Lactose: chemical structure, functions, digestion, and intolerance

Lactose, or milk sugar, is a reducing disaccharide composed of one β-D-galactose molecule and one α-D-glucose molecule joined by a β-(1→4) glycosidic bond.[1]

It is synthesized in the mammary gland by the lactose synthase complex (EC 2.4.1.22).[2][3]

In the adult diet, it accounts for 5–10% of total dietary carbohydrates and, together with starch and sucrose, is one of the three most common, being widely present in milk and milk-derived products.[4][5]

In the small intestine, lactose is hydrolyzed into glucose and galactose in a reaction catalyzed by lactase (EC 3.2.1.108).[6]

Lactose provides about 40% of the energy consumed by breastfed infants, and serves as a source of galactose used in the biosynthesis of glycosylated macromolecules required for the proper development of the central nervous system.[7]
It is used as an additive in the food and pharmaceutical industries.[8][9]

Insufficient lactase activity leads to hypolactasia and lactose malabsorption, which can trigger symptoms of lactose intolerance.[10]

Summary: Key Points

  • Chemical properties: a reducing disaccharide composed of one β-D-galactose and one α-D-glucose unit in pyranose form joined by a β-(1→4) glycosidic bond, with a sweetness of about 16% relative to sucrose.
  • Biosynthesis and digestion: synthesized in the mammary gland by the lactose synthase system and hydrolyzed in the small intestine into glucose and galactose by lactase.
  • Sources: naturally present in human and animal milk, its concentration varies inversely with dairy ripening.
  • Biological functions: serves as the primary energy source for breastfed infants, provides galactose for central nervous system neurodevelopment, and acts as the major osmotic regulator of milk volume.
  • Clinical significance: hypolactasia leads to lactose malabsorption, which can manifest as osmotic-fermentative diarrhea, bloating, and abdominal pain or present as rare congenital lactase deficiency.

Contents

Chemical properties

As with the disaccharides sucrose, maltose and trehalose, its molecular formula is C12H22O11 and its molecular weight is 342.30 g/mol.
According to IUPAC nomenclature, its systematic name is β-D-galactopyranosyl-(1→4)-α-D-glucopyranose.[1]

The glycosidic bond between galactose and glucose, in pyranose form, has a β configuration, that is, the bond from the anomeric carbon of galactose is directed upwards. The β-(1→4) glycosidic bond is also present in chitin and cellulose.[9]

Haworth projection of lactose: α and β anomers and interconversion via the open-chain form of the glucose residue with exposed aldehyde group.
Anomers of Lactose

Like monosaccharides, and maltose among disaccharides, it is a reducing sugar, since the β-(1→4) glycosidic bond does not affect the hemiacetal (anomeric) carbon of the glucose molecule; therefore, in solution the glucose ring can open and expose an aldehyde group.[11]

It is less soluble than other disaccharides, and is about 16% as sweet as sucrose.

Anomers and mutarotation

The open-chain or acyclic form of glucose is thermodynamically unstable, and, in solution, it is present only in trace amounts, less than 0.02%. The ring-closing reaction yields two cyclic pyranose configurations that differ in the spatial orientation of the hemiacetal carbon, known as the α-anomer and β-anomer. In solution, these forms continuously interconvert until an equilibrium is reached, a phenomenon known as mutarotation.

At 20 °C, the β configuration is the predominant anomeric form, about 63%, although the equilibrium ratio changes as a function of temperature, with only the β anomer present at temperatures >93.5 °C.[12]

Anomerism is a type of optical isomerism characteristic of carbohydrates, in which cyclic monosaccharides differ only in the configuration of the hemiacetal or hemiketal carbon, known as the anomeric center.

