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16.7: Glycolipids - Biology

16.7: Glycolipids - Biology



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Glycolipids are phospholipids attached to oligosaccharides, and as noted, are part of the glycocalyx. Glycolipids are synthesized in much the same way as glycoproteins. Specific enzymes catalyze initial glycosylation of either phospholipids or polypeptides, followed by the addition of more sugars. Along with glycoproteins, glycolipids play roles in cell-cell recognition and the formation of tissues. The glycans on the surfaces of one cell will recognize and bind to carbohydrate receptors (lectins) on adjacent cells, leading to cell-cell attachment as well as intracellular responses in the interacting cells. Glycoproteins and glycolipids also mediate the interaction of cells with extracellular molecular signals and with chemicals of the extracellular matrix (ECM). The ECM includes components of connective tissue, basement membranes, in fact any surface to which cells attach.


16.7 Role of Hormones in Osmoregulation

Science has been and always will be a passion of mine. As a successful science teacher and faculty leader it is my duty to make science accessible and fun for all, increasing prosperity and success within the science industry at a time where we need it most. These resources are aimed at changing the standard pedagogical approach to teaching and put a new and 21st Century touch to delivering science lessons through imagery and questioning.

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This resource guides a-level biologists through the role hormones play in osmoregulation. Stretch, challenge and lateral thinking questions are embedded throughout. This is a resource been made to be picked up and used by any teacher.

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This bundle covers topic 15 in AQA ALevel Biology and includes the following resources: 16.1 Principles of Homeostasis 16.2 Feedback Mechanisms 16.3 Hormones and Regulation of Blood Glucose 16.4 Diabetes & Control 16.5 Control of Water Potential - Structure of the Nephron 16.6 Role of the Nephron in Osmoregulation 16.7 Role of Hormones in Osmoregulation

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Science has been and always will be a passion of mine. As a successful science teacher and faculty leader it is my duty to make science accessible and fun for all, increasing prosperity and success within the science industry at a time where we need it most. These resources are aimed at changing the standard pedagogical approach to teaching and put a new and 21st Century touch to delivering science lessons through imagery and questioning.


What Is the Function of a Glycolipid?

A glycolipid is a lipid that has an attached carbohydrate its function is to contribute energy and act as a marker for cellular recognition. Glycolipids appear where carbohydrate chains have a connection to phospholipids that appear on the cell membrane's exoplasmic surface. The carbohydrates appear on the exterior surface of the cell membrane for all eukaryotic cells.

A glycolipid's carbohydrate structure depends on the glycolsyltransferases that bring in the lipids and glycosylhydrolases which change the glycan after they appear. Glycolipids reach from the phospholipids all the way to the aqueous area outside the membrane of the cell, and at that point, they serve as recognition points for particular chemicals while also maintaining the integrity of the cell membrane and connecting cells in order to create tissues.

Another effect of glycolipids is the determination of an individual's blood group. The glycolipids serve as receptors on the red blood cell's surface, which is important because this principle comes in handy when a swift classification is necessary in such situations as emergency transfusions. When a person receives the wrong type of blood, his immune system notices the difference and treats the new blood as a foreign substance which sometimes leads to death.


Glycoproteins: Synthesis and Role | Biochemistry

In this article we will discuss about Glycoproteins:- 1. Subject Matter of Glycoproteins 2. Oligosaccharides of Glycoproteins 3. Synthesis of Complex Carbohydrates 4. Lectins can be Used for Purification 5. Blood Group Antigens 6. Role in Fertilization 7. Proteoglycans 8. Tunicamycin.

  1. Subject Matter of Glycoproteins
  2. Oligosaccharides of Glycoproteins
  3. Synthesis of Complex Carbohydrates of Glycoproteins
  4. Lectins can be Used for Purification of Glycoproteins
  5. Blood Group Antigens
  6. Role of Glycoproteins in Fertilization
  7. Proteoglycans and Glycoproteins
  8. Tunicamycin Inhibits N-linked Glycoproteins

1. Subject Matter of Glycoproteins:

a. Their molecular weight ranges from 15,000 to over 1 million containing 15 or fewer sugar units per chain.

b. Their carbohydrate contents range from 1 to 85 per cent by weights.

c. They are present in plants, bacteria, fungi, viruses and animals. The most membrane proteins and secreted proteins are glycoproteins.

d. They act as structural molecules in cell walls, collagen, elastin, fibrins, and bone matrix as lubricants and protective agents in mucins, mucus secretions.

e. They are utilized as transport molecules for vitamins, lipids, minerals and trace el­ements as immunologic molecules for immunoglobins, histocompatibility anti­gens, complement and interferon as hor­mones in chorionic gonadotropin, thyro­tropin (TSH) as enzymes in proteases, nucleases, glycosidases, hydrolases, and clotting factors as recognition sites in cell-cell, virus-cell, bacterium-cell, and hor­mone receptors.

