Sialyl-Lewis X

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Sialyl-Lewis X
Sialyl lewis x.svg
Names
IUPAC name
(5-Acetamido-3,5-dideoxy-D-glycero-α-D-galacto-non-2-ulopyranosylonic acid)-(2→3)-β-D-galactopyranosyl-(1→4)-[α-L-fucopyranosyl-(1→3)]-N-acetyl-D-glucosamine
Systematic IUPAC name
(2S,4S,5R,6R)-5-Acetamido-2-{[(2S,3R,4S,5S,6R)-2-{[(2R,3R,4R,5R)-5-acetamido-1,2-dihydroxy-6-oxo-3-{[(2S,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexan-3-yl]oxy}-2,4-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-4-hydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]oxane-2-carboxylic acid
Other names
sialyl LeX, SLeX, CD15s, SSEA-1
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
MeSH sialyl+Lewis+X
PubChem CID
UNII
  • InChI=1S/C31H52N2O23/c1-9-18(43)21(46)22(47)28(51-9)53-24(12(5-34)32-10(2)38)25(15(42)7-36)54-29-23(48)27(20(45)16(8-37)52-29)56-31(30(49)50)4-13(40)17(33-11(3)39)26(55-31)19(44)14(41)6-35/h5,9,12-29,35-37,40-48H,4,6-8H2,1-3H3,(H,32,38)(H,33,39)(H,49,50)/t9-,12-,13-,14+,15+,16+,17+,18+,19+,20-,21+,22-,23+,24+,25+,26+,27-,28-,29-,31-/m0/s1 Yes check.svgY
    Key: LAQPKDLYOBZWBT-NYLDSJSYSA-N Yes check.svgY
  • InChI=1/C31H52N2O23/c1-9-18(43)21(46)22(47)28(51-9)53-24(12(5-34)32-10(2)38)25(15(42)7-36)54-29-23(48)27(20(45)16(8-37)52-29)56-31(30(49)50)4-13(40)17(33-11(3)39)26(55-31)19(44)14(41)6-35/h5,9,12-29,35-37,40-48H,4,6-8H2,1-3H3,(H,32,38)(H,33,39)(H,49,50)/t9-,12-,13-,14+,15+,16+,17+,18+,19+,20-,21+,22-,23+,24+,25+,26+,27-,28-,29-,31-/m0/s1
    Key: LAQPKDLYOBZWBT-NYLDSJSYBC
  • O=C(N[C@@H]1[C@@H](O)C[C@](O[C@H]1[C@H](O)[C@H](O)CO)(O[C@@H]2[C@@H](O)[C@@H](O[C@H](CO)[C@@H]2O)O[C@@H]([C@H](O[C@@H]3O[C@H]([C@@H](O)[C@@H](O)[C@@H]3O)C)[C@H](C=O)NC(=O)C)[C@H](O)CO)C(=O)O)C
Properties
C31H52N2O23
Molar mass 820.744 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Sialyl LewisX (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide carbohydrate which is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. It is also the means by which an egg attracts sperm; first, to stick to it, then bond with it and eventually form a zygote.

Contents

Sialyl-LewisX is also one of the most important blood group antigens and is displayed on the terminus of glycolipids that are present on the cell surface. The sialyl-LewisX determinant, E-selectin ligand carbohydrate structure, is constitutively expressed on granulocytes and monocytes and mediates inflammatory extravasation of these cells. Resting T and B lymphocytes lack its expression and are induced to strongly express sialyl-LewisX upon activation. The sialyl-LewisX determinant is expressed preferentially on activated Th1 cells but not on Th2 cells.

Structure

Sialyl-LewisX is a tetrasaccharide composed of a sialic acid, fucose and an N-acetyllactosamine. Its systematic name is 5-acetylneuraminyl-(2-3)-galactosyl-(1-4)-(fucopyranosyl-(1-3))-N-acetylglucosamine (Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAcβ). In humans, [1] [2] it is synthesized by four fucosyltransferases: FUT3, FUT5, FUT6 and FUT7. The other three enzymes of the sialyltransferase family, ST3GAL3, ST3GAL4, and ST3GAL6, participate in the synthesis of the sialyl-LewisX precursor. [2]

Function

Leukocyte homing

Sialyl-LewisX is important in leukocyte tethering and rolling. Leukocytes move through the blood stream and then tether themselves to the endothelial wall and roll along the endothelium before potentially exiting into the tissue. Sialyl-LewisX is a necessary partner for the three selectins that bind the leukocyte and endothelial cells. When sialyl-LewisX is part of an O-glycan and attached to CD34, it can then bind to L-selectin. For the binding to L-selectin to occur, sialyl-LewisX must undergo sulfation. For sialyl-LewisX to bind to P-selectin, an O-linked glycan near the N-terminus of P-selectin glycoprotein ligand-1 (PSGL-1) is modified with sialyl-LewisX and, in combination with nearby tyrosine residues modified with sulfate, forms the binding contact for P-selectin. For sialyl-LewisX to bind to E-selectin, it can be part of either an N-linked or O-linked glycan attached to cell surface glycoproteins such as PSGL-1, CD43 or CD44. This sialyl-LewisX-mediated binding to selectins allows circulating leukocytes to stick to and roll along endothelial cells lining blood vessels, thereby enabling the leukocytes to accumulate at a site of vascular inflammation.