Biosynthesis

Lactose is synthesized by epithelial cells of the mammary gland during lactation, in a reaction catalyzed by the lactose synthase system (EC 2.4.1.22), a heterodimer present in the Golgi apparatus and composed of β-1,4-galactosyltransferase 1 (EC 2.4.1.38), an intrinsic protein of the Golgi apparatus membrane, and α-lactalbumin, in a 1:1 ratio.[3] This protein-protein interaction is reversible and is promoted by monosaccharides and UDP-galactose.[13]

Lactose synthase

Lactose synthase catalyzes a condensation reaction between UDP-galactose and glucose, that is, the transfer of galactose to glucose to form a β-(1→4) glycosidic bond between the C1 of galactose and the oxygen atom of the 4-hydroxyl group of glucose.
Glucose is the primary precursor of monosaccharides that make up lactose, accounting for all of the glucose and about 70% of the galactose.[2]

The formation of the complex between β-1,4-galactosyltransferase 1 and α-lactalbumin occurs in the lumen of the Golgi apparatus. α-Lactalbumin, a secretory protein, is present during its passage through the cell as a soluble and transient component in the lumen of the Golgi apparatus, where it binds reversibly to β-1,4-galactosyltransferase 1 The transient nature of the interaction between α-lactalbumin and the galactosyltransferase ensures a linkage between milk protein synthesis and lactose synthesis during lactation.[13]

Lactose cannot cross the membrane of the Golgi apparatus, and, along with α-lactalbumin, is packaged into secretory vacuoles, whose contents are released from the cell by exocytosis.[14]

α-Lactalbumin

α-Lactalbumin is one of the main whey proteins and is catalytically inactive.

The synthesis of lactose requires the presence of α-lactalbumin, whose gene transcription is regulated by prolactin, also called luteotropin or luteotropic hormone. After childbirth, reduced progesterone levels stimulate an increase in prolactin synthesis, which stimulates the synthesis of α-lactalbumin in the epithelial cells of the mammary gland, and consequently the formation of the lactose synthase system.

Conversely, in non-lactating mammary glands, α-lactalbumin is not produced, the lactose synthase system is not formed and lactose is not synthesized.[15]

β-1,4-Galactosyltransferase 1

In mammals, β-1,4-galactosyltransferase 1 is part of a group of seven galactosyltransferases which catalyze the formation of β-(1→4) glycosidic bonds between galactose and different acceptors.[13]

It is expressed in most tissues where it catalyzes the addition of galactose to the 4-hydroxyl group of a non-reducing terminal N-acetyl-β-D-glucosamine residue of glycoproteins and glycolipids.[15]

β-1,4-Galactosyltransferase 1 has a low affinity for glucose, with a Km of about 2 mol/L.[14] During pregnancy, the enzyme is produced and stored in the epithelial cells of the mammary gland. The bond with α-lactalbumin triggers conformational changes in the active site region that increase its affinity for glucose by about 1,000 times and therefore decrease the Km for the monosaccharide to about 2 mmol/L. This allows, at physiological glucose concentrations, the preferential and efficient synthesis of lactose rather than the galactosylation of other acceptors.[13]

Food sources

Lactose is present in the milk of almost all mammalian species, although in different amounts. For example, it accounts for approximately 7.5% and 4.5% of human and cow milk composition, respectively.[16] Its concentration during lactation, on the other hand, remains relatively stable.[17]

In dairy products, lactose is present in variable amounts, inversely related to the degree of ripening. Products such as yogurt or ricotta have the largest amounts, whereas hard cheeses have the lowest amounts, often close to zero.[5]

It is present in very high amounts in products such as powdered milk and powdered whey.[8]

The lactose content in various milk species, dairy products, and foods (per 100 g)
Food source Lactose content (g)
Human milk 7.5
Whole cow’s milk 4.8
Semi-skimmed cow’s milk 4.9
Skimmed cow’s milk 4.9
Powdered milk 35.1
Skimmed milk powder 50.5
Whey powder 58–62
Buffalo milk 4.9
Goat milk 4.2
Yogurt 3.0–4.0
Cow’s milk ricotta 4.0
Fresh cheeses (e.g., mozzarella) 1.0–3.0
Emmental and semi-hard cheeses 0.1
Parmigiano Reggiano, Grana Padano, and hard cheeses ≈ 0

