Lewis blood group biosynthesis

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R-HSA-9037629
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Homo sapiens
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The Lewis antigen system is a human blood group system based upon genes on chromosome 19 p13.3 (the FUT3 gene aka the Le gene) and 19q13.3, (FUT2 gene aka the Se gene). Both genes are expressed in glandular epithelia and have dominant alleles (Le and Se, respectively) coding for enzymes with fucosyltransferase activity and recessive alleles (le and se, respectively) that are non-functional. There are two main Lewis antigens, Lewis A and Lewis B which can result in three common phenotypes: Le(A+B-), Le(A-B+) and Le(A-B-). Lewis antigens are components of exocrine epithelial secretions, and can be adsorbed onto the surfaces of red blood cells (RBCs), therefore are not produced directly by RBCs themselves (Ewald & Sumner 2016).

The same two oligosaccharides (Type 1 and Type 2) used to determine ABO blood types are also utilised by the Lewis system. Fucosyltransferase 3 (FUT3, Le) adds fucose to Type 1 chains to form the Lewis A antigen (LeA). IF the individual is a non-secretor (lacks the Se gene, homozygous sese), LeA is adsorbed onto the red cell, and that individual is LeA type. Approximately 80% of the population has the Se gene. Functional fucosyltransferase 2 (FUT2, Se) adds a fucose to LeA to form LeB. Both LeA and LeB present in the plasma of secretors but LeA preferentially adsorbs onto the RBC and therefore, the individual types as LeB. Other FUTs, especially FUT4, can add a fucose to Type 2 chains to form the Lewis X antigen (LeX). Further fucosylation of LeX by FUT2 produces the Lewis Y antigen (LeY). LeX and LeY are structural isomers of LeA and LeB. The formation of LeY is controlled by Se/se as in the case for LeB. LeA and LeX antigens can also undergo sialation to produce sialated forms of these antigens.

Aberrant glycosylation of tumour cells is recognised as a feature of cancer pathogenesis. Overexpression of fucosylated and sialated Lewis antigens frequently occurs on the surfaces of cancer cells and is mainly attributed to upregulated expression of the relevant fucosyltransferases (FUTs). The sialyl-Lewis A antigen (sLeA), also known as the CA19-9 antigen, is the most common tumour marker used primarily in the management of pancreatic and gastrointestinal cancers worldwide (Magnani 2004, Blanas et al. 2018).

Selectins (L-, E- and P-selectin) are type I membrane proteins composed of long N-terminus C-type lectin domains protruding into the extracellular space and with a short cytoplasmic tail. They bind carbohydrate structures through a Ca2+-dependent domain, the minimal sugar structure recognised fulfilled by sLeA and sLeX. Selectins are found on endothelial cells, platelets and leukocytes and are involved in trafficking of cells of the innate immune system, T lymphocytes and platelets, thereby playing important roles in chronic and acute inflammation and haemostasis. Selectins also play a role in cancer progression. Metastasis is facilitated by cell-cell interactions between cancer cells and endothelial cells in distant tissues. In addition, cancer cell interactions with platelets and leukocytes contribute to cancer cell adhesion, extravasation, and the establishment of metastatic lesions. Targeting selectins and their ligands as well as the enzymes involved in their generation, in particular sialyl transferases, could be a useful strategy in cancer treatment (Ley 2003, Laubli & Borsig 2010, Cheung et al. 2011, Natoli et al. 2016, Trinchera et al. 2017).

Literature References
PubMed ID Title Journal Year
15158662 The discovery, biology, and drug development of sialyl Lea and sialyl Lex

Magnani, JL

Arch. Biochem. Biophys. 2004
27599872 Blood type biochemistry and human disease

Ewald, DR, Sumner, SC

Wiley Interdiscip Rev Syst Biol Med 2016
29527514 Fucosylated Antigens in Cancer: An Alliance toward Tumor Progression, Metastasis, and Resistance to Chemotherapy

Blanas, A, Sahasrabudhe, NM, Rodríguez, E, van Kooyk, Y, Van Vliet, SJ

Front Oncol 2018
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