Proceedings of the Japan Academy. Series B, Physical and Biological Sciences. Jul/20/2010; 86(7): 731-747

PMID: 20689231

Structures and application of oligosaccharides in human milk

Tamio YAMAKAWA

Abstract

Introduction

Milk contains various oligosaccharides in addition to glycoproteins, glycopeptides and glycolipids, many of which are found specifically in this particular secretion. These components occur in large amounts in the milk secreted at early stages of lactation. Among them, casein and lactose are important nutritional ingredients, while IgA works as a component of transfer immunity for babies.¹⁾ Lactoferrin plays a role to suppress the growth of bacteria by binding to the iron in milk.^2,3)

However, the physiological roles of other minor components, such as oligosaccharides in milk, are mostly unknown. Among the milk of mammals, human milk is unique because it contains a large number of oligosaccharides.

In 1933, Polonovski and Lespagnol found a new oligosaccharide containing nitrogen in human milk, and named it “gynolactose”.⁴⁾ Over two decades later, Polonovski and Montreuil found that gynolactose is actually a mixture of more than ten oligosaccharides, and nitrogen is included only in part of them.⁵⁾

Independent to their study, Kuhn’s group in the Max Planck Institute in Heidelburg reached to the same conclusion by investigating the chemical entity of Bifidus factor.

It has been known since 1900 that the feces of breast-fed babies are more acidic than those of artificially nourished babies.^6,7) These papers drew widely scientist’s notice, when Grulee etal. reported that breast-feeding was strongly associated with a lower incidence of diarrhea, otitis media, and respiratory diseases⁸⁾ in suckling babies. Paul György, who was the Professor of Pediatrics in Pennsylvania University, considered that this is because Lactobacillusbifidus becomes a predominant intestinal flora of babies fed with human milk. This bacterium digests lactose, and produces large amounts of lactic acid and acetic acid. The acidic condition in the intestine of babies suppresses the growth of many other microorganisms, and may protect babies from harmful intestinal infection.

Schönfeld⁹⁾ reported that the whey fraction of human milk contains a growth-promoting factor for Lactobacillusbifidus var. pennsylvanics, and named it Bifidus factor. In collaboration with György, Kuhn started a series of systematic investigations to elucidate the chemical entity of Bifidus factor,^10–12) and found many oligosaccharides in human milk.

Until 1965, structures of fourteen oligosaccharides shown in Table 1 were determined by Kuhn’s group and Montreuil’s group.^13–25)

All of these oligosaccharides contain lactose at their reducing termini. An interesting finding was that some of these oligosaccharides showed haptenic activities of blood group determinants:^21,26) 2′-FL and LNF-I showed haptenic activity of H determinant, LND-I showed activity of Le^b determinant, and LNF-II showed activity of Le^a determinant. These findings of human milk oligosaccharides significantly contributed to the elucidation of the structures of H and Lewis blood group determinants.²⁷⁾

Elucidation of the biochemical basis of non-secretor phenomenon and Lewis-negative phenomenon based on the finding of correlation of the occurrence of fucose-containing oligosaccharides with blood types of the donors

In 1967, Grollman and Ginsburg²⁸⁾ found an interesting fact that 2′-FL was not detected in the milk samples obtained from individuals of non-secretor blood type. Non-secretor individuals express ABO blood types on the surface of their erythrocytes according to their genetic background of ABO locus, but not in the glycoproteins secreted from the epithelial cells of mucous glands. In order to extend this interesting finding further, Kobata etal.²⁹⁾ devised a new technique to fingerprint the oligosaccharides by using small amount of milk samples. As shown in Fig. 1A, the fourteen milk oligosaccharides in Table 1 were successfully fractionated by using approximately 10 ml of milk samples.

By analyzing around 50 human milk samples, three types of oligosaccharide profiles were found to occur in human milk. Approximately 80% of human milk contained all fourteen oligosaccharides as shown in Fig. 1A. Approximately 15% of human milk lacked four oligosaccharides as shown in Fig. 1B, and remaining 5% lacked three oligosaccharides as shown in Fig. 1C. The missing oligosaccharides were indicated in Fig. 1B and C by dotted lines. The small grey spots, detected at the positions of missing oligosaccharides, are minor oligosaccharides hidden under the major oligosaccharides.