It is present in many processed foods such as candies, chocolate, breakfast cereals, baked goods, and cured meats, in which it is used as a food additive.[5]

It is also used in the pharmaceutical industry, in concentrations on the order of milligrams, in the production of tablets and inhalers.[8]

Evolutionary exceptions among mammals

It is absent in the milk of a few species of mammals, like several species of the Otariidae family, such as the Cape fur seal (Arctocephalus pusillus pusillus) or the California sea lion (Zalophus californianus), or of the Phocidae family, such as the hooded seal (Cystophora cristata). In the Cape fur seal, the ability to produce lactose was lost due to mutations in the α-lactalbumin gene causing the absence of the protein.[18]

Lactose digestion

In humans, and in mammals in general, carbohydrate digestion occurs mainly in the duodenum and jejunum. Pancreatic α-amylase and the disaccharidases of the brush border of enterocytes hydrolyze polysaccharides, oligosaccharides and disaccharides into the constituent monosaccharides, namely, glucose, galactose and fructose. In the last step, absorption of monosaccharides occurs.[6]

The β-(1→4) glycosidic bond of lactose is hydrolyzed by lactase or lactase-phlorizin hydrolase. Under physiological conditions, lactase is present at birth as it is crucial for the digestion of lactose.[19] The enzyme has two active sites:

  • one with β-glucosidase activity, capable of hydrolyzing the β-(1→4) glycosidic bond;
  • the other with phlorizin-hydrolase (or β-glucosidase) activity, capable of hydrolyzing phlorizin and glycosylceramides (glycolipids).

Lactase activity is abundantly present in the mid-jejunum, and, among the hydrolases of the brush border of enterocytes, it is the only one capable of hydrolyzing the β-(1→4) glycosidic bond of lactose.[20]

Among disaccharidases, it is the last to appear during fetal life, about 8 weeks after conception. At 34 weeks’ gestation lactase activity is about one-third of that detected in full-term newborns, and reaches three quarters of that of full-term newborns between 35 and 38 weeks of gestation. In nearly all full-term newborns, lactase synthesis and activity are high and remain so throughout the first 4 years of life.[21]

Among the hydrolases of the brush border, lactase is often the first to be lost during intestinal diseases because it is expressed late in enterocyte differentiation, in cells near the tip of the villus, and protrudes significantly into the intestinal lumen.[21]

Functions

Lactose acts as an energy source, providing about 40% of the energy infants receive from breast milk.[22] The released glucose can directly enter glycolysis to produce ATP or be used for fatty acid and triglyceride synthesis, depending on cellular needs.

In the liver, galactose enters the Leloir pathway and is converted into glucose 1-phosphate for glycogen synthesis.[7] Although glucose 1-phosphate can theoretically enter glycolysis after conversion to glucose 6-phosphate, only a small percentage typically follows this route.

During infancy and early childhood, galactose is required to synthesize glycosylated macromolecules, such as mucoproteins, cerebrosides, and gangliosides, which form key components of the myelin sheaths in nerve cells. Once myelination and neural development are complete, galactose requirements decrease significantly; this reduced demand may explain the genetically programmed decline in lactase activity observed in many adult populations.[7]

Additionally, several erythrocyte membrane antigens, notably within the ABO blood group system, contain galactose residues.

Lactose is the primary osmotic component in milk. Because it cannot cross the membrane of the Golgi apparatus, it acts as an osmolyte, drawing water into the organelles and mammary epithelial cells, thereby determining total milk volume.[13]
Moreover, joining two monosaccharides into a single lactose molecule reduces the osmotic pressure of milk, maintaining it isotonic with maternal plasma.[9]

It plays a role in intestinal absorption of minerals, especially during early life. Glucose and galactose are primarily absorbed via SGLT1, a cotransporter that couples monosaccharide uptake with sodium transport, indirectly driving water and mineral absorption.[23]

In dairy processing, milk acidification results from the bacterial fermentation of lactose into lactic acid.

