Trehalose: structure, biosynthesis, digestion, function, foods

Trehalose or α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside is a disaccharide made up of two α-D-glucose molecules in the pyranose form joined by an α-(1→1) glycosidic bond.
As with lactose, maltose and sucrose, two other disaccharides, its molecular formula is C12H22O11 and molecular weight is 342.30 g/mol. It has about half the sweetness is sucrose.
Since the α-(1→1) glycosidic bond occurs between the aldehyde function of two glucose units, that is, their anomeric carbons, in solution, it cannot exist in a open chain form with a free aldehyde group, that would be act as a reducing agent. Hence, trehalose is a non-reducing sugar, and has a low chemical reactivity. In nature, sucrose, the main product of photosynthesis, is the other widely distributed non-reducing sugar.
Trehalose was discovered in an ergot fungi, genus Claviceps, by Wiggers H.A.L. in 1832. Twenty-seven years after Wiggers work, in 1859, Berthelot M. isolated the disaccharide from Trehala manna, hence the name, a cocoon-shaped substance produced by larval activity of weevils of Curculionidae family on some Echinops species.
It is present in all major groups of organisms such as bacteria, fungi, yeasts, algae, plants and invertebrates, but it is absent in vertebrates.
It can perform many functions such as carbohydrate storage, energy source, component of membrane lipids, signaling molecule between plants and symbiont or pathogenic microorganisms, protection against abiotic stress and, in phosphorylated form, is involved in the regulation of carbohydrate metabolism in plants. Mammals are able to use exogenous trehalose as a source of carbon and energy.
Natural dietary sources are some species of fungi (Amanita spp.), especially if young, yeasts, crustaceans, and honey. Since FDA authorized its use as a food additive in 2000, it has been used as a flavor enhancer and preservative. As it occurs in small amounts in few unprocessed foods, processed foods such as frozen shrimp, fish in pouches, cereals and baked goods, has become the major source of the disaccharide.



Five pathways of biosynthesis have been identified in prokaryotes, of which only one, probably the most common, is also present in eukaryotes and is described below.
It consists of two steps. In the first step, catalyzed by trehalose 6-phosphate synthase (EC, the condensation of UDP-glucose and glucose 6-phosphate leads to the formation of trehalose 6-phosphate. Trehalose 6-phosphate is then dephosphorylated to trehalose in the hydrolysis reaction catalyzed by trehalose 6-phosphate phosphatase (EC

Biosynthesis of trehalose in eukaryotes, and hydrolysis by trehalase
Biosynthesis and Hydrolysis of Trehalose

Its biosynthesis is strongly induced following exposure to abiotic stresses. The importance of this disaccharide is evidenced by the fact that some organisms have more than one metabolic pathway for its biosynthesis.
No gene involved in trehalose biosynthesis nor storage is present in vertebrates, which do not seem to have lost the ability to produce the disaccharide during the evolutionary process, but rather it seems that they have never acquired such capacity.

Trehalose in plants

It was first detected in plants in 1913, in Selaginella lepidophylla, also known as resurrection fern  or false rose of Jericho, a desiccation-tolerant vascular plant. It was subsequently found also in green algae, mosses, and liverworts, non-vascular plants of the Marchantiophyta division, and ferns. Its presence in angiosperms was long believed to be due to microbial or bacterial contamination, or to an analytical artifact. Things began to change when, from the 1990s, large amounts of the disaccharide was found in desiccation-tolerant angiosperms, such as Myrothamnus flabellifolius and Sporobolus spp, amounts that could not be ascribed to microbial contamination. Despite this, trehalose and its metabolism was considered unimportant or even absent in most angiosperms until two observations led to a paradigm shift. In 1998, in Arabidopsis thaliana, a desiccation-intolerant plant belonging to the Brassicaceae family, which is used as a model for higher plants, genes were identified that encode catalytically active trehalose 6-phosphate synthase and trehalose 6-phosphate phosphatase. Furthermore, again in angiosperms, the importance of trehalose metabolism has also arisen from attempt to engineer its production with the introduction of fungal or bacterial enzymes: transgenic plants were obtained with a broad spectrum of phenotypic anomalies, such as delayed senescence and altered leaf shapes. These observations therefore suggested that in angiosperms:

  • the capacity to synthesize trehalose is not limited to resurrection plants;
  • a disturbance of its metabolism has far-reaching effects on metabolism and development.

Currently, genes encoding trehalose 6-phosphate synthase and trehalose 6-phosphate phosphatase have been identified in all major plant taxa, suggesting that the capacity to synthesize the disaccharide is universal in the plant kingdom.

Role of trehalose

Trehalose performs multiple functions in very different organisms. Some functions are shared by different organisms, whereas others are peculiar to specific organisms.

