Approximately 70% of total cellular glycolipids are found cells, hence demonstrated dramatic changes in surface carbohydrates in rafts. Rafts are lateral assemblies of sphingolipids and cholesterol during oncogenesis. that form tight hydrophobic interactions between these molecules. Boggs et al. [16] suggested that galactosyl ceramide and cerebroside Brown and London [8] reported that sphingolipids associate laterally sulfate present in high concentrations in multilayered myelin sheath with one another through weak interactions between the carbohydrates was involved in carbohydrate- carbohydrate interactions between lipid heads of the glycosphingolipids and the hydrophobic interactions head groups. e Th interaction resulted in dehydration of the sulfate, between their saturated side chains and any void between associated changes in the intermolecular hydrogen bonding, interactions of the glycosphingolipids were filled by cholesterol molecules which interact sugar and other oxygens, decreased intermolecular hydrogen bonding with hydrophobic portions of glycolipids. e Th tight interactions between of the amide C=O of GalC and dehydration of the amide region of one cholesterol and glycolipids in the membrane are the driving force that or both of the lipids, and disordering of the hydrocarbon chains of segregates them from phospholipids that remain fluid in nature [9]. both lipids. e Th interaction between these two lipids could be either a lateral cis interaction in the same bilayer or a trans interaction between Carbohydrate-Carbohydrate Interaction of Glycolipids apposed bilayers and may be involved in stabilization of the myelin Cell-cell interactions play an important role in the development, sheath. maintenance, and host-pathogen interaction. e Th y are highly dynamic Schnaar [17] observed that human leukocytes were recognized by processes, which include migration, recognition, signaling, adhesion, E-selectins present on vascular endothelium during inflammation. e Th and finally attachment. Carbohydrates moieties of glycolipids, the recruitment of neutrophils to sites of inflammation was mediated by most prominently exposed structures on the surface of living cells, endothelial leukocytes adhesion molecule-1(ELAM-1) expressed on with flexible chains and many potential binding sites are ideal to serve activated endothelial cells of blood vessels walls. ELAM-1 is a member as important players in these events. Molecular interactions where of the selectin family of adhesion molecules that contain a lectin motif carbohydrates are involved are usually considered as weak interactions, thought to recognize carbohydrate ligands. e Th y observed that cell and therefore, there is biological relevance of carbohydrate-carbohydrate adhesion by ELAM-1 was mediated by a carbohydrate ligand, sialyl- and carbohydrate-protein interactions [10]. Lewis X (SLex; NeuAc alpha 2,3Gal beta 1,4(Fuc alpha 1,3)-GlcNAc-), Glycolipid-glycolipid interaction is a rapid process, as compared a terminal structure found on cell-surface glycoprotein and glycolipid with protein-protein interaction, although the strength of the carbohydrate groups of neutrophils. e Th sialyl Lewis A and sialyl Lewis interaction is weaker than that of protein-protein interaction [10]. A X, the carbohydrate determinants which are frequently expressed synergistic effect between cell adhesion based on glycosphingolipids- on human cancer cells, serve as ligands for a cell adhesion molecule glycosphingolipids interactions and adhesion based on integrins was of the selectin family, E-selectin, which is expressed on vascular observed by Bucior et al. [11]. e Th y postulated that glycosphingolipid- endothelial cells. es Th e carbohydrate determinants are involved in the glycosphingolipid interaction may define the initial specificity and adhesion of cancer cells to vascular endothelium and thus contribute direction of the cell recognition and regulate the adhesion process. to hematogenous metastasis of cancer by triggering the activation of integrin molecules through the action of several cytokines leading to One of the important properties of the bilayer is the ability to extravasation of cancer cells. orient and cluster glycolipid species in such a way so that interactions in the biological systems are maximized. e Th lipid moiety of Overall, it can be stated that carbohydrate-carbohydrate interactions glycolipids is generally buried in the cell membrane bilayer, leaving the play an important role in recognition and signaling events in a variety oligosaccharide moieties exposed but in close proximity to the bilayer of biological phenomena. surface [12]. This represents a unique environment for carbohydrate interactions with other molecules. Glycolipids cause two types of Biological Functions of Membrane Glycolipids interactions. e Th y interact side by side within the same membrane Membrane glycolipids perform a number of functions in biological to form clusters and by trans interactions in which two interfacing system. Glycolipids have roles in response to cell contact, as receptor membrane interact through their surface carbohydrates [13]. e Th y components, as anchors for proteins and as markers for tumor further reported