2. Oligosaccharides of Glycoproteins:

a. The oligosaccharide chains contain nine different sugar residues. Glucose (Glc) is found only in collagen, but galactose (Gal) and mannose (Man) are more common and widely distributed. The hexoses are N- acetylgalactosamine (Gal NAC) and N- acetyl glucosamine (Glc NAC). Fucose (Fuc) is a common constituent.

Two pentoses-arabinose (Ara) and Xylose (Xyl) are found and the ninth are the sialic acids (Sial) of which N- acetylneuraminic acid (Nana) is an example. The fucose and Nana residues are more distal in the chain, frequently at terminal sites.

b. The oligosaccharide chains are attached to the polypeptide backbone at one of five amino acid residues-asparagine (Asn), serine (Ser), threonine (Thr), hydro-xylysine (Hyl), or hydroproline (Hyp). Two types of chemical bonds that provide the attachment sites are (a) O-glycosidic links and (b) N-glycosidic links.

(a) O-glycosidic Links:

(i) The O-glycosidic links occur through the free alcoholic groups of Ser or Thr residues of the polypeptide in a tripeptide se­quence of Asn-Y-Ser (Thr), where Y is an amino acid other than aspartic acid.

(ii) Gal NAC is the most common sugar resi­due attached directly to the Ser or Thr resi­due. Six different types of oligosaccha­ride are attached to this Gal NAC-Ser (Thr) linkage.

(iii) The initiation and extension of different types of oligosaccharide chains of glycoproteins occur by the stepwise do­nation of sugar residues from pyrimidine or purine nucleotide sugars.

(iv) Oligosaccharides may be linked to pro­teins via O-glycosidic bonds to Hyl or Hyp which are amino acid residues found in collagens and some fibrous proteins of plants.

(b) N-glycosidic linkage:

(i) The N-linked oligosaccharide consists of a core region with the structure Man-β-1, 4-Glc NAC-β-1,4-Glc NAC-Asn. This core region is of two types—the high mannose (simple) type and the complex type. A sin­gle protein can contain oligosaccharide chains of both high mannose and com­plex types.

(ii) Although all high-mannose oligosaccha­rides are synthesized from nucleotide sug­ars, there exists an important lipid-linked precursor oligosaccharide that is trans­ferred en bloc from a lipid carrier to the Asn of the protein.

(iii) The complex N-linked oligosaccharides also contain the β-man-di-N-acetylchitobiose core structure but consist also of a variable number of outer chains contain­ing Sial, Gal, and Fuc residues linked to the core.

(iv) Complex N-linked oligosaccharide struc­tures are found only in higher animals whereas the high mannose types are com­mon in primitive organisms.

3. Synthesis of Complex Carbohydrates of Glycoproteins:

(i) The nucleotide of sialic acid, CMP-Sial, is formed from CTP by sialyltransferases located in the Golgi complex and in the nucleoplasm.

(ii) In animal cells, the sugars are linked to the nucleotides by the alpha-linkage with the exception of the beta-linkage of L-fucose to GDP. The alpha-bridges are con­verted to the beta-bridges and vice-versa during the transfer of the sugar moiety to the oligosaccharide.

(iii) A number of specific glycosyl transferase enzymes catalyze the transfer of the sugar moieties to generate the complex glyco­proteins. These enzymes require Mn ++ .

(iv) A Golgi-localized enzyme, UDP Glc NAC transferase 1, can then denote a Glc NAC to a linear or branched alpha-Man moiety to form Glc NAC-β-1, 2-Man linkages. A second transferase, UDP Glc NAC transferase 11, will denote its Glc NAC moiety only to a branched structure by the trans­ferase 1 enzyme.

(v) Fucosyl-transferases can then act on the products of GLc NAC transferase 1 or transferase 11. The galactosyltansferase enzymes are also located on the Golgi complex and attach a galactosyl residue usually to the end of a chain. The galactosyl residues are linked to Glc NAC by beta-1, 4-linkages but occasionally by beta-1, 6-linkages.

(vi) Four different sialyltransferase enzymes are found in the Golgi complex and use CMP-sialic acid as donor for the sialation of protein-linked oligosaccharides.

(vii) The elongation process generating the complex type oligosaccharides of glycoproteins occurs exclusively in the Golgi complex. Each linkage is carried out by a specific glycosyl-transferase thus, there seems to be a “one linkage, one glycosyltransferase” synthetic arrange­ment.