Fertilization

Sialyl-LewisX allows a sperm cell to recognize and fertilize an egg cell. For fertilization to occur, human sperm must bind to the zona pellucida (ZP), the translucent matrix covering the human egg composed of four glycoproteins—ZP1, 2, 3, and 4—and transit through the matrix in order to fuse with the oocyte. [3] The human ZP is coated with dense N- and O-glycans that are terminated with the sialyl-LewisX sequence. [4] The hemizona assay, which assesses sperm–ZP binding by counting the number of sperm bound to hemispheres of bisected nonliving human eggs in vitro, reveals that 0.5 mM sialyl-LewisX inhibits sperm–ZP binding by 63%. [4] Furthermore, adding purified and solubilized ZP3 or ZP4 from the human oocyte dose-dependently inhibits sperm–ZP binding in the hemizona assay. [5] Such evidence suggest that the early steps of human sperm–egg binding may be mediated by lectins for sialyl-LewisX present on human sperm.

Clinical significance

Leukocyte adhesion deficiency

Defective synthesis of the sialyl-LewisX antigen results in immunodeficiency (leukocyte adhesion deficiency type 2). Defective synthesis can be caused by the loss of fucosyltransferase, impairing the glycosylation of the glycosphingolipid. Sialyl-LewisX is being researched for detection and treatment of immune disorders because of its presence on leukocytes.

Blood cancers

Sialyl-LewisX mediates phagocytosis and chemotaxis, found in neutrophils; [6] it is expressed by cells present in Hodgkin disease, some B-cell chronic lymphocytic leukemias, acute lymphoblastic leukemias, and most acute nonlymphocytic leukemias. CD15 is present on almost all Reed–Sternberg cells, including their rare mononuclear variants, and, as such, can be used in immunohistochemistry to identify the presence of such cells in biopsies. The presence of these cells is diagnostic of Hodgkin's lymphoma. Reed–Sternberg cells display a characteristic pattern of sialyl-LewisX positivity, with membranous staining combined with staining of the Golgi apparatus. Immunohistochemical panels for the diagnosis of Hodgkin's disease typically employ CD15 along with CD30 and CD45; the latter does not stain Reed–Sternberg cells, but does stain almost all other lymphoid cells. Sialyl-LewisX is also present in about 50% of adenocarcinoma cells and can be used to distinguish such conditions from mesothelioma, which is typically negative. [7]

Cancer metastasis

Sialyl-LewisX plays a critical role in cancer metastasis, facilitating the extravasation of cancer cells out of the bloodstream when they are moving through the body. Its expression is related to tumor stage, recurrence, and overall patient survival. [8] Therefore, sialyl Lewis x is being used as a target in studies to fight tumors and cancer cell growth. There is frequent overexpression of sialyl-LewisX on cancer cells, and it is found on both N-glycan and O-glycans. Sialyl-LewisX is being researched with CD markers to find new ways to create biosensors for cancer cells. It is also being used in new ways to target cancer cells specifically for cancer treatment.

In vitro fertilization

Sialyl-LewisX is being used to achieve greater rates of fertilization of eggs in women by coating the eggs with sialyl-LewisX.

Immunity and inflammation

Sialyl-LewisX plays a key role in the inflammatory response and may be used to increase the leukocyte response to infections. Sialyl-LewisX is also an inflammation-associated antigen on liver cells. It is overexpressed on diseased liver cells and can be used as a way to detect liver disease in a patient.

MERS coronavirus binding

In June 2019, before the onset of the COVID-19 pandemic, the receptor for sulfated sialyl-LewisX oligosaccharide (particularly with α2,3 linkages) was found to be the preferred binding site, both in humans and in dromedary camels, for the coronavirus causing Middle East respiratory syndrome (MERS), the sixth coronavirus to be described. [9] [10]

History

The term "Lewis" in the name comes from a family of people with a red blood cell incompatibility. The studies done on these individuals' red blood cells led to the discovery of sialyl-LewisX. Sialyl-LewisX is an important red blood cell antigen present on the glycolipids on the plasma membrane of the cell.