Finally, when undigested lactose reaches the colon, it can be metabolized by the gut microbiota, functioning as a prebiotic substrate.[4]

Hypolactasia and lactose intolerance

Hypolactasia, or lactase deficiency, is the primary cause of disaccharide malabsorption in the small intestine. When undigested lactose reaches the colon, the resident gut microbiota subjects it to anaerobic fermentation, producing gases such as hydrogen, carbon dioxide, and methane, along with short-chain fatty acids. This process, combined with the osmotic retention of water within the intestinal lumen, triggers the classic clinical symptoms of lactose intolerance, including abdominal pain, bloating, flatulence, and diarrhea.[4][10]

Etiologically, three main forms of enzyme deficiency are recognized. Primary hypolactasia in adults is the most prevalent condition, resulting from a genetically programmed decline in lactase expression following weaning. Secondary hypolactasia is a transient state caused by intestinal mucosal damage from infections, celiac disease, or inflammatory disorders. Lastly, congenital lactose intolerance is an extremely rare autosomal recessive metabolic error characterized by a complete absence of lactase activity from birth.[10]

Crucially, lactose malabsorption does not always manifest clinically, with symptoms occurring in only 30–50% of hypolactasic individuals. The onset of intolerance is modulated by various physiological parameters, including the total amount of lactose ingested, gastric emptying rate, intestinal transit time, and individual colonic microbiota composition.[5][10]

References

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  4. ^ a b c Misselwitz B., Butter M., Verbeke K., Fox M.R. Update on lactose malabsorption and intolerance: pathogenesis, diagnosis and clinical management. Gut 2019;68(11):2080-2091. doi:10.1136/gutjnl-2019-318404
  5. ^ a b c d Di Stefano M. Il malassorbimento e l’intolleranza al lattosio. Fisiopatologia, diagnosi e approccio terapeutico. SIMG 2012;5:40-45.
  6. ^ a b Rosenthal M.D., Glew R.H. Medical biochemistry: human metabolism in health and disease. A John Wiley & sons, Inc., Publication, 2009.
  7. ^ a b c Conte F., van Buuringen N., Voermans N.C., Lefeber D.J. Galactose in human metabolism, glycosylation and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865(8):129898. doi:10.1016/j.bbagen.2021.129898
  8. ^ a b c Portnoy M., Barbano D.M. Lactose: use, measurement, and expression of results. J Dairy Sci 2021;104(7):8314-8325. doi:10.3168/jds.2020-18706
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  11. ^ Nelson D.L., Cox M.M. Lehninger. Principles of biochemistry. 8th Edition. W.H. Freeman and Company, 2021.
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  13. ^ a b c d e Zhang Y., Brew K. Milk proteins | Alpha-Lactalbumin. Editor(s): Roginski H. Encyclopedia of dairy sciences. Elsevier, 2002;1924-1932. doi:10.1016/B0-12-227235-8/00319-9
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  19. ^ Zecca L., Mesonero J.E., Stutz A., Poirée J.C., Giudicelli J., Cursio R., Gloor S.M., Semenza G. Intestinal lactase-phlorizin hydrolase (LPH): the two catalytic sites; the role of the pancreas in pro-LPH maturation. FEBS Lett 1998;435(2-3):225-8. doi:10.1016/s0014-5793(98)01076-x
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Domande Frequenti

What is lactose molecule from a chemical perspective?

Lactose is a reducing disaccharide composed of β-D-galactose and α-D-glucose linked by a β-1,4-glycosidic bond. Having formula C12H22O11, it is water-soluble and undergoes mutarotation between its α and β anomeric forms.

Which cheeses contain trace or minimal amounts of lactose?

Long-aged hard cheeses like Parmigiano Reggiano and Grana Padano contain virtually no lactose. Lactic acid bacteria fermentation and whey separation remove almost all lactose content during the traditional cheesemaking process.

How is lactose digested in the human digestive system?

Lactose is hydrolyzed in the small intestine by the lactase enzyme (lactase-phlorizin hydrolase), located on the brush border of enterocytes. The enzyme splits the disaccharide into glucose and galactose for systemic blood absorption.

Biochemistry and Metabolism