ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

Abstract

Enzymes catalyze biochemical reactions and play critical roles in human health and disease. Enzyme variants and deficiencies can lead to variable expression of glycans, which can affect physiology, influence predilection for disease, and/or directly contribute to disease pathogenesis. Although certain well-characterized enzyme deficiencies result in overt disease, some of the most common enzyme deficiencies in humans form the basis of blood groups. These carbohydrate blood groups impact fundamental areas of clinical medicine, including the risk of infection and severity of infectious disease, bleeding risk, transfusion medicine, and tissue/organ transplantation. In this review, we examine the enzymes responsible for carbohydrate-based blood group antigen biosynthesis and their expression within the human population. We also consider the evolutionary selective pressures, e.g. malaria, that may account for the variation in carbohydrate structures and the implications of this biology for human disease.

Keywords: Biochemistry; Biological sciences; Evolutionary biology.

Graphical abstract

Figure 1

Glycosidic bond nomenclature The anomeric carbon is defined as the carbonyl carbon in the acyclic form of a monosaccharide. This is often the first carbon, although in monosacchrides such as sialic acid, the second carbon serves as the anomeric carbon. If the hydroxyl group on the anomeric carbon is downward in the cyclic form, it can create an α glycosidic linkage with another monosaccharide. If the hydroxyl group is upward, it can form a β glycosidic linkage.

Figure 2

Overview of ABO(H) and Lewis blood group antigen biosynthesis ABO(H) and blood group antigen biosynthesis occurs in a stepwise fashion. Inheritence of enzymes capable of creating distinct modifications results in positivity for the respective blood group antigen. Many of these modifications can be found on glycolipids or glycoproteins. The i antigen is a precursor to the I antigen. Symbol nomenclature for each monosacchride is shown. Black text corresponds with black linkage, and red text corresponds with red linkage. GlcNAc = N-acetylglucosamine, GalNAc = N-acetylgalactosamine.

Figure 3

Overview of FORS, P, and NOR blood group antigen biosynthesis Similar to ABO(H) and blood group antigen biosynthesis, the formation of FORS1, P, NOR, and related antigens occurs in a stepwise fashion. However, these antigens are distinct in that they are exclusively expressed on glycolipids. Inheritence of enzymes capable of creating distinct modifications results in positivity for the respective blood group antigen. Symbol nomenclature for each monosacchride is shown. GlcNAc = N-acetylglucosamine, GalNAc = N-acetylgalactosamine.