Important evidence was that all mothers whose milk gave the profile Fig. 1B were non-secretors, and those who gave the profile Fig. 1C were all Lewis negative, lacking both Le^a and Le^b antigens.

The four oligosaccharides: 2′-FL, LD, LNF-I, and LND-I, which were missing in the milk of non-secretor individuals, contain the Fucα1-2Gal group in common. Namely, the secretory organs of non-secretor individuals probably lack the fucosyltransferase responsible for formation of the disaccharide group. The three oligosaccharides: LNF-II, LND-I, and LND-II, which were missing in Lewis negative individuals, all contain the Fucα1-4GlcNAc group, indicating that these mothers may lack another fucosyltransferase responsible for formation of the Fucα1-4GlcNAc group.

These estimations were proven by enzymatic studies.^30,31)

Finding of minor oligosaccharides, which contain blood group A determinant, in human milk

In Table 2, the structures of H antigenic determinant, which is the major antigen of human O-blood type, and blood type A and B antigenic determinants are summarized. As easily speculated from the structures of the three antigenic determinants, blood types A and B antigenic determinants are formed by adding GalNAc residue and Gal residue to H antigenic determinant, respectively. Although oligosaccharides containing blood type A and B antigenic determinants were not included among the milk oligosaccharides listed in Table 1, an α-N-acetylgalacosaminyltransferase (A-enzyme) and an α-galactosyltransferase (B-enzyme) were found to occur in the milk of blood type A and B individuals, respectively.^32,33) These enzymes catalyze the addition of an α-GalNAc residue and an α-Gal residue to the C-3 position of the Gal residue of the Fucα1-2Gal group, respectively. GalNAcα1-3(Fucα1-2)Galβ1-4Glc and GalNAcα1-3(Fucα1-2)Galβ1-3GlcNAcβ1-3Galβ1-4Glc, which were formed respectively from 2′-FL and LNF-I by the catalysis of partially purified A-enzyme, showed haptenic activity of blood type A.³⁴⁾ Occurrence of these haptenic tetrasaccharide (P_I) and hexasaccharide (P_II) in the milk samples of blood type A secretor individuals was confirmed as summarized in Table 3. The amounts of both haptenic oligosaccharides in blood type A milk samples varied by individuals from 0.2 to 13 nmol per ml of milk. These values are from one-hundredth to one-thousandth of those for LNT, LNF-I and LNF-II.

Structures of the minor oligosaccharides detected in the milk samples obtained from non-secretor individuals and Lewis negative individuals

As named by white letters in Fig. 1B and C, five novel oligosaccharides in total were found in the milk samples of non-secretor and Lewis negative individuals. Structures of these oligosaccharides were elucidated as summarized in Table 4.^35–39)

Among them, LNF-III served as an important haptenic oligosaccharide to investigate the functional role of Le^x antigen.⁴⁰⁾ LNH and LNnH served as useful models of branched core structures in the later studies of many blood group related antigens.^41,42)

Before the structures of these oligosaccharides were elucidated, lactose, LNT and LNnT were considered as the cores of human milk oligosaccharides. Branched hexasaccharides: LNH and LNnH were newly added as cores, and a large number of fucosyl and sialyl derivatives of these newly added cores were found in human milk as shown in Tables 5–7.^38,43–55)

For the structural studies of these novel milk oligosaccharides, many new sensitive analytical techniques, such as tritium-labeling,⁵⁶⁾ sequential exoglycosidase digestion,^57,58) and sensitive methylation analysis suitable for the amino sugar-containing oligosaccharides⁵⁹⁾ were established. These new techniques play important roles in the later structural study of the sugar chains of various glycoconjugates. In addition to the physicochemical analyses such as NMR and mass-spectrometry, recycling chromatography devised by Donald etal.⁴³⁾ was found to be effective for the study of milk oligosaccharides.

