Lacto-N-tetraose

Last updated
Lacto-N-tetraose
Lacto-N-Tetraose Structure.jpg
Chemical structure of lacto-N-tetraose
Names
IUPAC name
N-[(4-Deoxy-D-glucos-4-yl 3-deoxy-β-D-galactopyranosid-3-yl) β-D-galactopyranosyl-(1→3)-(2-deoxy-β-D-glucopyranosid-2-yl)]acetamide
Systematic IUPAC name
N-[(2S,3R,4R,5S,6R)-2-{[(2R,3S,4S,5R,6S)-3,5-Dihydroxy-2-(hydroxymethyl)-6-{[(2R,3R,4R,5R)-1,2,4,5-tetrahydroxy-6-oxohexan-3-yl]oxy}oxan-4-yl]oxy}-5-hydroxy-6-(hydroxymethyl)-4-{[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}oxan-3-yl]acetamide
Other names
β-D-Gal-(1→3)-β-D-GlcNAc-(1→3)-β-D-Gal-(1→4)-D-Glc
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C26H45NO21/c1-6(32)27-11-21(47-25-18(39)15(36)12(33)7(2-28)44-25)13(34)8(3-29)43-24(11)48-22-14(35)9(4-30)45-26(19(22)40)46-20-10(5-31)42-23(41)17(38)16(20)37/h7-26,28-31,33-41H,2-5H2,1H3,(H,27,32)/t7-,8-,9-,10-,11-,12+,13-,14+,15+,16-,17-,18-,19-,20-,21-,22+,23?,24+,25+,26+/m1/s1
    Key: AXQLFFDZXPOFPO-FSGZUBPKSA-N
  • CC(=O)N[C@@H]1[C@H]([C@@H]([C@H](O[C@H]1O[C@H]2[C@H]([C@H](O[C@H]([C@@H]2O)O[C@@H]3[C@H](OC([C@@H]([C@H]3O)O)O)CO)CO)O)CO)O)O[C@H]4[C@@H]([C@H]([C@H]([C@H](O4)CO)O)O)O
Properties
C26H45NO21
Molar mass 707.632 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Lacto-N-tetraose is a complex sugar found in human milk. It is one of the few characterized human milk oligosaccharides (HMOs) and is enzymatically synthesized from the substrate lactose. It is biologically relevant in the early development of the infant gut flora.

Contents

Structure

Lacto-N-tetraose is a tetrasaccharide composed of four monosaccharide units in the order galactose, N-acetylglucosamine, another galactose, and glucose, joined by "1-3 β-linkages" in a linear chain. [1] It has the chemical formula C26H45NO21, shared with its related human milk oligosaccharide isomer lacto-N-neotetraose. [2] The molecule consisting of the first two monosaccharide units is called lacto-N-biose (presumably because it is a biose containing a nitrogen atom and involved in milk). and when this is attached to a lactose molecule the tetrasaccharide is called lacto-N-tetraose. [3]

It is a reducing sugar with a free anomeric center at the terminal glucose molecule indicating an equilibrium between the alpha (α) and beta (β) anomers. This characteristic of reducing sugars is seen through a positive Benedict's Test.

Lactose-N-tetraose has the oligosaccharide nomenclature β-D-galactosyl-(1→3)-N-acetyl-β-D-glucosaminyl-(1→3)-β-D-galactosyl-(1→4)-D-glucose, and consists of lactose with an additional lactose-N-biose disaccharide at the non-reducing end. [1] [4] [5]

Lacto-N-tetraose is classified as a type I chain oligosaccharide due to the β(1→3) linkage at the non-reducing end. The β(1→4) linkage at the non-reducing end of lacto-N-neotetraose makes it a type II chain.

Through chemical and structural characterization, it has been identified that related oligosaccharides are often modifications of a single disaccharide. This has been observed for human milk oligosaccharides, with lactose as the common sugar, and in the raffinose-series plant oligosaccharides which are based on sucrose. [6]

Biological significance

Lacto-N-tetraose is considered a prebiotic, facilitating the growth of healthy bacteria in the gut microbiome. It is one of the first functional foods that the infant consumes. Humans do not have the enzymes to cleave the glycosidic bonds of human milk oligosaccharides, and so these sugars have no caloric value to humans and function as a dietary fiber in the intestine. [7]

Only a small fraction of HMOs are absorbed undigested through the epithelium and are detectable in circulation, which may indicate other systemic functions of these compounds currently unknown. [8] [9] Lacto-N-tetraose and other human milk oligosaccharides are subsequently found excreted in the urine after consumption of human milk. [8] [9]

