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Transcript of Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to...
![Page 1: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/1.jpg)
Essentials of Glycobiology
May 5th., 2008
Ajit Varki
Lecture 12
Chapter 13. Sequences Common to Different Glycan Classes
Chapter 33. Galectins
![Page 2: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/2.jpg)
Major Glycan Classes in Vertebrate Cells
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Shared Terminii in Different Glycan Classes of Vertebrate Cells
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Essentials Second Edition Symbols
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General Questions for Lecture 111. Propose a function for the allelic variation observed in the ABO blood group system. If
non-primates do not express the ABO locus due to evolutionary loss of the gene, how would this affect your answer?
2. Hyperacute (graft) rejection occurs after transplantation of organs from non-human donors into humans and results from an immediate reaction of circulating anti-GalGal antibodies with the transplanted tissue. Suggests ways to modify the donor or acceptor to prevent HAR.
3. Compare and contrast "LacNAc" and "LacdiNAc" units. How does the presence of these terminal disaccharides affect the addition of sialic acid and fucose?
4. Based on what you know about terminal structures on FSH and LH, propose several glycan-based mechanisms that could account for infertility in humans.
5. Certain strains of E. coli bind to P-blood group antigens and cause urinary tract infections. What evolutionary advantage might exist for retaining the transferases for a deleterious glycan?
6. Why do changes in glycan branching pathways and sialylation have the potential to impact galectin function?
7. How do galectins achieve high-affinity binding to cell surface glycans?
8. How do you explain the finding that galectins are not routinely found in large amounts in body fluids, even though they are soluble secreted proteins?
9. Explain how a galectin could act as a receptor for microbial infection
10. How do galectins send signals through cell surface receptors?
![Page 7: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/7.jpg)
FIGURE 13.2. Terminal GlcNAc residues are usually galactosylated in Vertebrate Cells
3. Compare and contrast "LacNAc" and "LacdiNAc" units
"LacNAc"
![Page 8: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/8.jpg)
FIGURE 13.3. Poly-N-acetyllactosamine chains are found on N-glycans, O-glycans, and glycolipids
“Polyllactosamine” Chains
N-acetyllactosamine
Unit
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FIGURE 13.4. i and I antigen synthesis
Embryonic
AdultCold-dependent agglutinating antibodies
(cold agglutinins) in patients withacquired hemolytic anemia (see Chapter 43). Cold agglutinin antibodies react with
red blood cells of most blood donorsIncluding patient’s own cells!
![Page 10: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/10.jpg)
FIGURE 13.5. Type-1 and -2 H, A, and B antigens that form the O (H), A, and B blood group determinants on N- and O-glycans
“O” “A” “B”
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FIGURE 13.8. Synthesis of H (O), A, and B blood group determinants
“O”
“A”
“B”Anti-A
Anti- B Anti-A
Anti-B
“AB”
NoAntibodies
“Universal Donor”
“Universal Acceptor”
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O-glycans
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Glycosphingolipids
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FIGURE 13.10. Type-1 and -2 Lewis determinants
3. How does the presence of terminal disaccharides affect the addition of sialic acid and fucose?
Some of these are Ligands for
Selectins
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Type-1 Lewis blood group determinants on glycoproteins
and glycolipids (R) are characterized by the presence or
absence of the Secretor locus α1-2FucT and the Lewis locus
α1-3/α1-4FucT.
FIGURE 13.11. Lewis blood groups based on Type 1 LacNAc
![Page 17: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/17.jpg)
3. Propose a function for the allelic variation in the ABO blood group system. If non-primates do not express the ABO locus due to evolutionary loss of the gene, how would this affect answer?
“O”
“A”
“B”Anti-A
Anti- B Anti-A
Anti-B
“AB”
NoAntibodies
![Page 18: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/18.jpg)
FIGURE 13.12. Biosynthesis of antigens of the P blood group system: Pk, P, and P1.
5. Certain strains of E. coli bind to P-blood group antigens and cause urinary tract infections. What evolutionary advantage might exist for retaining transferases for a deleterious glycan?
E.coli
E.coli
Parvovirus B19
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Alpha-Gal Epitope Anti-alpha Gal Antibodies
Owl Word Monkeys Apes & Humans - +Other Mammals + -
2. Hyperacute (graft) rejection occurs after transplantation of organs from non-human donors into humans and results from an immediate reaction of circulating anti-GalGal antibodies with the transplanted tissue. Suggests ways to modify the donor or acceptor to prevent HAR.
