Oligosaccharides of human milk: Structures of three lacto-N-hexaose derivatives with H-haptenic structure

doi:10.1016/0003-9861(77)90536-7

Archives of Biochemistry and Biophysics

Volume 182, Issue 2, August 1977, Pages 546-555

https://doi.org/10.1016/0003-9861(77)90536-7 Get rights and content

Abstract

Three oligosaccharides which have lacto-N-hexaose as their core structures are isolated by borate paper electrophoresis. These sugars occur in the milk of secretors but are completely absent in the milk obtained from nonsecretor women. By sequential glycosidase digestion and by methylation analysis, their structures were elucidated as Fucαl → 2 Gal/β1 → 3GlcNAcβ1 → 3[Galβ1 → 4GlcNAcβ1 → 6] Galβ1 → 4 Glc (fucosyllacto-N-hexaose I), Fucαl → 2Galβ1 → 3GlcNAcβ1 → 3 [Galβ1 → 4(Fucα1 → 3)GlcNAcβ1 → 6]Galβ1 → 4Glc (difucosyllacto-N-hexaose I), and Fucαl → 2Galβ1 → 3GlcNAcβ1 → 3[NeuAcα2 → 6Galβ1 → 4GlcNAcβ1 → 6]Galβ1 → 4 Glc (sialyl fucosyllacto-N-hexaose I). A-enzyme, which is responsible for the formation of blood group A determinant, can transfer N-acetylgalactosamine from UDP-GalNAc to both fucosyllacto-N-hexaose I and difucosyllacto-N-hexaose I, but not to sialyl fucosyllactoN-hexaose I.

