Meta-Biol

• Pathways

Perhaps the most important and widely studied blood group is the ABO blood group. It consists of antigens found on the outer surface of red cells and corresponding antibodies in plasma. The majority of the world's population (~80%) are 'secretors' which means that the antigens present in their blood will also be found in other body fluids such as saliva. An individual can be a Secretor (Se) or a non-secretor (se) and this is completely independent of whether the individual is of blood type A, B, AB, or O. From a very early age, the immune system develops antibodies against whichever ABO blood group antigens are not found on the individual's RBCs. Thus, a blood group A individual will have anti-B antibodies and a blood group B individual will have anti-A antibodies. Individuals with the most common blood group, O, will have both anti-A and anti-B in their plasma. Blood group AB is the least common, and these individuals will have neither anti-A nor anti-B in their plasma.

The primary structure of these antigens is an oligosaccharide precursor sequence on to which one or more sugars are attached at specific locations. The blood group oligosaccharide antigens A, B and H are produced by enzymes expressed by these genes and form the basis of the ABO 'blood type' phenotypes. A and B antigens were originally identified on red blood cells (RBCs) but later identified on other cell types and in bodily secretions. The ABO blood group system is important in blood transfusion, cell/tissue/organ transplantation and forensic evidence at crime scenes.

The H antigen is formed with the addition of a fucose sugar onto one of two precursor oligosaccharide sequences (Type 1 chains are Gal β1,3 GlcNAc β1,3 Gal R and Type 2 chains are Gal β1,4 GlcNAc β1,3 Gal R; where R is a glycoprotein (Type 1) or glycosphingolipid (Type 2). Type 2 chains are only found on RBCs, epithelial cells and endothelial cells. The H gene expressed in hematopoietic cells produces α-1,2-fucosyltransferase 1 (FUT1) which adds a fucose to Type 2 chains to form the H antigen in non-secretors. Type 1 chains are found in secretors. The Se gene expressed in secretory glands produces α-1,2-fucosyltransferase 2 (FUT2) which adds a fucose to Type 1 chains to form the H antigen in secretors.

The H antigen is abundant in individuals with blood group O and is the essential precursor for the production of A and B antigens. A and B antigens are formed by the action of glycosyltransferases encoded by functional alleles at the ABO genetic locus. The co dominant A allele encodes A transferase, which transfers an N acetylgalactosamine (GalNAc) sugar to the H antigen forming the A antigen. Similarly, the co dominant B allele encodes B transferase, which transfers a galactose (Gal) sugar to the H antigen forming the B antigen. Individuals who have both A and B alleles form the AB antigen. Individuals who are homozygous for the recessive O allele express the H antigen but do not form A or B antigens as they lack both the glycosyltransferase enzymes for their formation. Mutant alleles of the corresponding FUT1 or FUT2 genes result in either a H– phenotype (Bombay phenotype, Oh) or a weak H phenotype (para Bombay) where the affected individual cannot form H, A or B antigens (Kaneko et al. 1997, Koda et al. 1997). The biosyntheses of the A, B and H antigens are described in this section (Ewald & Sumner 2016, Scharberg et al. 2016).

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.