Meta-Biol

• Pathways

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).

Starches and sugars are major constituents of the human diet and the catabolism of monosaccharides, notably glucose, derived from them is an essential part of human energy metabolism (Dashty 2013). Glucose can be catabolized to pyruvate (glycolysis) and pyruvate synthesized from diverse sources can be metabolized to form glucose (gluconeogenesis). Glucose can be polymerized to form glycogen under conditions of glucose excess (glycogen synthesis), and glycogen can be broken down to glucose in response to stress or starvation (glycogenolysis). Other monosaccharides prominent in the diet, fructose and galactose, can be converted to glucose. The disaccharide lactose, the major carbohydrate in breast milk, is synthesized in the lactating mammary gland. The pentose phosphate pathway allows the synthesis of diverse monosaccharides from glucose including the pentose ribose-5-phosphate and the regulatory molecule xylulose-5-phosphate, as well as the generation of reducing equivalents for biosynthetic processes. Glycosaminoglycan metabolism and xylulose-5-phosphate synthesis from glucuronate are also annotated as parts of carbohydrate metabolism.

The digestion of dietary starch and sugars and the uptake of the resulting monosaccharides into the circulation from the small intestine are annotated as parts of the “Digestion and absorption” pathway.

Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. The processes of energy metabolism can be classified into two groups according to whether they involve carbohydrate-derived or lipid-derived molecules, and within each group it is useful to distinguish processes that mediate the breakdown and oxidation of these molecules to yield energy from ones that mediate their synthesis and storage as internal energy reserves. Synthetic reactions are conveniently grouped by the chemical nature of the end products, such as nucleotides, amino acids and related molecules, and porphyrins. Detoxification reactions (biological oxidations) are likewise conveniently classified by the chemical nature of the toxin.

At the same time, all of these processes are tightly integrated. Intermediates in reactions of energy generation are starting materials for biosyntheses of amino acids and other compounds, broad-specificity oxidoreductase enzymes can be involved in both detoxification reactions and biosyntheses, and hormone-mediated signaling processes function to coordinate the operation of energy-generating and energy-storing reactions and to couple these to other biosynthetic processes.