Looking at the structures of these oligosaccharides silhouettes several interesting structural rules. As shown in Table 6, the Fucα1-2Gal group is not evenly distributed to the two Galβ1-GlcNAc groups of the branched arms of LNH, but is rather limited to the arm extending from C-3 position of the branching Gal.⁴²⁾ Finding of the Fucα1-3Gal group in a fucosylated LNH is also noteworthy.⁴⁹⁾ This group is limited to the Type II chain in contrast to the Fucα1-2Gal group. Many fucosyltransferases have been cloned in recent years.⁶⁰⁾ However, no enzyme to catalyze the formation of the Fucα1-3Gal group has been reported.

Several oligosaccharides containing both Fucα1-2Gal group and sialic acid were detected. It was confirmed that these oligosaccharides could not work as the substrate of A-enzyme (Kobata etal., unpublished data). Therefore, sialylation of the sugar chains may inhibit the conversion of H-antigen to A-antigen.

Many novel cores were found in the human milk oligosaccharides

As described already, structural study of human milk oligosaccharides get started by the interest of their relation to blood group antigens. The development of research as introduced so far and the possibility of important functions of these oligosaccharides aroused the interest of many researchers, and the structures of remaining larger oligosaccharides were investigated. As shown in Table 8, we found four novel core oligosaccharides: para-Lacto-N-hexaose,⁶¹⁾para-Lacto-N-neohexaose,⁶¹⁾ Lacto-N-octaose,⁶²⁾ and Lacto-N-neooctaose⁶²⁾ in human milk. Other groups found three additional novel core oligosaccharides: iso-Lacto-N-octaose,⁶³⁾para-Lacto-N-octaose,⁵⁵⁾ and Lacto-N-decaose.⁶⁴⁾ Quite recently, Amano etal.⁶⁵⁾ reported the occurrence of an isomeric decasaccharide as another core in milk oligosaccharides. Therefore, at least 13 core oligosaccharides have been found for human milk oligosaccharides until now.

All of these core oligosaccharides contain lactose at their reducing termini. Based on this evidence, all human milk oligosaccharides are considered to be produced by the action of glycosyltransferases of epithelial cells, which are responsible for formation of the sugar chains of glycoproteins and glycolipids in the cells. Namely, by the action of iGnT⁶⁶⁾ on lactose, which is synthesized in a large amount by the action of β4GalT-I and α-lactalbumin, GlcNAcβ1-3Galβ1-4Glc is formed as shown in Fig. 2. All linear core oligosaccharides might be formed by the concerted actions of β4GalT⁶⁷⁾ and iGnT as shown in the left hand side of Fig. 3. The sugar chains, produced by the concerted action of the two glycosyltransferases, are all neo-type, which has only the repeating structures of the Galβ1-4GlcNAcβ1-3 group. However, when the Galβ1-3GlcNAcβ1-3 group is formed by the action of β3GalT⁶⁸⁾ instead of β4GalT, extension of the sugar chain might stop there.

Core milk oligosaccharides with branched structures might be produced by the action of IGnT⁶⁹⁾ as shown in Fig. 2, and in the right hand side of Fig. 3.

The thirteen core oligosaccharides, thus formed, are further elongated to the fucosylated and/or sialylated oligosaccharides by the actions of fucosyltransferases and/or sialyltransferases. In Tables 5–7, and Tables 9 and 10, all sialylated and fucosylated oligosaccharides, reported so far, are summarized. Many fucosyl derivatives of Lacto-N-decaose and its isomer were reported by Chai etal.,⁷⁶⁾ and Amano etal.⁶⁵⁾ Although only one tetra-fucosyl derivative was reported for para-Lacto-N-octaose,⁵⁵⁾ many fucosyl and/or sialyl derivatives will be found for this core oligosaccharide in the future.

Important evidence is that Lacto-N-octaose and Lacto-N-neooctaose were not detected by mass-spectrometric analysis.⁵⁵⁾ This evidence should be explained in the future for the sound development of mass-spectrometric methods.

Various problems related to the activity of Bifidus factor in milk

The problem of the chemical entity of Bifidus factor had been considered to be solved, when Lactobaccilusbifidus var. pennsylvanicus was found to request GlcNAc as a growth factor and only the milk oligosaccharides containing GlcNAc residue as Bifidus factor. However, the project is developing now to a new aspect by the finding that human milk oligosaccharides show a growth activity working specifically for various Bifidus strains as described below.