4. Lectins can be Used for Purification of Glycoproteins:

a. Lectins, the sugar-binding protein, that precipitate glycoconjugates. Immunoglo­bulins that react with sugars are not lectins. Lectins contain at least two sugar-bind­ing sites proteins with a single sugar-bind­ing site will not precipitate glycoconju­gates.

b. Enzymes, toxins, and transport proteins can be classed as lectins if they bind car­bohydrate.

c. Lectins such as concanavalin A (con A) can be attached covalently to inert sup­porting media such as sepharose. The re­sulting sepharose-con A may be used for the purification of glycoproteins.

d. Smaller amounts of certain lectins are re­quired to cause agglutination of tumor cells than of normal cells.

e. When mammalian cells in tissue culture are exposed to appropriate concentrations of certain lectins (e.g., Con A), most are killed, but a few resistant cells survive. Such cells are found to lack certain en­zymes involved in oligosaccharide syn­thesis. The cells are resistant because they do not produce oligosaccharide chains that interact with the lectin used.

5. Blood Group Antigens:

In 1900, Landsteiner described the ABO blood groups. Today, there are more than twenty blood group systems expressing more than 160 distinct antigens. These erythrocyte antigens are linked to specific membrane proteins by O-glycosidic bonds in which Gal NAC is the most proximal sugar resi­due.

The specific oligosaccharides exist in three forms:

(i) As glycosphingolipids and glycoproteins on the surfaces of erythrocytes and other cells,

(ii) As oligosaccharides in milk and urine, and

(iii) As oligosaccharides attached to mucins secreted in the gastrointestinal, genitourinary, and respiratory tracts.

Four independent gene systems are related to the expressions of these oligosaccharide antigens.

This codes for a fucosyltransferase that attaches a fucose residue in alpha-1, 2- linkage to a Gal residue, itself attached in beta-1, 4-linkage to an oligosaccharide. Fuc-α-1, 2- Gal-β- R is a precursor for the formation of both the A and B oligosaccharide antigens.

The h allele of the H locus codes for an inactive fucosyltransferase. Therefore, individuals with the hh genotype can­not generate this necessary precursor of the A and B antigens. Hence hh genotypic persons will be type O.

This controls the appear­ance of the H-specifie Fuctransferase in some se­cretory organs, such as the exocrine glands, but not in the erythrocytes. Accordingly, individuals with the Hh or HH genotype and an Se allele will gener­ate the A and B antigen precursor in the exocrine glands that form saliva.

The individuals who are SeSe or Sese and possess an H allele will be secretors of the A or B antigens (or both), when the A- or B- specific transferase are present. Individuals who are sese genotype will not secrete A or B antigens but if they possess an H allele and A or B allele, their erythrocytes will express the A, B or both antigens.

These codes for two specific transferases that act to transfer specific Gal moie­ties to the Fuc-α-1, 2-Gal-β-R precursor oligosac­charide formed by the action of the H allele-coded fucosyltransferase.

Persons possessing an A allele will attach a Gal NAC moiety to the precursor gen­erated by the H allele transferase and an individual possessing a B allele will transfer a Gal moiety to the same precursor. Individuals possessing both A and B allele will generate both A and B alleles (00 homozygotes) will not attach either Gal NAC or Gal to the precursor.

When neither Gal NAC nor Gal is at the reducing terminus of this oligosaccha­ride, it will not be recognized by either anti-A or anti-B antisera, and the blood group antigen is said to be type O Individuals with the hh genotype in­capable of attaching the Fuc moiety to the appro­priate Gal-β-R oligosaccharide is incapable of ex­pressing the A or the B antigen determinant and thus is considered to be of the O type blood group.

The Lewis-dependent fucosyltransferase is not specific about what is not the Gal-1, 3-β group. When no H allele is present (hh), the product of the Lewis α-1, 4-fucosyltrans­ferase is referred to as the Lea antigen which cannot have A or B antigenicity even when the A or B transferases are also present.

When both the H al­lele and the Le allele fucosyltransferases have acted on the Gal-1, 3-R oligosaccharide, the product is referred to as the Le b antigen. The Le b antigen may also exist without A antigenicity or B antigenicity on the same molecule. The le allele codes for an inactive Lewis transferase, and thus neither Le a nor Le b antigens will be formed in a person with lele genotype.

6. Role of Glycoproteins in Fertilization:

(a) A sperm has to traverse the zona pellucida (ZP) which contains three glycoproteins ZPI-3, particularly ZP3, (an O-linked glycoprotein that functions as a receptor for the sperm) to reach the plasma mem­brane of an oocyte.

(b) A protein on the sperm surface interacts with oligosaccharide chains of ZP3. This interaction induces the acrosomal reaction in which proteases and hyaluronidase, and other contents of the acrosome of the sperm are released. The liberation of these en­zymes helps the sperm to pass through the zona pellucida and reach the plasma mem­brane of the oocyte.

(c) Another glycoprotein pH-30 is important in binding of the PM of the sperm to the PM of oocyte. These interactions enable the sperm to enter and thus fertilize the oocyte.

(d) It is also possible to inhibit fertilization by developing drugs or antibodies that in­terfere with the normal functions of ZP3 and PH-30 and which thus act as contra­ceptive agents.

