Evolution of milk oligosacharides and lactose

Abstract

Living mammals comprise monotremes, marsupials and eutherians (placental mammals). These three Infraclasses, although they differ markedly in their patterns of reproduction, have in common the phenomenon of lactation, i.e. the production of milk by the female subsequent to hatching (monotremes) or birth (marsupials, eutherians). The dominant carbohydrate in the milk of most eutherians is the disaccharide lactose, whose synthesis by the lactating mammary gland is catalysed by lactose synthase, which is a complex consisting of β4galactosyltransferase I and α-lactalbumin. α-Lactalbumin is found only in mammals and is believed to have evolved from lysozyme, an ancient protein which is widely distributed in the animal kingdom. The α-lactalbumin content within the mammary gland is the controlling factor determining the rate of lactose synthesis. The dominant carbohydrates in the milk of monotremes and marsupials and of a few eutherian species are oligosaccharides, i.e. sugars which consist of three or more monosaccharide residues. The milk and colostrum of humans and of some other eutherians also contains significant amounts of oligosaccharides. Milk oligosaccharide synthesis is catalysed by a variety of glycosyltransferases which transfer monosaccharide residues (galactosyl, fucosyl, sialyl or N-acetylglucosaminyl) either to free lactose or to another monosaccharide residue attached to lactose. In terms of chemical structures, eutherian and monotreme oligosaccharides resemble each other whereas the marsupial oligosaccharides are mostly unique, but almost all contain lactose at their reducing ends. Milk oligosaccharides are now recognised as being very significant as anti-microbial compounds against pathogenic microorganisms as well as being an energy source for the young of monotremes and marsupials. Milk oligosaccharides may also provide specific monosaccharides which are required for the postnatal biosynthesis of glycoconjugates, particularly of the nervous system. We propose the following hypothesis for the evolution of milk oligosaccharides. The primitive mammary glands of the first common ancestor of mammals contained lysozyme and a variety of glycosyltransferases but little or no α-lactalbumin. When α-lactalbumin first appeared, its content within the lactating mammary glands was low and lactose was synthesised at a relatively slow rate. Because of the presence of glycosyl transferases, almost all of the lactose was utilised for the synthesis of oligosaccharides and did not accumulate, its steady-state concentration remaining low. Consequently the predominant saccharides in the proto-lacteal secretions or milk produced by this common ancestor were oligosaccharides and not free lactose. Initially, the oligosaccharides served mainly as anti-infection factors against pathogenic organisms. They were then recruited as an energy source for the neonates, and natural selection favoured an increase in their concentration. This was achieved by an increase in the synthesis of α-lactalbumin and possibly also of the glycosyltransferases. The two biological roles of anti-infection and provision of energy were preserved in both monotremes and marsupials but in most eutherians the milk concentration of free lactose increased due to a significant increase in α-lactalbumin synthesis by the mammary gland. Lactose therefore became a significant energy source for most eutherians while oligosaccharides continued to serve mainly as anti-microbial agents. The advent of milk lactose at relatively high concentrations necessitated the prior evolution or co-evolution of brush border small intestinal lactase, which provided an efficient mechanism for the digestion of lactose.