It was found that most of human milk oligosaccharides are not degraded by the action of exoglycosidases in digestive tract and reach to intestine. Because of this characteristics, these oligosaccharides are now classified as water-soluble fibers.^77–81) Accordingly, these oligosaccharides must first be digested to their monosaccharide constituents in order to be used by intestinal flora as nutrients. However, it is not so easy for bacteria in intestine to digest human milk oligosaccharides, because most of the β-galactosidases of intestinal bacteria hydrolyze the Galβ1-4GlcNAc group but not the Galβ1-3GlcNAc group, which amply occurs at the non-reducing termini of human milk oligosaccharides.⁵⁸⁾

The research group of Kenji Yamamoto found that a lacto-N-biosidase, reported by Sano etal.⁸²⁾ in the culture fluid of Streptomyces sp. 142, was widely found in Lactobaccilusbifidus strains, but not in other intestinal bacteria.⁸³⁾ This endoglycosidase effectively releases the Galβ1-3GlcNAc group from non-reducing termini of various oligosaccharides. They also found a transporter in the membrane of L.bifidus strains. This transporter specifically transports Galβ1-3GlcNAc from culture medium into cells.⁸⁴⁾

Meanwhile, Kitaoka etal.⁸⁵⁾ found in the culture fluid of Bifidobacteriumbifidum JCM1254 an enzyme, which converts the Galβ1-3GlcNAc to Galα1-PO₄ and GlcNAc, and named it lacto-N-biose phosphorylase. An interesting evidence is that this enzyme also works on the Galβ1-3GalNAc, which is released from O-linked sugar chains by the action of endo-α-N-acetylgalactosaminidase,⁸⁶⁾ and convert it to Galα1-PO₄ and GalNAc, but not on the Galβ1-4GlcNAc group. They successfully cloned the gene of this enzyme from Bifidobacteriumlongum JCM1217, and further found a series of genes of enzymes, which are responsible for the metabolism of monosaccharides constructing human milk oligosaccharides, in the operon containing the gene of lacto-N-biose phosphorylase. Based on this finding, they proposed the metabolic pathway of human milk oligosaccharides by the bacterium.

These results indicated that L.bifidus strains are equipped with a series of special catabolic mechanism, which specifically uses the oligosaccharides having the Galβ1-3GlcNAc group in their termini for metabolic sources. Therefore, human milk oligosaccharides, which are enriched in the Galβ1-3GlcNAc group in their non-reducing termini, specifically work as nutritional sources for L.bifidus strains.

A trial to apply human milk oligosaccharides as drugs to prevent bacterial and viral infection

As already described, human milk oligosaccharides are synthesized by the concerted action of a series of glycosyltransferases, which are responsible for formation of the sugar chains of glycoproteins and glycolipids produced by the epithelial cells of mammary gland. Accordingly, human milk oligosaccharides may be useful for elucidating the structures of potential ligands for cell adhesion molecules.⁸⁷⁾ Actually, LNF-III was effectively used to elucidate the physiological role of Le^x antigen.⁴⁰⁾

It was known that the infection of many bacteria and viruses starts by binding to particular sugar chains of glycoconjugates on the surface of cells, which are constructing the mucous epithelium of digestive tracts and respiratory tracts. Therefore, human milk oligosaccharides might be useful for elucidating the structure of target sugar chain of each bacterium or virus on the surface of epithelial cells.