7. Proteoglycans and Glycoproteins:

Each polysaccharide of proteoglycans consists of repeating disaccharide units in which D- glucosamine or D-galactosamine is always present. Each disaccharide contains a uronic acid, glu­curonic acid (G1C UA), L-iduronic acid (ldUA). All polysaccharides contain sulphate groups with the exception of hyaluronic acid.

The linkage of the polysaccharides to their polypeptide chain is one of three types:

(i) An O-glycosidic bond between Xyl and Ser, a bond that is unique to proteoglycans.

(ii) An O-glycosidic bond between Gal NAC and Ser (Thr), present in keratan sulphate II.

(iii) An N-glycosylamine bond between G1C NAC and the amide nitrogen of Asn.

The elongation process of chain involves the nucleotidyl sugars acting as donors. The reactions are performed by the substrate specificities of the specific glycosyltransferases. Thus, “one enzyme, one linkage” relationship holds. The specificity of these reactions is dependent upon the nucleotide sugar donor, the acceptor oligosaccharide.

The polysaccharide chain growth termination results from (i) capping effects of isolation by the specific sialyl transferases, (ii) sulfation, particu­larly at the 4-positions of the sugars, and (iii) the progression of the particular polysaccharide away from the site in the membrane where the catalysis occurs. After formation of the polysaccharide chain, numerous chemical modifications take place.

Inherited defects in the degradation of the polysaccharide chains lead to the group of diseases known as mucopolysaccharidoses and mucolipi­doses.

Seven types of polysaccharides are covalently attached to the proteins of proteoglycans. Six of them contain alternating uronic acid and hex­osamine residues. Except hyaluronic acid all con­tain sulphated sugars. These seven types of polysaccharides are distinguished by their monomer composition, their glycosidic linkage, and the amount and location of their sulphate substituents.

Functions of Glycosaminoglycans and Proteoglycans:

1. Glycosaminoglycans can interact with ex, tracellular macromolecules, plasma pro­teins, cell surface components, and intra­cellular macromolecules.

2. Because of their polyanionic nature the binding of this is generally electrostatic.

3. These with IdU A bind proteins with greater affinities than those containing GlcUA as their only uronic acid constituent.

4. The binding between these and other ex­tracellular macromolecules contributes to the structural organization of connective tissue matrix.

A. Interactions with Extracellular Macremetecules:

(i) All glycosaminoglycan’s except those that lack sulphate groups or carboxyl groups bind to collagen electrostatically at neu­tral pH. Tighter binding is promoted by the presence of IdUA and the proteo­glycans interact more strongly than glycosaminoglycan’s.

(ii) The chondroitin sulphate and keratan sul­phate chains of proteoglycans aggregate with hyaluronic acid.

B. Interactions with Plasma Proteins:

(i) Dermatan sulphate binds plasma lipoproteins and appears to be the major glycosaminoglycan synthesized by arte­rial smooth muscle cells. This dermatan sulphate may play an important role in the development of atherosclerosis.

(ii) Heparin with its high negative charge den­sity (due to the IdUA and sulphate residues) interacts strongly with several plasma com­ponents.

It interacts with antithrombin 111. Heparin sulphate is also capable of accel­erating the action of antithrombin 111, but is much less potent than heparin. Heparin can bind to lipoprotein lipase present in capillary walls and causes a release of that triglyceride-degrading enzyme into the cir­culation. Hepatic lipase also binds heparin but with lower affinity.

C. Cell Surface Molecules:

(i) Heparin associates with blood platelets, arterial endothelial cells, and liver cells. Chondroitin sulphate, dermatan sulphate, and heparan sulphate bind to independ­ent sites on surface of cells such as fibroblasts. At those sites, the glycosaminoglycan’s and proteoglycans are taken up by fibroblasts and degraded.

(ii) Some proteoglycans serve as receptors and carriers for macromolecules. These proteoglycans are involved in the regula­tion of cell growth.

D. Intracellular Macromolecules:

(i) Proteoglycans and their glycosaminoglycan components have effects on protein synthesis and intra-nuclear func­tions. Glycosaminoglycan’s are found in significant quantities in nuclei from dif­ferent cell types.

(ii) The acid hydrolases in lysosomes may be naturally complexed with glycosaminoglycan’s to provide a protected and inac­tive form. Chondroitin sulphates, dermatan sulphates, and heparin can affect the ac­tivities of various lysosomal acid hydro­lase in negative or positive ways.

(iii) Many storage or secretory granules such as the chromaffin granules in adrenal me­dulla, the prolactin secretory granules in the pituitary gland, and the basophilic granules in mast cells contain sulphated glycosaminoglycan’s. The glycosamino- glycan-peptide complexes that occur in these granules play a role in the release of biogenic amines.

