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Human milk oligosaccharides

Structure and terminology of human milk oligosaccharides

Different terms are synonomyously used to describe human milk oligosaccharide structures, and are summarised here. Human milk oligosaccharides are composed of five building blocks and always contain lactose, which is depicted with a residue. Based on the residue, human milk oligosaccharides are classified into different categories: fucosylated human milk oligosaccharides, sialylated or acidic human milk oligosaccharides, and non-fucosylated neutral human milk oligosaccharides.

Terminology of HMO

The literature on human milk oligosaccharides (HMO) is diverse and stretches over many decades. Certain terms are used synonymously. We summarised these terms here:

  • The oligosaccharide fraction of human milk
  • consists of 200+ HMO species or isoforms or molecules or types.
  • Together, these form a HMO profile (e.g. HPLC analysis) or cluster or conglomerate.
  • The cluster/profile/conglomerate can be split into three HMO categories
  • in which HMO with a specific structure are sorted or grouped by their residues.
  • These structures are all built from the same three to five residues or molecules or monomers or building blocks that are monosaccharides and
  • differ in the combination of building blocks and glycosidic bond i.e. connection type.

Building blocks of HMO

All human milk oligosaccharides (HMO) can be described with an equation such as this:

Human milk oligosaccharide equation
Figure 412-3 The human milk oligosaccharide equation. All HMO can be described with this equation. It describes the three to five building blocks of HMO. From the right, a lactose molecule (galactose (yellow circle) glucose (blue circle)) is depicted at the reducing end. This disaccharide component is present in all HMO. In brackets, two optional dimers are described that only differ by the way the same two building blocks galactose (yellow circle) and N-acetylglucosamine (blue square) are connected. Up to 15 of these dimers can be added selectively to lactose and form linear or branched HMO isoforms. In addition, three alternative building blocks can be added selectively as shown on the right: Either fucose (red triangle) or sialic acid (also termed N acetylneuraminic acid or Neu5Ac, purple diamond) or galactose can be added to the lactose-core or the dimer chain with different bond types (Fucose α1-2, -3, -4; Sialic acid α2-3, -6; Galactose β1-3, -4, -6). Depending on the presence or absence of fucose and sialic acid, the respective HMO isoform can be sorted into three major categories. These are fucosylated HMO, sialylated, acidic HMO, or neutral, non-fucosylated HMO (Bode, 2012; see figures 412-7, -8, -9). The most basic HMO is a trisaccharide/ trimer of the lactose molecule linked to either a sialic acid, fucose or galactose molecule (Newburg et al., 2016; see figures 412-7, -8, -9).

HMO are composed of 5 different mono­saccharides

Five building blocks of human milk oligosaccharides
Legend 412-4 The five building blocks of human milk oligosaccharides. Human milk oligosaccharides are composed of three to five monosaccharides. These are D galactose (Gal, yellow circle), D glucose (Glc, blue circle), N acetylglucosamine (GlcNAc, blue square), L fucose (Fuc, red triangle), and N-acetylneuraminic acid (Neu5Ac, purple diamond), the latter also termed "sialic acid". One galactose and one glucose molecule connected via a β1-4 glycosidic bond form lactose. Lactose is always a component of HMO (Kunz et al., 2000, Bode, 2012). Symbols and coloration according to guidelines (Neelamegham et al., 2019).

To break down this complicated seeming equation, we start with the three to five monosaccharides or monomers that are the building blocks of HMO (Figure 412-3). Depending on the way these five building blocks are combined together with a number of different structural ways to connect, they form more than 200 HMO isoforms (Thurl et al. 2010).

The disaccharide lactose is a combination of D‑glucose (Glu, blue circle Figures 412-3 and 412-4) with D-galactose (Gal, yellow circle, Figures 412-3 and 412-4) connected via a β1-4 bond (Figure 412-5). As free disaccharide or dimer, lactose is the major carbohydrate in mother's milk and thus called milk sugar. Lactose is a core component of all HMO isoforms. It is located at the terminal end of all HMO and further modified by the addition of galactose, N‑acetyllactosamine, fucose, or sialic acid, elongated and branched in various ways to form the multitude of known HMO isoforms (Figure 412-4) (Bode. 2012⁠).

Different bonds in HMO cause structural diversity

Core and bonds of human milk oligosaccharides
Figure 412-5 The core of all human milk oligosaccharides. The lactose molecule is a disaccharide of D-glucose (blue circle) and D-galactose (yellow circle) connected via a β1 4 glycosidic bond. This disaccharide is present at the reducing end of all currently known human milk oligosaccharides (Bode, 2012).

The type of connection ‑ that is the glucoside bond ‑ plays a crucial role in HMO formation. It can define the 3D structure, thus determine interaction of the HMO to microorganisms (decoy receptor) or access of enzymes and other metabolites, and therefore affect functionality of the HMO isoform that was synthesised.

