The Power of Carbohydrates 

Carbohydrates exist and play a significant role in our everyday lives. From the breakfast we consume and our main source of energy, to adding fiber into your diet to help protect against diseases. In fact, some antigens are made up of carbohydrates as well, including Sialyl Lewis. 

Similar to lego, carbohydrates can be built into chains starting from monomer, single-units such as monosaccharides, to polymer, multi-unit polysaccharides. Sialyl Lewis in particular are tetrasaccharide molecules made with sialic acid, and are typically located on the terminal carbohydrate; which are key for immune recognition (Galustian et al. 2002). The group of Sialyl Lewis molecules can exist as both ‘a’ and ‘x’ antigens, as they differ by one chain. Sialyl Lewis X (sLe^x) is a type 2 chain, typically used to help white blood cells stick onto blood vessels, Figure 1a. Whereas, Sialyl Lewis A (sLe^A), a type 1 chain, is known as a biomarker, shown in Figure 1b (Di et al. 2024). The type 1 and 2 chains differ in their structure by their L-Fucose (fuc), D-Galactose (Gal) and N-Acetylglucosamine (GlcNAc) linkages. 

With more recent applications, the “x” antigen has been used as a therapeutic cancer agent through its binding capability to selectins and activation of leukocytes. Selectins are a family of calcium-dependent transmembrane proteins, which bind to carbohydrate ligands, such as Sialyl Lewis X for the roll out of leukocytes (Rachel and Chang-Chun 2013) There are three main selectins, P (on the surface of platelets), E (on endothelial cells) and L (on leukocytes) (Sacanella et al. 2005); Sialyl Lewis X only binds to P and E selectins. However, in order to get to this final product, it is important to recognize the vital elements in the sLe^x structure, for its function. As highlighted in Figure 1, Fucose nor Galactose can bind onto a calcium molecule on its own. However, with the internal structure of the two molecules,“α-1,3/α-1,4” and “β-1,4” linkages, this is possible. Overall, the backbone of this structure allows for basic cell communication and for broader predictions of biomolecular complexes and activation of essential biomolecules (Sladek et al. 2023).  

On the other end of the spectrum, Sialyl Lewis X and A antigens are also associated with malignancy, with respect to colon cancer (Dall’Olio et al. 2021). In a normal colon, the overexpression of enzymes against sialic acid can keep sLe^A/X levels low. However, in cancerous situations, the overexpression of sLe^A/X levels cannot be controlled and biosynthetic antigens need to be created. 

References

Dall’Olio, Fabio, Michela Pucci, and Nadia Malagolini. 2021. “The Cancer-Associated Antigens Sialyl Lewisa/X and Sda: Two Opposite Faces of Terminal Glycosylation.” Cancers 13 (21): 5273. https://doi.org/10.3390/cancers13215273.

Di, Wang, Katarina Madunić, Oleg A. Mayboroda, Lageveen-Kammeijer, Guinevere S.M, and Wuhrer Manfred. 2024. “(Sialyl)Lewis Antigen Expression on Glycosphingolipids, N-, and O-Glycans in Colorectal Cancer Cell Lines Is Linked to a Colon-Like Differentiation Program.” Molecular & Cellular Proteomics 23 (6): 100776. https://doi.org/10.1016/j.mcpro.2024.100776.

Galustian, Christine, Robert A Childs, Mark Stoll, Hideharu Ishida, Makoto Kiso, and Ten Feizi. 2002. “Synergistic Interactions of the Two Classes of Ligand, Sialyl-Lewis(a/X) Fuco-Oligosaccharides and Short Sulpho-Motifs, With the P- and L-Selectins: Implications for Therapeutic Inhibitor Designs.” Immunology (England) 105 (3): 350–59. PubMed. https://doi.org/10.1046/j.1365-2567.2002.01369.x.

Kannagi, Reiji. 2002. “Regulatory Roles of Carbohydrate Ligands for Selectins in the Homing of Lymphocytes.” Current Opinion in Structural Biology 12 (5): 599–608. https://doi.org/10.1016/s0959-440x(02)00365-2.

Rachel, Hevey, and Ling Chang-Chun. 2013. “Recent Advances Toward the Development of Inhibitors to Attenuate Tumor Metastasis via the Interruption of Lectin–Ligand Interactions.” Advances in Carbohydrate Chemistry and Biochemistry, January 1, 125–207. https://doi.org/10.1016/b978-0-12-408093-5.00005-8.

Sacanella, E, R Estruch, JM Nicolás, and J Fernández-Solá. 2005. “Adhesion Molecules and Alcohol Consumption Supported by Grant PI/020611 From Fondo De Investigación Sanitaria, Instituto De Salud Carlos III, Ministerio De Sanidad Y Consumo, Spain..” Elsevier. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/selectin.

Sladek, Vladimir, Šmak Pavel, and Igor Tvaroška. 2023. “How E‑, L‑, and P‑Selectins Bind to sLex and PSGL-1: A Quantification of Critical Residue Interactions.” J. Chem. Inf. Model. 63 (17): 5604–18. https://doi.org/10.1021/acs.jcim.3c00704.