Its localization to the cell surface of cells led to its alternative nomenclature as a cluster of differentiation. Clusters of differentiation are a naming system devised in 1982 to classify cell-surface antigens on leukocytes identified via monoclonal antibodies. Sialyl-LewisX was assigned the name CD15.

See also

Related Research Articles

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

An oligosaccharide is a saccharide polymer containing a small number of monosaccharides. Oligosaccharides can have many functions including cell recognition and cell adhesion.

<span class="mw-page-title-main">Glycolipid</span> Class of chemical compounds

Glycolipids are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the connections that allow cells to connect to one another to form tissues. Glycolipids are found on the surface of all eukaryotic cell membranes, where they extend from the phospholipid bilayer into the extracellular environment.

<span class="mw-page-title-main">Zona pellucida</span> Glycoprotein layer surrounding the plasma membrane of mammalian oocytes

The zona pellucida is the specialized area surrounding mammalian oocytes (eggs). It is also known as an egg coat. The zona pellucida is essential for oocyte growth and fertilization.

<span class="mw-page-title-main">P-selectin glycoprotein ligand-1</span> Protein-coding gene in the species Homo sapiens

Selectin P ligand, also known as SELPLG or CD162, is a human gene.

<span class="mw-page-title-main">Selectin</span> Family of cell adhesion molecules

The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.

<span class="mw-page-title-main">Human fertilization</span> Union of a human egg and sperm

Human fertilization is the union of an egg and sperm, occurring primarily in the ampulla of the fallopian tube. The result of this union leads to the production of a fertilized egg called a zygote, initiating embryonic development. Scientists discovered the dynamics of human fertilization in the 19th century.

<span class="mw-page-title-main">L-selectin</span> Mammalian protein found in Homo sapiens

L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the SELL gene. L-selectin belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant. L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events. These tethering interactions are essential for the trafficking of monocytes and neutrophils into inflamed tissue as well as the homing of lymphocytes to secondary lymphoid organs. L-selectin is also expressed by lymphoid primed hematopoietic stem cells and may participate in the migration of these stem cells to the primary lymphoid organs. In addition to its function in the immune response, L-selectin is expressed on embryonic cells and facilitates the attachment of the blastocyst to the endometrial endothelium during human embryo implantation.

<span class="mw-page-title-main">E-selectin</span> Mammalian protein found in Homo sapiens

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.

<span class="mw-page-title-main">ZP3</span> Protein-coding gene in the species Homo sapiens

Zona pellucida sperm-binding protein 3, also known as zona pellucida glycoprotein 3 (Zp-3) or the sperm receptor, is a ZP module-containing protein that in humans is encoded by the ZP3 gene. ZP3 is the glycoprotein in the zona pellucida most important for inducting the acrosome reaction of sperm cells at the beginning of fertilization.

<span class="mw-page-title-main">CA19-9</span> Chemical compound

Carbohydrate antigen 19-9 (CA19-9), also known as sialyl-LewisA, is a tetrasaccharide which is usually attached to O-glycans on the surface of cells. It is known to play a role in cell-to-cell recognition processes. It is also a tumor marker used primarily in the management of pancreatic cancer.

<span class="mw-page-title-main">Leukocyte extravasation</span> Passage of a leukocyte

Leukocyte extravasation is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.

<span class="mw-page-title-main">FUT7</span> Protein-coding gene in the species Homo sapiens

Alpha-(1,3)-fucosyltransferase is an enzyme that in humans is encoded by the FUT7 gene.

<span class="mw-page-title-main">GCNT1</span> Protein-coding gene in the species Homo sapiens

Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the GCNT1 gene.

<span class="mw-page-title-main">FUT6</span> Protein-coding gene in the species Homo sapiens

Alpha-(1,3)-fucosyltransferase is an enzyme that in humans is encoded by the FUT6 gene.

<span class="mw-page-title-main">ZP2</span> Protein-coding gene in the species Homo sapiens

Zona pellucida sperm-binding protein 2 is a protein that in humans is encoded by the ZP2 gene.

<span class="mw-page-title-main">FUT5</span> Protein-coding gene in the species Homo sapiens

Alpha-(1,3)-fucosyltransferase is an enzyme that in humans is encoded by the FUT5 gene.

<span class="mw-page-title-main">Cell–cell recognition</span>

Cell–cell recognition is a cell's ability to distinguish one type of neighboring cell from another. This phenomenon occurs when complementary molecules on opposing cell surfaces meet. A receptor on one cell surface binds to its specific ligand on a nearby cell, initiating a cascade of events which regulate cell behaviors ranging from simple adhesion to complex cellular differentiation. Like other cellular functions, cell-cell recognition is impacted by detrimental mutations in the genes and proteins involved and is subject to error. The biological events that unfold due to cell-cell recognition are important for animal development, microbiomes, and human medicine.