After entering into 1990th, several research groups started to report the phenomenon that some of the human milk oligosaccharides inhibit attachment of intestinal bacteria to the surface of the epithelial cells of intestine.^88–90) Based on these findings, Newburg started to investigate the possibility that human milk oligosaccharides may be useful for developing new drugs to protect suckling babies from bacterial and viral infections.⁹¹⁾

Newburg reviewed that addition of various oligosaccharides and glycoconjugates to milk prevents babies from infectious diseases.⁹²⁾

One of the toxins produced by enterotoxigenic E.coli is called stable toxin (STa), because of its stability to organic solvent and heat. STa induces secretory diarrhea by activating guanylate cyclase of the surface of intestinal epithelial cells.⁹³⁾ It was known that T84 cells, established by Dharmsathaphorn, differentiate in culture and express various features of intestinal epithelium including formation of microvillae and transmembrane guanylate cyclase.^94–96)

By using this cultured cells, Crane etal. found that a crude mixture of human milk oligosaccharides showed a dose-dependent inhibition for the STa-induced cGMP production.⁹⁷⁾ The inhibition activity was expressed by the fucosylated oligosaccharide fraction, but not by the non-fucosylated oligosaccharide fraction, which were obtained by passing through an immobilized Ulexeuropaeus column. More recently, Morrow etal. reported that only the milk oligosaccharides, containing the Fucα1-2Gal group at their non-reducing termini, showed the inhibitory activity.⁹⁸⁾

Ruiz-Palacios etal. found that adhesion of Campyrobacterjejuni to the surface of intestinal epithelia is inhibited by the human milk oligosaccharides, which contain the Fucα1-2Galβ1-4GlcNAc group (H-2 antigen) at their non-reducing termini.⁹⁹⁾ They further confirmed that adhesion of Campyrobacterjejuni to H-2 antigen expressed on the surface of the epithelial cells of human small intestine is essential for its infection, by indicating that the bacterium cannot bind to the surface of CHO cells, but binds well to the surface of CHO cells transfected with human α1,2-fucosyltransferase gene.

According to Le Pandu,¹⁰⁰⁾ non-secretor individuals are resistant to Norwalk virus (NV) infection. This evidence indicated that H-1 antigenic determinant expressed on the surface of the epithelial cells of human intestine is working as the receptor to trigger NV infection. Actually, it was found that NV infection was inhibited by milk obtained from secretor mothers, which are known to contain a large amount of oligosaccharides containing the H-1 antigenic determinant, but not by milk from non-secretor mothers.

In 2005, Perret etal.¹⁰¹⁾ found that PA-IIL, a lectin purified from Pseudomonasaeruginosa, binds specifically to 3-FL and human milk oligosaccharides containing Le^a antigenic determinant, and estimated that Le^a and Le^x antigenic determinants on the surface of mucous epithelial cells are the target to start the infection of P.aeruginosa.

F18-fimbriated E.coli infection to weaned piglet induces diarrhea and dropsy. Its infection starts by binding FedF, which is included in F18-fimbria, to the wall of small intestine of piglet. Quite recently, Coddens etal.¹⁰²⁾ found that the adhesion of this bacteria to the microvilli of piglet small intestine is inhibited by LNF-I, but not by LNT. Based on this finding, they investigated the structures of glycolipids in the mucosa of piglet small intestine, which bind to FedF, and showed that glycolipids containing either H-1 antigenic determinant or blood type A or B antigenic determinant of Type I chain bind strongly to FedF. Because H-2 and blood type A or B determinants of Type II chain cannot bind to FedF, they concluded that H-1 is the basic structure of FedF ligand, and further addition of Gal or GalNAc at the C-3 position of the Gal residue of the ligand enhances the binding to FedF.

Future prospects

As shown by the data, so far introduced, studies of human milk oligosaccharides are expected to be very useful for the development of drugs, which are effective for protection of babies from harmful infections.

The key to lead to the success of this line of studies is how one will be able to develop an effective method to pick up minor but useful oligosaccharides from the mixture of a large number of different milk oligosaccharides.

Kitagawa etal. reported the structures of a series of human milk oligosaccharides, which were retained by an immobilized column of anti-CA19-9 antibody.¹⁰³⁾ As shown by A–D in Fig. 4, they are oligosaccharides of various sizes containing the sialyl-Le^a determinant in common. Among them, two oligosaccharides, C and D, which occur as very minor components in the oligosaccharide fraction retained by the column, have unusual features. They do not contain lactose, but contain either GlcNAc or Gal residue at their reducing termini.