8. Tunicamycin Inhibits N-linked Glycoproteins:

a. Many compounds are involved in inhib­iting various reactions of glycoproteins. Tunicamycin, deoxynojirimycin, and swainsonine are the agents which can be used experimentally to inhibit various stages of glycoprotein biosynthesis. If cells are grown in the presence of tunicamycin, no glycosylation of their normally N-linked glycoproteins will oc­cur.

In certain cases, lack of glycosylation increases the susceptibility of these pro­teins to proteolysis.

b. Inhibition of glycosylation does not have a consistent effect upon the secretion of glycoproteins that are normally secreted.

c. The inhibitors of glycoprotein processing do not affect the biosynthesis of O-linked glycoproteins. The extension of O-linked chains can be prevented by GalNAC- benzyle. This compound competes with natural glycoprotein substrates.


2 Data and methodologies

2.1 Data

The applicant has submitted a dossier to support the safety evaluation of the present application on long-chain glycolipids from Dacryopinax spathularia proposed as a preservative food additive in certain beverages (Documentation provided to EFSA No. 1).

Following the request for additional data sent by EFSA on 23 September 2020, the applicant requested a clarification teleconference held on 21 October 2020, after which the applicant provided additional data on 22 December 2020 (Documentation provided to EFSA No. 2).

Following the request for additional data sent by EFSA on 24 February 2021 the applicant provided additional data on 25 February 2021 (Documentation provided to EFSA No. 3).

2.2 Methodologies

This opinion was formulated following the principles described in the EFSA Guidance of the Scientific Committee on transparency with regard to scientific aspects of risk assessment (EFSA Scientific Committee, 2009 ) and following the relevant existing Guidance documents from the EFSA Scientific Committee. The current ‘Guidance for submission for food additive evaluation’ (EFSA ANS Panel, 2012 ) has been followed by the FAF Panel for evaluating the present application.


Invariant natural killer T cells

Natural Killer (NK) T cells originally derived their name from the fact that some of them express receptors such as CD161, which are encoded in the NK complex. However, unlike NK cells, which are primarily controlled by NK locus-encoded proteins and lack TCRs, the central mechanism of NK T-cell activation involves CD1d-mediated presentation of glycolipids to TCRs ( Bendelac et al., 1995 Kawano et al., 1997). The TCRs found on NK T cells are composed of nearly invariant TCRα chains, Vα14Jα18 in mice and Vα24Jα18 in humans. NK T cells are a particularly abundant population of specialized T cells, which compromise between 0.1 and 10% of all T cells in humans and mice ( Benlagha et al., 2000 Matsuda et al., 2000 Gumperz et al., 2002). Unlike conventional MHC-restricted T cells, which generally require more than a week to expand to large numbers and become fully activated, NK T cells can be rapidly activated within minutes to hours to produce cytokines that influence the functions of many other immune cells. In human and murine models of systemic diseases, NK T cells are activated or influence the outcomes of in vivo models of autoimmunity, infection, allergy, and infectious disease (reviewed in Kronenberg, 2005).

The first known and most potent antigens for NK T cells are α-galactosyl ceramide (αGalCer) and α-glucosyl ceramide, which were discovered through a high-throughput screen of synthetically produced glycolipids in assays of immune-mediated regression of experimental tumors (Figure 3) ( Cui et al., 1997 Kawano et al., 1997). The anomeric linkage is critical to antigenicity, as β-galactosyl ceramide shows no ability to activate NK T cells (Figure 3). Most mammalian monosacharides have a β-linkage to the sphingosine base, which leads to the speculation that the NK T-cell specificity for the α-linkage might have physiologic significance in preventing autoreactivity to common self-glycosyl ceramides, while recognizing α-linked ceramides and their natural homologs as foreign. Although α-galactosyl ceramides are only known to be made by marine sponges and synthetic chemists, naturally occurring bacterial α-linked galacturonide and glucuronide antigens for NK T cells have recently been identified in Sphingomonas and related bacteria ( Kinjo et al., 2005 Mattner et al., 2005).

Antigens for NK T cells. The glycolipid α-galactosyl ceramide occurs naturally in marine sponges. Closely related glucuronide- and galacturonide-based α-linked glycospingolipids from gram-negative Sphingomonas represent bacterial antigens for NK T cells. PE represents a self-lipid presented by CD1d to NK T cells. The gangliosides GM1 and GD3 are important self-glycolipids bearing complex carbohydrate head groups. GD3 is important in apoptosis and is overexpressed in some tumor cells. Lipophosphoglycans (reviewed in Turco and Descoteaux, 1992) from the protozoan parasite Leishmania donovani are foreign glycolipids that can activate NK T cells. The glycosphingolipid iGb3 is β-linked to ceramide, unlike other known antigens recognized by NK T cells.