that trans interactions between the glycolipids progression and cell differentiation [18]. provides the basis for glycosphingolipids-dependent cell to cell adhesion, which takes place through specific complementary structures Glycolipids as signal transducers catalyzed in many cases by calcium ions. er Th efore, cell surface complex Glycolipids have been known to be modulators of signal carbohydrate has emerged as key recognition molecules, mediating transduction. Glycosphingolipids and sphingomyelin in animal cells are physiological interactions between cells. Typically glycans on one cell clustered and organized as membrane microdomains closely associated surface engaged by complementary carbohydrate binding proteins on opposing cells, initiate a cellular responses [14]. e Th preliminary with various signal transducer molecules such as cSrc, Src family Biochem Anal Biochem Volume 1 • Issue 2 • 1000108 ISSN:2161-1009 Biochem, an open access journal Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A Review. Biochem Anal Biochem 1:108. doi:10.4172/2161- 1009.1000108 Page 3 of 5 kinases, small G-proteins (e.g. RhoA, Ras), and focal adhesion kinase. on cholera toxin binding to the lipid-based receptor ganglioside GM1 Glycosphingolipid clustering in such microdomain causes adhesion to and association with detergent-insoluble membrane microdomains. complementary glycosphingolipids on the surface of counterpart cells Cholera toxin action depends on the stable formation of the cholera through carbohydrate-carbohydrate interaction. Glycosphingolipids toxin B-subunit- GM1 complex. dependent cell adhesion in microdomain causes activation of the signal Bock et al. [26] studied that enterohaemorrhagic E. coli bind to transducers, leading to cell phenotypic changes [19,20] neutral glycosphingolipids having an alpha-1,4 galabiose moieties in Glycosphingolipid microdomains mediate signal response either by the sugar chain, such as galabioside (Ga2Cer) and ceramide trihexoside associating with GPI-anchored proteins or Immuno and growth factor (Gb3Cer).They suggested that E. coli bind to glycosphingolipid by receptors. Kasahara et al. [20] reported that GPI anchored proteins recognizing not only the terminal sequence but also the internal and acylated proteins like src-family tyrosine kinases and trimeric-G sequence of the sugar chain. Propionibacterium, which causes skin proteins are known to associate with glycosphingolipid microdomains. disease, recognizes the lactosyl moiety of glycosphingolipids as a GPI-anchored proteins having saturated acyl chains were likely to insert binding epitope. es Th e bacteria bind strongly to lactosylceramide and preferentially into glycosphingolipid microdomains. e Th y observed also bind to isoreceptors such as asialo GM1 (GA1) and asialo GM2 that antibody (or ligand)-mediated crosslinking of GPI-anchored (GA2). This bacterium could not bind to any glycosphingolipids proteins induces activation of src-family kinases and transient increase composed of a dihydroxy base and nonhydroxy fatty acid in ceramide, in tyrosine phosphorylation of several substrates. Reports showed even though they contain a lactosylmoiety. that enzymatic removal of the carbohydrate moiety from cell-surface Glycolipids in modulation of cell proliferation glycosphingolipids impairs the activation of the src-family kinase by antibody-mediated crosslinking of GPI-anchored protein. Several observations underline the role of the glycolipids in regulation of cell growth by interacting through growth factor receptors Glycosphingolipid microdomains are also involved in signaling [22]. Auge et al. [27] observed that intracellularly produced ceramide, by immunoreceptors and growth factor receptors [21]. Efficient T-cell Lac Cer stimulated DNA synthesis in endothelial smooth muscle cells. activation requires one signal from a T-cell antigen receptor and a e Th y also potentiated the mitogenesis induced by various growth second signal from the co-stimulatory molecule. e Th co-stimulation factors including platelet-derived growth factor. e Th lactosylceramide leads to the recruitment of glycosphingolipid microdomains to the site (LacCer, Galβ4Glcβ1Cer) activates NADPH oxidase to modulate the of cell-cell contact between the T cell and antigen-presenting cell. intercellular adhesion molecule-1 expression on human umbilical Iwabuchi et al. [22] reported that adhesion process is based vein endothelial cells and to induce the proliferation of human aortic essentially on a glycosphingolipid-enriched microdomain (GEM) at smooth muscle cells. Reports showed that decrease in ceramide content the B16 cell surface. More than 90% of GM3 present in the original cells via increased activity of ceramidase, sphingomyelin synthase or GlcCer were found in GEM. GEM is also enriched in several signal transducer synthase correlated with proliferative response of smooth muscle cells. molecules, e.g. c-Src, Ras, Rho, and focal adhesion kinase. Sphingolipid breakdown products, sphingosine and e Th general function of glycosphingolipid microdomains in signal lysosphingolipids, inhibit protein kinase C, an important enzyme in cell transduction may be to concentrate receptors and effectors on both regulation