The zona pellucida-like domain is a large protein region of about 260 amino acids. It has been recognised in a variety of receptor-like eukaryotic glycoproteins. All of these molecules are mosaic proteins with a large extracellular region composed of various domains, often followed by either a transmembrane region and a very short cytoplasmic region or by a GPI-anchor.

<span class="mw-page-title-main">Fucosyltransferase 4</span> Protein-coding gene in the species Homo sapiens

Fucosyltransferase 4 is a protein that in humans is encoded by the FUT4 gene.

References

  1. ↑ de Vries, T.; Knegtel, R. M.; Holmes, E. H.; Macher, B. A. (October 2001). "Fucosyltransferases: structure/function studies". Glycobiology. 11 (10): 119R–128R. doi: 10.1093/glycob/11.10.119r . ISSN   0959-6658. PMID   11588153.
  2. 1 2 Trinchera, Marco; Aronica, Adele; Dall’Olio, Fabio (2017-02-23). "Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers". Biology. 6 (1): 16. doi: 10.3390/biology6010016 . ISSN   2079-7737. PMC   5372009 . PMID   28241499.
  3. ↑ Clark, G. F. (2013). "The role of carbohydrate recognition during human sperm-egg binding". Human Reproduction. 28 (3): 566–577. doi: 10.1093/humrep/des447 . PMID   23315069.
  4. 1 2 Pang, Poh-Choo; Chiu, Philip C. N.; et al. (18 August 2011). "Human Sperm Binding Is Mediated by the Sialyl-Lewisx Oligosaccharide on the Zona Pellucida". Science. 333 (6050): 1761–1764. Bibcode:2011Sci...333.1761P. doi:10.1126/science.1207438. hdl: 10044/1/15584 . PMID   21852454. S2CID   23610213.
  5. ↑ Chiu, P. C. N.; Wong, B. S. T.; Chung, M. -K.; Lam, K. K. W.; Pang, R. T. K.; Lee, K. -F.; Sumitro, S. B.; Gupta, S. K.; Yeung, W. S. B. (2008). "Effects of Native Human Zona Pellucida Glycoproteins 3 and 4 on Acrosome Reaction and Zona Pellucida Binding of Human Spermatozoa". Biology of Reproduction. 79 (5): 869–877. doi: 10.1095/biolreprod.108.069344 . PMID   18667750.
  6. ↑ Kerr MA, Stocks SC (November 1992). "The role of CD15-(Le(X))-related carbohydrates in neutrophil adhesion". Histochem. J. 24 (11): 811–26. doi:10.1007/BF01046353. PMID   1362195. S2CID   8602651.
  7. ↑ Leong, Anthony S-Y; Cooper, Kumarason; Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2nd ed.). Greenwich Medical Media, Ltd. pp. 83–84. ISBN   1-84110-100-1.
  8. ↑ Liang, Jin-xiao; Liang, Yong; Gao, Wei (2016-05-24). "Clinicopathological and prognostic significance of sialyl Lewis X overexpression in patients with cancer: a meta-analysis". OncoTargets and Therapy. 9: 3113–3125. doi: 10.2147/OTT.S102389 . ISSN   1178-6930. PMC   4888715 . PMID   27307752.
  9. ↑ Tortorici, M. Alejandra; Walls, Alexandra C.; Lang, Yifei; Wang, Chunyan; Li, Zeshi; Koerhuis, Danielle; Boons, Geert-Jan; Bosch, Berend-Jan; Rey, Félix A.; de Groot, Raoul J.; Veesler, David (June 2019). "Structural basis for human coronavirus attachment to sialic acid receptors". Nature Structural & Molecular Biology. 26 (6): 481–489. doi:10.1038/s41594-019-0233-y. PMC   6554059 . PMID   31160783.
  10. ↑ Li, Wentao; Hulswit, Ruben J. G.; Widjaja, Ivy; Raj, V. Stalin; McBride, Ryan; Peng, Wenjie; Widagdo, W.; Tortorici, M. Alejandra; Dieren, Brenda van; Lang, Yifei; Lent, Jan W. M. van; Paulson, James C.; Haan, Cornelis A. M. de; Groot, Raoul J. de; Kuppeveld, Frank J. M. van; Haagmans, Bart L.; Bosch, Berend-Jan (3 October 2017). "Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein". Proceedings of the National Academy of Sciences. 114 (40): E8508–E8517. Bibcode:2017PNAS..114E8508L. doi: 10.1073/pnas.1712592114 . PMC   5635925 . PMID   28923942. S2CID   20912646.

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