Antigens for NK T cells. The glycolipid α-galactosyl ceramide occurs naturally in marine sponges. Closely related glucuronide- and galacturonide-based α-linked glycospingolipids from gram-negative Sphingomonas represent bacterial antigens for NK T cells. PE represents a self-lipid presented by CD1d to NK T cells. The gangliosides GM1 and GD3 are important self-glycolipids bearing complex carbohydrate head groups. GD3 is important in apoptosis and is overexpressed in some tumor cells. Lipophosphoglycans (reviewed in Turco and Descoteaux, 1992) from the protozoan parasite Leishmania donovani are foreign glycolipids that can activate NK T cells. The glycosphingolipid iGb3 is β-linked to ceramide, unlike other known antigens recognized by NK T cells.

NK T cells can also be activated by natural lipids that have structures unrelated to α-linked sphingolipids, including phosphatidylinositol-based compounds ( Gumperz et al., 2002), phosphatidylethanolamine (PE) ( Rauch et al., 2003), gangliosides ( Wu et al., 2003), isoglobosides ( Zhou et al., 2004), and leishmania lipophosphoglycans ( Amprey et al., 2004). Although each of these naturally occurring compounds can activate NK T cells, they are generally less potent or activate a smaller percentage of NK T cells than seen with α-galactosyl ceramides, leading to the idea that α‐galactosyl ceramides are a kind of lipid “superantigen” for NK T cells. Representative lipid stimulants of NK T cells are shown in Figure 3, and inspection of these structures shows that among these various lipids, only Sphingomonas-derived galacturonyl ceramides show substantial homology with α-galactosyl ceramide. The conserved α-anomeric linkage and the sphingolipid base structure suggest that these two antigens activate NK T cell using substantially similar molecular mechanisms.

However, it is not yet clear how the other structures, which have much larger glycans or diacylglycerol units, can activate NK T cells expressing TCRs similar or identical to those which recognize α-linked ceramides. One possibility is that subsets of NK T cells have differing specificities for antigen based on subtle and as yet poorly understood differences in the Vβ chains present in the “nearly invariant” TCRs ( Behar and Cardell, 2000). A second possibility is that, despite the obvious differences in the overall structures among each of these antigens, some conserved feature, such as a proximal saccharide in a larger glycan unit, provides a minimal epitope to facilitate TCR binding to CD1d. A third possibility is that certain of these antigens may function to promote NK T-cell activation by a mechanism that is independent of CD1d contact with TCRs. Although it is certain that CD1d-α-galactosyl ceramide complexes bind to the TCR ( Sidobre et al., 2002), gram-negative lipopolysaccharide can stimulate NK T cells by a mechanism that does not involve the presentation of the carbohydrate to the TCR but instead involves a TCR-independent mechanism whereby receptors on the APC trigger IL-12 release ( Brigl et al., 2003). Determining whether each of these antigens activates via TCR-dependent or TCR-independent mechanisms is an active area of inquiry.


What is the role of glycolipids in cells?

Glycolipids play an important role in several biological functions such as recognition and cell signalling events.

Explanation:

Glycolipids are lipids with a carbohydrate attached by a glycosidic bond or covalently bonded. They are found on the outer surface of cellular membranes where it plays a structural role to maintain membrane stability, and also facilitate cell-cell communication acting as receptors , anchors for proteins.

Glycolipids and glycoproteins form hydrogen bombs bonds with the water molecules surrounding the cells and thus help to stabilise membrane structure. However, more importantly, they are used as receptor molecules binding with hormones or neurotransmitters to trigger a series of chemical reactions within the cell itself.

They can also serve as antibodies, which are used in allowing cells to recognise each other. Blood types are an example of how glycolipids on cellmembranes mediate cell interactions with the surrounding environment.


GLYCOCONJUGATES Structure and Functions of Proteoglycans, Glycoproteins and Glycolipids

Polysaccharides and oligosaccharides act also as information carrier molecules. Informational carbohydrate is covalently joined to a protein or lipid to form glycoconjugates. As the name suggests, the glycoconjugates are conjugate (joined) molecules of carbohydrates other macromolecules such as proteins or lipids. The present post discusses the structure, classification and functions of important glycoconjugates.

Functions of Glycoconjugates

Ø Glycoconjugates acts as information carrier molecules.

Ø They serve as destination labels for some proteins.

Ø They serve as mediators of specific cell-cell interaction.

Ø They can act as the mediators of interactions between cell and ECM.

Ø They form Glycocalyx (Glycocalyx is a carbohydrate layer formed by specific oligosaccharide chains attached to components of the plasma membrane).

Ø Specific carbohydrate-containing molecules from the glycocalyx help in:

$. Cell migration during development

Examples of Glycoconjugates

Ø There are THREE important types of glycoconjugates in the cells. They are:

(1). Proteoglycans

(2). Glycoproteins

(3). Glycolipids and Lipopolysaccharides (LPS)

(1). Proteoglycan

Ø In proteoglycan, one or more sulfated glycosaminoglycan chains are joined covalently to a membrane protein or a secreted protein.