The disaccharide lactose is a combination of D‑glucose (Glu, blue circle Figures 412-3 and 412-4) with D-galactose (Gal, yellow circle, Figures 412-3 and 412-4) connected via a β1-4 bond (Figure 412-5). As free disaccharide or dimer, lactose is the major carbohydrate in mother's milk and thus called milk sugar. Lactose is a core component of all HMO isoforms: It is located at the terminal end of all HMO and further modified by the addition of galactose, N‑acetyllactosamine, fucose, or sialic acid, elongated and branched in various ways to form the multitude of known HMO isoforms (Figure 412-4) (Bode. 2012⁠).

Core and bonds of human milk oligosaccharides
Figure 412-6 The bond makes all the difference. From the same monomers of D-galactose (yellow circle) and N acetylglucosamine (blue square) two HMO isoforms are formed either via a β1-3 or β1-4 bond. Lacto N biose is therefore chemically described as Gal β1-3 N acetylglucosamine and N-acetyllactosamine as Gal β1-4 N-acetylglucosamine (Bode, 2012) (Ayechu-Muruzabal et al. 2018). The box illustrates how the different glycosidic bonds are depicted. Symbols and coloration according to guidelines (Neelamegham et al. 2019).

HMO can be categorisied by their residues

Human milk oligosaccharides structures are described by a basic blueprint (Figure 412-3): Lactose is a core component linked with at least one further residue or unit. Based on the presence of these residues, HMO can be sorted into three different categories:

  1. Fucosylated HMO (Figure 412-7) are linked with at least one L-fucose residue.

  2. Sialylated or acidic HMO (Figure 412-8) are oligosaccharides linked with at least one sialic acid residue.

  3. Non-fucosylated or neutral HMO (Figure 412-9) are linked with at least one galactose, N‑acetyllactosamine, or lacto‑N‑biose unit. They are neither linked with fucose nor sialic acid (Ayechu-Muruzabal et al. 2018⁠; Kunz et al. 2000).

Non-fucosylated neutral human milk oligosaccharides are the most diverse and extensive category representing between 42 ‑ 55% of the entire human milk oligosaccharide fraction, followed by fucosylated human milk oligosaccharides with 35 ‑ 50%. Sialylated, acidic human milk oligosaccharides are the least extensive category, representing approx. 13% of total human milk oligosaccharides (Donovan and Comstock. 2016).

Structure of fucosylated human milk oligosaccharides
Figure 412-7 Fucosylated human milk oligosaccharides. Based on their building blocks, HMO are classified into three basic categories (Ayechu-Muruzabal et al. 2018). Fucosylated HMO are characterised by the presence of at least one fucose residue (red triangle) that is added to either glucose (blue circle), galactose (yellow circle) or N acetylglucosamine (blue square) via alpha-1-2, alpha-1-3, or alpha-1-4 glycosidic bonds. The lactose core of glucose and galactose is always present. Symbols and coloration according to guidelines (Neelamegham et al., 2019)
Sialylated human milk oligosaccharides
Figure 412-8 Sialylated human milk oligosaccharides. Based on their building blocks, HMO are classified into three basic categories (Ayechu-Muruzabal et al. 2018). Sialylated or acidic HMO are characterised by the presence of at least one N-acetylneuraminic acid residue (sialic acid, purple diamond) added via alpha-2-3 or alpha-2-6 bonds to galactose (yellow circle) or N-acetylglucosamine (blue square) but not glucose (blue circle). HMO that contain sialic acid and fucose also exist (Thurl et al., 2017). Symbols and coloration according to guidelines (Neelamegham et al., 2019)
Neutral, non-fucosylated human milk oligosaccharides
Figure 412-9 Neutral, non-fucosylated human milk oligosaccharides. Based on their building blocks, HMO are classified into three basic categories (Ayechu-Muruzabal et al. 2018). Neutral, non-fucosylated HMO comprise the combination of lactose (galactose β1-4 glucose; yellow circle bound to blue circle) with either at least one lacto-N-biose (Gal β1-3 N-acetylglucosamine; yellow circle connected to blue square) or N-acetyllactosamine module (Gal β1-4 N-acetylglucosamine, yellow circle connected to blue square; see Figure 412-6). These dimers can occur as repeated units up to 15 times (Bode 2012). Fucose (red triangle) or sialic acid (purple diamond) are absent. If either one of these monomers is present, the HMO type is categorised differently. The smallest neutral HMO is a trisaccharide of lactose bound to one galactose monomer (yellow circle) via beta-1-3, beta-1-4, or beta-1-6 bonds. Symbols and coloration according to guidelines (Neelamegham et al., 2019)

Bibliography

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