Another unusual oligosaccharide (E in Fig. 4), which does not contain the core structures of milk oligosaccharides so far introduced, was isolated from human milk. However, this oligosaccharide also contains lactose at its reducing terminus. Therefore, the mechanism to produce oligosaccharides C and D, which lack lactose group, is totally unknown. They might be produced by an unknown degradation mechanism from larger milk oligosaccharides.

In any event, the report of Kitagawa etal. indicated that we would be able to pick up even a very minor oligosaccharide with particular ligand specificity, if a proper affinity chromatographic method is devised by isolating receptor proteins on the surface of bacteria and viruses. Perhaps, this can be performed in the near future by collaborating with the bacteriologists and virologists, who are investigating the virulent factors by cloning the surface lectins of bacteria and viruses.

The report of Perret etal.¹⁰¹⁾ can be considered as a pioneering work for this line of investigation.

For further development of such study, elucidation of the structures of all human milk oligosaccharides is also indispensable. As described already, 13 different core oligosaccharides were found for human milk oligosaccharides. Whether additional larger cores exist or not, and the rules in locations of additional fucoses and sialic acid residues remain to be elucidated. Accumulation of such results may be useful for elucidating the structural rules in the polylactosamine chains, which occur widely in the sugar chains of glycoproteins, glycolipids and proteoglycans.

Human milk contains more than three times of sialylated oligosaccharides of cow’s milk. It is known that these sialylated oligosaccharides are absorbed from digestive tracts of babies, and used for the biosynthesis of glycoproteins and glycolipids in their brain.¹⁰⁴⁾ It was also found that learning and memory are improved in piglets by administering sialic acid.¹⁰⁵⁾ Development of this line of studies will afford another improvement for artificial nourishment of babies.

I would like to recommend readers of this review to read another comprehensive review of structures and functions of human milk oligosaccharides written recently by Urashima etal.¹⁰⁶⁾

Figure 1.

Three typical fingerprinting patterns obtained from the oligosaccharide fraction of milk sample, collected from a single donor. The fraction numbers as indicated by “TUBE NUMBER” in abscissa were obtained by Sephadex G-25 column chromatography of human milk oligosaccharide fraction. Aliquot of the fractions were spotted at the origin of a sheet of a filter paper, and subjected to chromatography using ethylacetate/pyridine/acetic acid/water (5:5:1:3) as solvent. Black spots represent oligosaccharides visualized by alkaline-AgNO₃ reagent, and hatched ones encircled by black line represent those detected by both alkaline-AgNO₃ reagent and thiobarbituric acid reagent. Spots shown by dotted lines were missing in the pattern. Grey spots detected at the positions of missing oligosaccharides are minor oligosaccharides hidden under the major oligosaccharides. A, the pattern obtained from milk samples of Le^a+b+ individuals; B, the pattern obtained from milk samples of Le^a+b− (non-secretor) individuals; C, the pattern obtained from milk samples of Le^a−b− individuals. Revised from the figure in Glycoconj. J. 17, 443–464 (2000) with kind permission from Springer Science+Business media.

Figure 2.

Elongation of lactose and N-acetyllactosamine group of the sugar chain of glycoconjugates by the action of iGnT and IGnT. R represents the aglycon moieties of glycoconjugates. Revised from the figure in Chang Gung Medical J. 26, 620–636 (2003).

Figure 3.

Biosynthetic pathways leading to various core oligosaccharides from GlcNAcβ1-3Galβ1-4Glc and GlcNAcβ1-6(GlcNAcβ1-3)Galβ1-4Glc.

Figure 4.

Structures of milk oligosaccharides containing the sialyl-Le^a group (A–D), and three human milk oligosaccharides (C–E), which do not contain the known core oligosaccharides. Taken from the figure in Chang Gung Medical J. 26, 620–636 (2003).

Table 1.

Structures of human milk oligosaccharides found until 1965

Table 2.

Structures of ABO blood group antigenic determinants

*Those containing Galβ1-3GlcNAcβ1- and Galβ1-4GlcNAcβ1- are discriminated by the name of H-1 and H-2, respectively.

Table 3.