Ø They are macromolecules of cell surface and extracellular matrix.

Ø Glycan moiety commonly forms the greater fraction by mass.

Ø In proteoglycan, glycan forms the main part of biological activity.

Ø Glycan part provides provisions for hydrogen bonding due to the presence of many – OH groups.

Ø Glycan part provides electrostatic interactions (due to the presence of sulfate groups in glycosaminoglycans) with other proteins of ECM.

Ø Proteoglycans are major components of connective tissue such as cartilage.

Structural Organization of Proteoglycans

Ø Proteoglycans have a bottlebrush-like molecular architecture with ‘bristles’.

Ø ‘Bristles’ are attached non-covalently to a filamentous hyaluronate backbone.

Ø The ‘bristles’ consist of a core protein to which glycosaminoglycans (GAGs) are covalently linked.

Ø The GAGs are most often chains of keratan sulfate and chondroitin sulfate.

Ø Interaction between core protein and hyaluronate is stabilized by a link protein.

Ø Smaller oligosaccharides are usually attached to the core protein near its site of attachment to hyaluronate.

Ø These oligosaccharides are glycosidically linked to the protein via the amide N of specific Asparagine residues (and are therefore known as N-linked oligosaccharides).

Ø The keratan sulfate and chondroitin sulfate chains are glycosidically linked to the core protein via oligosaccharides that are covalently bonded to the side-chain O atoms of specific Serine or Threonine residues (i.e., O-linked oligosaccharides).

Types of Proteoglycans

Ø Proteoglycans are categorized based on two criterion.

(1). Based on their relative size: Large Proteioglycans and Small Proteoglycans

(2). Based on the type of their glycosaminoglycan chains

Ø Based on the glycosaminoglycan chain, there are three categories of proteoglycans:

$. Heparan sulfate proteoglycan (HSPGs)

$. Chondroitin sulfate proteoglycan (CSPGs)

$. Keratan sulfate proteoglycan (KSPGs)

(2). Glycoprotein

Ø Glycoproteins have one or several oligosaccharides of varying complexity joined covalently to proteins.

Ø Usually the protein part in glycoprotein will be the bulky part when compared to proteoglycan.

Ø Glycoproteins are found on the:

$. Outer surface of plasma membrane

$. In the extracellular matrix

Ø Inside the cells they are found in specific cell organelles such as Golgi complex, Secretory granules and Lysosomes.

Ø Carbohydrate part is attached to proteins through its anomeric carbon.

Ø The anomeric carbon attached to the protein through:

(a). An O-glycosidic link to the —OH of a Ser or Thr residue (O-linked)

(a). An N-glycosidic link to the amide nitrogen of an Asn residue (N-linked)

Ø Most of the glycoproteins contain many carbohydrate units.

Ø The carbohydrate content of glycoprotein range from 1% to 70% of the total mass.

Ø Some glycoproteins have a single oligosaccharide chain.

Ø About half of all proteins of mammals are glycosylated.

Functions of Glycoproteins

Ø The glycan part in the glycoprotein carries rich information.

Ø They form highly specific sites for recognition, binding and interactions for other proteins.

Ø Glycoproteins are important for the recognition of white blood cell.

Ø Glycoproteins are also involved in the immune system of mammals.

Ø Antibodies (immunoglobulins), which directly with antigens contain are glycoproteins.

Ø Many molecules of MHC (Major Histocompatibility Complex) are glycosylated proteins belong to glycoprotein category.

Ø The Sialyl Lewis X antigen on the surface of leukocytes is glycoproteins.

Ø The H antigen of the ABO blood is a glycoprotein.

Ø The follicle-stimulating hormone gonadotropin is a glycoprotein.

Ø The zona pellucida of ovum contains many glycoproteins, which helps in the recognition and interaction between egg and sperm cells.

Ø GP-120 (Glycoprotein-120) and GP-41 (Glycoprotein-41) are HIV viral coat proteins.

Ø Egg white and blood plasma proteins are mainly glycoproteins, they form viscous fluids.

Glycoprotein vs Proteoglycan:

Ø In glycoproteins the carbohydrate portion is smaller than that in proteoglycan.

Ø In glycoproteins the carbohydrate moiety shows more structural diversity than proteoglycan.

(3a). Glycolipids

Ø They are membrane lipids in which the hydrophilic head groups are oligosaccharides.

Ø Glycerolipids and Sphingolipids are the two important categories of glycolipids which have glycerol or sphingosine backbones respectively.

Ø Similar to glycoprotein, glycolipids also act as specific sites for recognition by carbohydrate-binding proteins.

Ø The gangliosides (a heavily carbohydrate attached membrane lipid) are membrane lipids of eukaryotic cells.

Ø In gangliosides the polar head group is a complex oligosaccharide chain with one or many sialic acid residues.