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Human colostrum and mature milk contain 22–24 g/L and 12–13 g/L of oligosaccharides, respectively. Human milk oligosaccharides (HMOs) are the third largest solid component in human milk after lactose and lipids. So far 169 HMO structures have been characterized; they are classified into 20 series, based on their core structures. Almost all HMOs contain lactose at their reducing ends, in addition to the monosaccharide residues GlcNAc, Gal, Fuc and Neu5Ac. It has been known that HMOs stimulate the growth of colonic bifidobacteria in breastfed infants consuming their mother's milk, and their metabolic pathways by bifidobacteria have been recently clarified. In Bifidobacterium bifidum HMOs are hydrolyzed by extracellular glycosidases including lacto-N-biosidase and utilized by intracellular lacto-N-biose/galacto-N-biose phosphorylase. In Bifidobacterium longum subsp. infantis the intact HMOs are imported by the action of a transporter and then hydrolyzed to monosaccharides by several intracellular glycosidases. In addition to these pathways, the bifidobacteria have FL transporters, which import fucosyllactoses into the bacterial cells, to be utilized for their growth. HMOs also have other biological functions such as antiinfection, antiinflammation, prevention of necrotizing enterocolitis, stimulation of brain activity and amelioration of malnutrition.
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Recent observations on health benefits of breastfeeding and the related functions of human milk components have increased the interest in their structural analysis. Using biosynthetic rules, we can now computationally estimate all oligosaccharide structures that could occur in human milk; this virtual human milk glycan (HMG) database of more than 50,000 structures is available at http://unicarbkb.org/milk. Milk glycan functions are investigated by screening biologically relevant glycan binding proteins on a human milk shotgun glycan microarray with subsequent structural analysis of bound glycans using a metadata-assisted glycan sequencing approach, which combines binding and mass spectrometry data to define structure. The GlycomeSeq algorithm, implemented in a web application (http://glycomeseq.emory.edu), automatically predicts structure from the experimental metadata as a potentially high throughput, automatable method. Predicting structures based on matching experimental data against a knowledge base of all possible structures in a virtual or latent glycome represents a valid approach to defining any glycome.
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Comparative study of the fingerprinting patterns of oligosaccharides in individual human milk revealed the presence of three different patterns. Four oligosaccharides containing the Fucα1-2Gal group were missing in the milk of nonsecretor mothers, and three oligosaccharides containing the Fucα1-4GlcNAc group were missing in the milk of Lewis-negative individuals. Disappearance of some oligosaccharides in these samples led to the finding of five novel minor oligosaccharides, which were hidden under the missing oligosaccharides. Structures of many novel milk oligosaccharides were then elucidated. At least 13 core oligosaccharides were found among these oligosaccharides. By adding α-fucosyl residues and sialic acid residues to these core oligosaccharides, more than 100 oligosaccharides were formed. All these oligosaccharides contain lactose at their reducing termini. This evidence, together with the deletion phenomena found in the milk oligosaccharides of nonsecretor and Lewis negative individuals, suggested that the oligosaccharides are derived from lactose via the concerted action of glycosyltransferases, which are responsible for elongation and branching of the Galβ1-4GlcNAc group in the sugar chains of glycoconjugates on the surface of epithelial cells. Therefore, oligosaccharides in human milk could include many structures, starting from the Galβ1-4GlcNAc group in the sugar chains of various glycoconjugates produced by epithelial cells of the mammary gland, and play roles as various recognition signals.
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The important roles played by human milk oligosaccharides (HMOS), the third major component of human milk, in the health of breast-fed infants have been increasingly recognized, as the structures of more than 100 different HMOS have now been elucidated. Despite the recognition of the various functions of HMOS as prebiotics, antiadhesive antimicrobials, and immunomodulators, the roles and the applications of individual HMOS species are less clear. This is mainly due to the limited accessibility to large amounts of individual HMOS in their pure forms. Current advances in the development of enzymatic, chemoenzymatic, whole-cell, and living-cell systems allow for the production of a growing number of HMOS in increasing amounts. This effort will greatly facilitate the elucidation of the important roles of HMOS and allow exploration into the applications of HMOS both as individual compounds and as mixtures of defined structures with desired functions. The structures, functions, and enzyme-catalyzed synthesis of HMOS are briefly surveyed to provide a general picture about the current progress on these aspects. Future efforts should be devoted to elucidating the structures of more complex HMOS, synthesizing more complex HMOS including those with branched structures, and developing HMOS-based or HMOS-inspired prebiotics, additives, and therapeutics.
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Citation Excerpt :
This line of study further led them to propose the importance of carbohydrate–carbohydrate interactions in cell–cell recognitions [43]. LNH and LNnH were used as the models of the branched core portions of blood group determinants in the later studies of many blood group related antigens [44,45]. Before the structures of these oligosaccharides were elucidated, lactose, LNT, and LNnT were considered as the core structures of human milk oligosaccharides.
Application of a finger-printing method to the analysis of human milk oligosaccharides led to the finding that several oligosaccharides were missing in the milk of non-secretor or Lewis-negative individuals. This finding helped us in opening the door of elucidating the enzymatic basis of blood types in human. Based on these successful studies, a strategy to establish reliable techniques to elucidate the structures and functions of the N-linked sugar chains of glycoproteins was devised. It was to contrive enzymatic and chemical means to release quantitatively the N-linked sugar chains as oligosaccharides, and finger-print them by using appropriate methods to demonstrate the sugar pattern of a glycoprotein. These methods enabled us to determine that the N-linked sugar chains of glycoproteins can be classified into three subgroups: high mannose-type, complex-type, and hybrid-type. By comparative studies of the sugar patterns of a glycoprotein produced by different organs and different animals, occurrences of organ- and species-specific glycosylation were found in many glycoproteins. By comparative studies of the glycosylation patterns of the subunits constructing human chorionic gonadotropin and other glycoproteins, occurrence of site-directed N-glycosylation was also found, indicating that the processing and maturation of the N-linked sugar chains of a glycoprotein might be controlled by the structure of polypeptide moiety. Furthermore, these methods enabled us to elucidate the structural alteration of the sugar chains of a glycoprotein induced by diseased state of the producing cells, such as rheumatoid arthritis and malignancy. Recent studies of glycoproteins in the brain-nervous system through aging revealed that N-glycosylation of P₀ in the rat spinal cord is induced by aging. Therefore, glycobiology is expanding tremendously into fields such as pathological and gerontological research.

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This work has been supported in part by research grants from the Ministry of Education, Science and Culture of Japan and the Toray Science Foundation.

This paper is part IX of a series. Part VIII appears in Biochemistry15, 3950 (1976).

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Oligosaccharides of human milk: Structures of three lacto-N-hexaose derivatives with H-haptenic structure☆

Abstract

Arch. Biochem. Biophys

Arch. Biochem. Biophys

J. Biol. Chem

Anal. Biochem

Arch. Biochem. Biophys

Arch. Biochem. Biophys

J. Biol. Chem

Biochem. Biophys. Res. Commun