Contents of P_I and P_II in human milk

Donors	Blood type	Secretor status	Oligosaccharides

			P_I	P_II
			nmol/ml milk
B.J.	A₂	secretor	13	4
E.K.	A₂	secretor	3	2
E.W.	A₁	secretor	0.4	0.2
M.C.	A₁	secretor	8	4
M.R.	A₁	secretor	0.2	0.3
K.C.	A₁	secretor	6	1
B.B.	A₁	non-secretor	<0.1	<0.1
H.S.	O	secretor	<0.1	<0.1
M.S.	B	secretor	<0.1	<0.1

Table 4.

Novel oligosaccharides isolated from milk of non-secretor and Lewis negative individuals

Table 5.

Human milk oligosaccharides with lactose, LNT and LNnT as cores

Table 7.

Human milk oligosaccharides with LNnH as a core

Table 6.

Human milk oligosaccharides with LNH as a core. Numbers in the parentheses indicate those of references

Table 8.

Various core structures found in human milk oligosaccharides

Table 9.

Human milk oligosaccharides containing para-Lacto-N-hexaose (para-LNH) and para-Lacto-N-neohexaose (para-LNnH) as cores

Table 10.

Human milk oligosaccharides containing Lacto-N-octaose, Lacto-N-neooctaose, and iso-Lacto-N-octaose as coses. The numbers in the parentheses indicate the numbers of references

Abbreviations

2′-FL2′-fucosyllactose

3-FL3-fucosyllactose

Fuc

l-fucose

Gal

d-galactose

6′-GalL6′-galactosyllactose

GalNAc

N-acetyl-d-galactosamine

Glc

d-glucose

GlcNAc

N-acetyl-d-glucosamine

LDlactodifucotetraose

Le^aLewis a

Le^bLewis b

Le^xLewis x

LND-I

lacto-N-difucohexaose I

LND-II

lacto-N-difucohexaose II

LNF-I

lacto-N-fucopentaose I

LNF-II

lacto-N-fucopentaose II

LNF-III

lacto-N-fucopentaose III

LNF-V

lacto-N-fucopentaose V

LNH

lacto-N-hexaose

LNnH

lacto-N-neohexaose

LNT

lacto-N-tetraose

LNnT

lacto-N-neotetraose

Neu5Ac

N-acetylneuraminic acid

Type I chainGalβ1-3GlcNAcβ1-

Type II chainGalβ1-4GlcNAcβ1-

Profile

Akira Kobata was born in 1933, graduated from Faculty of Pharmaceutical Science, School of Medicine, the University of Tokyo in 1956, and received Ph.D. degree from the University in 1962. In 1967, he joined the Section of Biochemistry (Chief, Victor Ginsburg), Laboratory of Biochemical Pharmacology, National Institute of Arthritis and Metabolic Diseases in NIH as a visiting scientist. There, he was involved in elucidating the whole biosynthetic pathway of ABH and Lewis antigenic determinants, based on the finding that human milk can be classified into three groups by their oligosaccharide profiles. In 1971, he moved to Kobe University as the Professor of the First Department of Biochemistry, School of Medicine. While elucidating the structures of many novel oligosaccharides in human milk, he developed a series of new sensitive methods to investigate the structures of the sugar chains of glycoproteins. In 1982, he moved to the University of Tokyo as the Professor and Chairman of the Department of Biochemistry, a newly founded Department in the Institute of Medical Science, and expanded his research to the functions and pathologies of the N-linked sugar chains of glycoproteins. He received many Prizes including C. S. Hudson Award from American Chemical Society, and the 1992 Japan Academy Prize. He was a Fogarty Scholar-in-Residence in NIH from 1985 to 1987, Auckland Foundation Visiting Professor in New Zealand in 1988, and also served as the Director of the Institute of Medical Science from 1990 to 1992. Upon retiring from the University of Tokyo in 1993, he was appointed as the Director of Tokyo Metropolitan Institute of Gerontology (TMIG), and became a Professor Emeritus of the University of Tokyo. In this last carrier as a scientist, he developed a new glycobiology area in the field of aging research. From 2000, he has been the Director Emeritus of TMIG. Currently, he is the scientific advisor of Noguchi Institute, a non-profit institution established for the study of carbohydrate chemistry and biology.

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