![Page 20: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/20.jpg)
![Page 21: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/21.jpg)
FIGURE 13.15. Structure and synthesis of N-glycans bearing terminal N-acetylgalactosamine (GalNAc), including sulfated GalNAc on pituitary hormones lutropin (LH) and thyrotropin (TSH).
4. Based on what you know about terminal structures on FSH and LH, propose several glycan-based mechanisms that could account for infertility in humans.
3. Compare and contrast "LacNAc"
and "LacdiNAc" units
"LacNAc""LacdiNAc"
![Page 22: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/22.jpg)
FIGURE 13.16. Synthesis of the human Sda or mouse CT antigen and the glycolipid GM2
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FIGURE 13.17. Synthesis of glycoproteins and glycolipids bearing terminal α2-3 sialic acid transferred by the ST3Gal family of sialyltransferases
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FIGURE 13.18. Synthesis of α2-6 sialic acids (see Chapters 9 and 10)
TumorAntigen
Cosmc
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FIGURE 13.19. Structure and synthesis of polysialic acid on N-glycans
Embryonic
Adult
NeuralPlasticity
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FIGURE 13.20. Structure and synthesis of polysialic acid on glycolipids.
NeuralFunctions?
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CD57 NK cell MarkerAntigen in Myeloma
P0 Ligand?Cellular Interactions
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FIGURE 13.22. Synthesis of keratan sulfate. Different 6-O-sulfotransferases (SulfoT) transfer sulfate to 6-position of Gal and GlcNAc in poly-N-acetyllactosamine chains.
KS is attached to proteins (R) via an N-glycan (KS type I) or an O-glycan (KS type II).
Human Macular Corneal Dystrophy
Is Ks and Glycosaminoglycan (GAG)?
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FIGURE 33.3. (a) Ribbon diagram of crystal structure of human galectin-1, complexed with lactose. Homodimer shown with each monomer colored differently and orthogonal views are presented. The subunit interface is based on interactions between the carboxy- and amino-terminal domains of each subunit.
(c) Primary sequence of human galectin-1 with the numbered residues corresponding tothose highlighted in the crystal structure above.
(b) Interactions between key amino acid residues within the CRD of galectin-1 when lactose is bound (left panel) and when no sugar is bound(right panel).
![Page 30: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/30.jpg)
7. How do galectins achieve high-affinity binding to cell surface glycans?
![Page 31: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/31.jpg)
8.How do you explain the finding that galectins are not routinely found in large amounts in body fluids, even though they are soluble secreted proteins?
FIGURE 33.2. Possible biosynthetic routes for galectins in animal cells.
![Page 32: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/32.jpg)
FIGURE 33.4. Functional interactions of galectins with cell-surface glycoconjugates and extracellular glycoconjugates can lead to cell adhesion and signaling. Interactions with intracellular ligands may also contribute to regulation of intracellular pathways.
10.How do galectins send signals through cell surface receptors?
![Page 33: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/33.jpg)
FIGURE 33.5. A list of known and putative functions and biological activities of galectins toward cells in the immune system.
![Page 34: Essentials of Glycobiology May 5th., 2008 Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins.](https://reader037.fdocuments.net/reader037/viewer/2022103005/56649d8a5503460f94a714fd/html5/thumbnails/34.jpg)
General Questions for Lecture 111. Propose a function for the allelic variation observed in the ABO blood group system. If non-primates do not express
the ABO locus due to evolutionary loss of the gene, how would this affect your answer?
2. Hyperacute (graft) rejection occurs after transplantation of organs from non-human donors into humans and results from an immediate reaction of circulating anti-GalGal antibodies with the transplanted tissue. Suggests ways to modify the donor or acceptor to prevent HAR.
3. Compare and contrast "LacNAc" and "LacdiNAc" units. How does the presence of these terminal disaccharides affect the addition of sialic acid and fucose?
4. Based on what you know about terminal structures on FSH and LH, propose several glycan-based mechanisms that could account for infertility in humans.
5. Certain strains of E. coli bind to P-blood group antigens and cause urinary tract infections. What evolutionary advantage might exist for retaining the transferases for a deleterious glycan?
6. Why do changes in glycan branching pathways and sialylation have the potential to impact galectin function?
7. How do galectins achieve high-affinity binding to cell surface glycans?
8. How do you explain the finding that galectins are not routinely found in large amounts in body fluids, even though they are soluble secreted proteins?
9. Explain how a galectin could act as a receptor for microbial infection
10. How do galectins send signals through cell surface receptors?