and signal transduction. Sphingolipids and lysosphingolipids sides of the membrane, thus speeding up binding during signaling and ae ff ct significant cellular responses and exhibit antitumor promoter preventing inappropriate crosstalk between pathways. activities in various mammalian cells. es Th e molecules may function as endogenous modulators of cell function and possibly as second Glycolipids as receptors of bacteria and bacterial toxins messengers [28]. Ceramides in turn activate the serine-theronine Binding of pathogenic bacteria and bacterial toxins to host cell protein phosphatases PP1 and PP2A. Ceramide activated protein surfaces is an essential step in establishing infection in tissues and phosphates leads either to cell cycle arrest or to apoptosis [18] producing toxic effect. Glycolipids on cell surfaces are receptors for Some gangliosides are apoptotic inducers. Ceramide is a mediator binding to cells. Many pathogenic bacteria bind to glycolipids of host of programmed cell death signaling in lymphoid cells. GD3 is potent cell surface for colonization and infection. mediator of cell death. De Maria [29] reported that the apoptotic signal triggered by CD 95 in lymphoid and myeloid tumor cells increases the Rodighiero et al. [23] reported that many bacterial toxins bind to ceramide levels, which is followed by an increase in ganglioside GD3 gangliosides as the receptors on cell surface and invade host cells. e Th synthesis. Addition to cells in culture damaged mitochondria with best known of these is the cholera toxin, an enterotoxin produced by Vibrio cholerae, and its specific cell surface receptor was identified as consequent dissipation of mitochondrial transmembrane potential ganglioside GM1. e Th entry of cholera toxin into target epithelial cells and caused DNA fragmentation in HuT78 cell. Glycosphingolipids are abundant components of external leaflet of the plasma membrane of and the induction of toxicity depend on the cholera toxin binding to cancer cells. Addition of anti-ganglioside GD2 monoclonal antibodies ligand-based receptor GM1 and association with the glycosphingolipid into cell medium results in apoptosis in GD2 expressing human lung microdomain [24]. Cholera toxin consists of a pentameric B subunit that binds to GM1 and an A subunit with direct toxic activity. e Th cancer cells. binding of B subunit to membrane GM1 induces a conformational Glycolipids as biosurfactant change in the toxin, resulting in the entry of the A subunit into the cell. Wolf et al. [25] observed that to induce toxicity cholera toxin must bind Biosurfactants are amphiphilic compounds containing hydrophobic ganglioside GM1 at plasma membrane, enter the cell by endocytosis and hydrophilic moieties that reduce surface tension and interfacial and then retrograde into endoplasmic reticulum. e Th y proposed that tensions between individual molecules at the cell surface and interface GM1provides the sorting motif necessary to retrograde trafficking into respectively. Glycolipids are the most common types of biosurfactants. biosynthetic, secreatory pathway of host cells. e Th entry of cholera e Th polar moiety is a carbohydrate and the nonpolar moiety is a long toxin into target epithelial cells and the inductions of toxicity depend carbon chain fatty acid. Mannosylethritol lipids (MELs) are microbial Biochem Anal Biochem Volume 1 • Issue 2 • 1000108 ISSN:2161-1009 Biochem, an open access journal Citation: Malhotra R (2012) Membrane Glycolipids: Functional Heterogeneity: A Review. Biochem Anal Biochem 1:108. doi:10.4172/2161- 1009.1000108 Page 4 of 5 interaction provides adhesion force and specificity for cellular recognition. J extracellular glycolipids composed of mannosylethritol and fatty acids Cell Biol 165: 529-537. as hydrophilic and lipophilic moieties, respectively. e Th y are produced by Schizonella melanograma, Candida antarctica T-34 [30] and Ustilago 12. Marrow MR, Singh D, Lu D, Grant CW (1995) Glycosphingolipid fatty acid arrangement in phospholipid bilayer: Cholesterol effects. Biophys J 68: 179- maydis [31]. MEL glycolipids produced by Candida antarctica T-34 showed excellent surface and interfacial tension lowering actions and exhibited antimicrobial activity particularly against Gram-positive 13. Hakomori SI, Handa K (2002) Glycosphingolipid-dependent cross-talk between glycosynapses interfacing tumor cells with their host cells: essential basis to bacteria, thereby suggesting a strong potential for their industrial use. define tumor malignancy. FEBS Letts 531: 88-92. e Th excellent surface tension reducing and emulsifying characteristics of MELs glycolipids and its stability over a wide range of temperature 14. Evans IV, Roger MC (1999) Characterization of protein-glycolipid recognition at and pHs, made MELs important for commercial application. MELs the membrane bilayer. J Mol Recognit 12: 155-168. glycolipids were potent inducers of apoptosis and differentiation in 15. Kojima N, Hakomori S (1991) Cell adhesion, spreading, and motility of GM3- mouse melanoma cells. expressing cells based on glycolipid-glycolipid interaction. J Biol Chem 266: 17552-17558. Role of glycolipids in calcium homeostasis 16. 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