Lacto-N-tetraose in particular has been found to specifically promote growth of the species Bifidobacterium longum subspecies infantis. [10] [6] B. infantis aids in digestion and is considered "good" bacteria. [6] Genetic studies of B. infantis has pinpointed a locus for HMO metabolism that is conserved across all strains observed to date. [10] This suggests a possible co-evolution of the bacterium with the infant gut and composition of human milk. [10]

Bifidobacterium have a metabolic pathway for the uptake and digestion of specific human milk oligosaccharides. [11] This is accomplished through specific transporter proteins and glycosidases to cleave chemical bonds found in lacto-N-tetraose, lacto-N-neotetraose, and other human milk oligosaccharides. [10] [11] Cleavage of lacto-N-tetraose and lacto-N-neotetraose require different enzymes due to their distinct glycosidic bond at the non-reducing end. [12] Bifidobacterium in the human intestine have been found to contain type I chain lacto-N-biosidases capable of cleaving lacto-N-tetraose to lactose-N-biose and lactose. [11]

Lacto-N-tetraose is a non-competitive food source for B. infantis with other enteric bacteria lacking the required proteins and incapable of degrading the sugar into usable sources of carbon for glycolysis. [11] When the infant consumes human milk, lacto-N-tetraose confers a growth advantage to Bifidobacterium as they are able to metabolize this sugar for ATP production whereas other gut bacteria cannot. [6] This overgrowth of the healthy bacteria B. infantis may additionally hinder growth of other pathogenic bacteria in the gut. [6]

Studies have indicated that only certain species of Bifidobacteria, such as those in the infant intestine, contain the lacto-N-biosidase gene. [11] Analysis of Bifidobacteria in the gut of domestic animals found no evidence of this enzyme. [11] Strains of B. infantis highly adapted to utilizing human milk oligosaccharides further suggests a selective co-evolution between the gut microbiome and infant. [10] [11]

It has been found that the gut microbiome of breast-fed versus formula-fed infants are vastly different. [11] For this reason, adding HMOs to infant formulas is an area of interest.

Methods of synthesis

Isolating single oligosaccharides is needed to further study their biological function. Human milk is inaccessible in large amounts and its complex makeup makes separation of the individual molecular components a challenge. Synthesis of lacto-N-tetraose has been reported in total chemical synthesis as well as in recombinant Escherichia coli cells. [4] [13] The increasing availability of this compound is an area of ongoing research to further uncover the physiological and biochemical role of lacto-N-tetraose and other human milk oligosaccharides in the body. [8]

Related Research Articles

<span class="mw-page-title-main">Disaccharide</span> Complex sugar

A disaccharide is the sugar formed when two monosaccharides are joined by glycosidic linkage. Like monosaccharides, disaccharides are simple sugars soluble in water. Three common examples are sucrose, lactose, and maltose.

<span class="mw-page-title-main">Lactose</span> Carbohydrate

Lactose is a disaccharide sugar synthesized by galactose and glucose subunits and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from lac (gen. lactis), the Latin word for milk, plus the suffix -ose used to name sugars. The compound is a white, water-soluble, non-hygroscopic solid with a mildly sweet taste. It is used in the food industry.

<span class="mw-page-title-main">Lactase</span> Mammalian protein found in Homo sapiens

Lactase is an enzyme produced by many organisms. It is located in the brush border of the small intestine of humans and other mammals. Lactase is essential to the complete digestion of whole milk; it breaks down lactose, a sugar which gives milk its sweetness. People who have deficiency of lactase, and consume dairy products, may experience the symptoms of lactose intolerance. Lactase can be purchased as a food supplement, and is added to milk to produce "lactose-free" milk products.

<span class="mw-page-title-main">Galactose</span> Monosaccharide sugar

Galactose, sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molecule linked with a glucose molecule forms a lactose molecule.

<span class="mw-page-title-main">Beta-galactosidase</span> Family of glycoside hydrolase enzymes

β-Galactosidase, is a glycoside hydrolase enzyme that catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosides.

An oligosaccharide is a saccharide polymer containing a small number of monosaccharides. Oligosaccharides can have many functions including cell recognition and cell adhesion.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

<span class="mw-page-title-main">Acarbose</span> Chemical compound

Acarbose (INN) is an anti-diabetic drug used to treat diabetes mellitus type 2 and, in some countries, prediabetes. It is a generic sold in Europe and China as Glucobay, in North America as Precose, and in Canada as Prandase. It is cheap and popular in China, but not in the U.S. One physician explains the use in the U.S. is limited because it is not potent enough to justify the side effects of diarrhea and flatulence. However, a recent large study concludes "acarbose is effective, safe and well tolerated in a large cohort of Asian patients with type 2 diabetes." A possible explanation for the differing opinions is an observation that acarbose is significantly more effective in patients eating a relatively high carbohydrate Eastern diet.