Ø Oligosaccharide groups of gangliosides determine the ABO blood group in human.

(3b). Lipopolysaccharides (LPS)

Ø Lipopolysaccharides (LPS) are found in the outer membrane of Gram-negative bacteria (Eg. E. coli).

Ø LPS is a very complex macro-molecule of lipid and carbohydrates.

Ø Different bacteria have different structure of LPS, but they have a common structural backbone.

Ø All LPS have a common structure of:

§ Fatty acid residues (Called Lipid-A, or Endotoxin)

§ an “O-specific” chain (O-antigen)

Ø The O-antigen the principal determinant of the serotype of the bacterium.

Ø LPS is responsible for the production of antibodies by the animal immune system as a response to microbial infection.

Ø LPS provoke Tol-like-receptor (TLR) and promote inflammation in mammalian cells.

Ø The outer membranes of the gram-negative bacteria S. typhimurium and E. coli contain so many lipopolysaccharide molecules that the cell surface is virtually covered with O-specific chains.

@. Lehninger A.B., (2018), Textbook of Biochemistry, Ed. 5, Pearson International, New York

@. Voet, D., Voet, J.G. and Pratt, C.W., 2013. Fundamentals of biochemistry: life at the molecular level

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Function

Carbohydrates on glycolipids are the most exposed structures on the extracellular surface of cells and are flexible with numerous binding sites which make them optimal for cell signaling. Since the lipid moiety is usually buried within the membrane, carbohydrate-carbohydrate interactions are the predominant interactions that may occur between glycolipids. They can interact side by side within the same membrane or trans interactions between two membranes. Trans interactions between glycolipids was reported to be the basis for glycosphingolipid-dependent cell to cell adhesion which involves calcium ions [8]. Further studies reported that cell surface carbohydrates play major roles in cell-substrate recognition in oncogenesis, myelin sheath regulation, and cell adhesion in metastasis [9-11]. Glycolipids play an important role in several biological functions such as recognition and cell signaling events below are a few biological functions glycolipids play a role in.

Signal Transduction

Glycosphingolipids and sphingomyelin are clustured into microdomains where they can associate with serveral different proteins such as cSrc, G-proteins, and focal adhesion kinase to mediate cellular events [12]. In the plasma membrane, glycosphingolipids form rafts with cholesterol where these regions have relatively less phospholipids. Shown in Figure (PageIndex<3>), glycosphingolipids form rafts with cholestorol to anchor GPI proteins to the extracellular leaflet and src family kinases to the cystolic leaflet. Thus, glycosphingolipids have been These microdomains can cause cellular responses by associating with GPI-anchored proteins which may induce activation of specific kinases to transduce the phosphorylation of different substrates [13]. The glycosphingolipid microdomains have also been associated with mediating immunoreceptors and growth factor receptors [14].

Figure (PageIndex<3>). Interaction Glycolipids and membrane bound proteins.

Cell Proliferation

Glycolipids have been observed to play a role in the regulation of cell growth via interactions with growth factor receptors. Intracellular ceramide stimulated DNA synthesis in endothelial smooth muscle cells and also induced mitogenesis by platelet-derived growth factor [15]. Lactosylceramide activates NADPH oxidase to modulate interacellular adhesion molecule -1 expression on human umbilical vein endotheial cells and to induce proliferation of human aortic smooth muscle cells. With the reduction of ceramide, there was increased ceramidase activity, sphingomyelin synthase which is associated with the proliferation of smooth muscle cells. In addition, gangliosides are known to be involved in inducing apoptosis. Apoptotic signal triggered by CD95 in lymphoid and myeloid tumor cells increase ceramide levels which results in the increase in ganglioside GD3 synthesis GD3 is known to be a potent mediatior of cell death. Abundant amounts of glycosphingolipids are found in the plasma membrane of cancer cells where antibodies targeting these gangliosides result in apoptosis [16]. Treatment with anti-ganglioside GD2 monoclonal antibodies induces apoptosis in GD2 expressing human lung cancer cells.

Calcium Signaling

Gangliosides are associated with calcium ions which is thought to have a role in neuronal function. Ganglioslide micelles bind to calcium ions with high affinity and may play a significant role in synaptic transmission. It has been reported that sphingosine and ceramide mediate the release of calcium from intracellular stores. Gangliosides may also play a role in calcium homeostasis and signaling. These glycolipids induce changes in cellular calcium through the modulation ofcalcium influx channels, calcium exchange proteins, and calcium dependent enzymes which were altered through the association of gangliosides. [17]. In addition, increased levels of intracellular glucosylceramide resulted in increased calcium stores in neurons [18]. Glycolipid galactocerebroside have been observed in the opening of calcium channels in oligodendrocyte cells.


Watch the video: H2 Biology Tuition. H1 Biology Tuition. Glycoprotein and Glycolipid in Cell Membranes (August 2022).