<span class="mw-page-title-main">Raffinose</span> Chemical compound

Raffinose is a trisaccharide composed of galactose, glucose, and fructose. It can be found in beans, cabbage, brussels sprouts, broccoli, asparagus, other vegetables, and whole grains. Raffinose can be hydrolyzed to D-galactose and sucrose by the enzyme α-galactosidase (α-GAL), an enzyme which in the lumen of the human digestive tract is only produced by bacteria in the large intestine. α-GAL also hydrolyzes other α-galactosides such as stachyose, verbascose, and galactinol, if present. The enzyme does not cleave β-linked galactose, as in lactose.

<span class="mw-page-title-main">Gut microbiota</span> Community of microorganisms in the gut

Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota. The gut is the main location of the human microbiome. The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.

A bifidus factor is a compound that specifically enhances the growth of bifidobacteria in either a product or in the intestines of humans and/or animals. Several products have been marketed as bifidogenic factors, such as several prebiotics and methyl-N-acetyl D-glucosamine in human milk.

<span class="mw-page-title-main">Galactooligosaccharide</span> Class of prebiotics

Galactooligosaccharides (GOS), also known as oligogalactosyllactose, oligogalactose, oligolactose or transgalactooligosaccharides (TOS), belong to the group of prebiotics. Prebiotics are defined as non-digestible food ingredients that beneficially affect the host by stimulating the growth and/or activity of beneficial bacteria in the colon. GOS occurs in commercially available products such as food for both infants and adults.

<i>Bifidobacterium longum</i> Species of bacterium

Bifidobacterium longum is a Gram-positive, catalase-negative, rod-shaped bacterium present in the human gastrointestinal tract and one of the 32 species that belong to the genus Bifidobacterium. It is a microaerotolerant anaerobe and considered to be one of the earliest colonizers of the gastrointestinal tract of infants. When grown on general anaerobic medium, B. longum forms white, glossy colonies with a convex shape. B. longum is one of the most common bifidobacteria present in the gastrointestinal tracts of both children and adults. B. longum is non-pathogenic, is often added to food products, and its production of lactic acid is believed to prevent growth of pathogenic organisms.

<i>Bifidobacterium</i> Genus of bacteria

Bifidobacterium is a genus of gram-positive, nonmotile, often branched anaerobic bacteria. They are ubiquitous inhabitants of the gastrointestinal tract though strains have been isolated from the vagina and mouth of mammals, including humans. Bifidobacteria are one of the major genera of bacteria that make up the gastrointestinal tract microbiota in mammals. Some bifidobacteria are used as probiotics.

<span class="mw-page-title-main">2'-Fucosyllactose</span> Chemical compound

2′-Fucosyllactose (2′-FL) is an oligosaccharide, more precisely, fucosylated, neutral trisaccharide composed of L-fucose, D-galactose, and D-glucose units. It is the most prevalent human milk oligosaccharide (HMO) naturally present in human breast milk, making up about 30% of all of HMOs. It was first discovered in the 1950s in human milk. The oligosaccharide's primary isolation technique has been in use since 1972.

N-acetylhexosamine 1-kinase is an enzyme with systematic name ATP:N-acetyl-D-hexosamine 1-phosphotransferase. This enzyme catalyses the following chemical reaction

Lacto-N-biosidase (EC 3.2.1.140) is an enzyme with systematic name oligosaccharide lacto-N-biosylhydrolase. This enzyme catalyses the following chemical reaction

Microbiota-accessible carbohydrates (MACs) are carbohydrates that are resistant to digestion by a host's metabolism, and are made available for gut microbes, as prebiotics, to ferment or metabolize into beneficial compounds, such as short chain fatty acids. The term, ‘‘microbiota-accessible carbohydrate’’ contributes to a conceptual framework for investigating and discussing the amount of metabolic activity that a specific food or carbohydrate can contribute to a host's microbiota.

Human milk oligosaccharides (HMOs), also known as human milk glycans, are short polymers of simple sugars that can be found in high concentrations in human breast milk. Human milk oligosaccharides promote the development of the immune system, can reduce the pathogen infections and improve brain development and cognition. The HMO profile of human breast milk shapes the gut microbiota of the infant by selectively stimulating bifidobacteria and other bacteria.

<span class="mw-page-title-main">Human milk microbiome</span> Community of microorganisms in human milk

The human milk microbiota, also known as human milk probiotics (HMP), refers to the microbiota (community of microorganisms) residing in the human mammary glands and breast milk. Human breast milk has been traditionally assumed to be sterile, but more recently both microbial culture and culture-independent techniques have confirmed that human milk contains diverse communities of bacteria which are distinct from other microbial communities inhabiting the human body.

References

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