  • In plants, insects, nematodes and bacteria, it is involved in the adaptive response to abiotic stresses, such as extreme temperatures, changes in osmotic pressure and salinity, nutrient deprivation or desiccation from salt or drought. By accumulating in the cell, it helps to overcome stressful conditions by limiting damage to biological molecules. In plants, trehalose accumulation under stress conditions is related to transcriptional activation of the genes encoding biosynthesis enzymes or to inhibition of trehalase activity.
    Once stress condition is relieved, trehalose returns to normal levels.
  • It can act as a storage carbohydrate and carbon transport molecule.
    In some bacterial spores, it is accumulated up to about 25% of the spore dry weight.
    Some bacteria can use it as an exogenous carbon source.
    It is stored in fungi and yeasts during dormancy.
    It is the main sugar present in insect hemolymph, where it constitutes 80-90% of the carbohydrates, and is a rapidly available source of energy for flight.
  • It is a potential signaling metabolite in the interactions between plants and symbiotic and pathogenic microorganisms, as well as herbivorous insects. Moreover, some bacteria and fungi rely on its metabolism for infectivity.
  • It is a component of lipids found in cell wall of bacteria belonging to the genera Corynebacterium and Mycobacterium, where it plays a structural role. For example, M. tubercolosis cell wall contains glycolipids derived from trehalose, such as sulfolipids, and diacyl-, triacyl- and polyacyltrealoses, where fatty acids are linked to the hydroxyl groups of trehalose and not of glycerol.
  • It is believed to protect unsaturated fatty acids with cis double bonds from oxidative damage. It has also been proposed that it is able to prevent protein aggregation by interacting with cis double bonds present in the side chains of aromatic amino acids and by limiting the acetylation of the ε-amino group of side chain of lysine residues, which would increase protein hydrophobicity.
  • It plays a key role in the growth and development of insects, accounting for about 20% of the total carbohydrate pool in certain stages of their development.
  • Trehalose 6-phosphate, which is an intermediate in its biosynthesis, is essential for the embryonic and vegetative development of plants, as well as for the metabolism of sucrose and starch. It has been hypothesized that the main role of trehalose 6-phosphate is to signal and regulate, acting as a negative feedback regulator, sucrose levels.

Molecular mechanisms of protective potential

Trehalose it is involved in the response to abiotic stresses in different organisms.
It is believed that its protective potential is due to several mechanisms that act together, and are a consequence of its chemical properties, in particular that of being a non-reducing sugar.
Due to its low chemical reactivity, it does not readily interact with other molecules present in the cell, such as proteins, DNA or RNA.
Its high hydrophilicity allows it to form strong hydrogen bonds with water, bonds that are stronger than the water-water bonds; and, although other disaccharides can displace water, its hydration number is greater than that of the other disaccharides. Its low chemical reactivity and high hydrophilicity allow it to be compatible with cellular metabolism even at high concentrations.
The flexibility of the α-(1→1) glycosidic bond, greater than the flexibility of glycosidic bond of other disaccharides, allows trehalose to conform with the polar groups of the molecules easily.
The strong resistance of the α-(1→1) glycosidic bond to cleavage by glucosidases and acid hydrolysis is also important.
However, the key difference that sets trehalose apart from other disaccharides is its ability to form a sort of glassy structure around molecules. This structure would be stable even at high temperatures and in case of desiccation. What appears to be occurring is that trehalose, displacing water molecules normally linked by hydrogen bonds with biological molecules, such as proteins, would keep them properly folded in their native structure.

Intestinal digestion

In mammals, most of carbohydrate digestion takes place in the duodenum. Pancreatic alpha-amylase and hydrolases of the brush border of enterocytes hydrolyze disaccharides, oligosaccharides, and polysaccharides into the constituent monosaccharides, that is, glucose, fructose, and galactose. This is followed by absorption of the monosaccharides.
The α-(1→1) glycosidic bond of trehalose is cleaved in the hydrolysis reaction catalyzed by trehalase (EC Two molecules of D-glucose are released for each hydrolytic cleavage.
There are two genes in the human genome that encode for trehalase isoforms. Mutations in the genes coding for trehalase lead to the biosynthesis of mutant proteins with little or no function. As a result, undigested trehalose can cause osmotic diarrhea and, once in the colon, interact with bacteria of the gut microbiota, which is part of the larger human microbiota. Bacteria produce gas, fatty acids and alcohol which cause the other signs and symptoms of trehalose intolerance such as osmotic-fermentative diarrhea, malabsorption, and other abdominal symptoms.
Since there is no cure for trehalase deficiency currently, the only treatment is to avoid or reduce the consumption of foods that contain trehalose.
Trehalase deficiency is quite rare, although it is more frequent in Greenland affecting about eight percent of the population.

Note: osmotic diarrhea is caused by the accumulation in the lumen of the distal portion of the small intestine and colon of osmotically active but non-absorbable solutes. This occurs, for example, as a result of the deficiency of one or more disaccharidases of the brush border membrane, which leads to an accumulation of disaccharides in the intestinal lumen and an increase in osmotic pressure. In turn, this causes water to rush into the lumen leading to an excessive loss of fluids and electrolytes with the stool.


  1. Anselmino O. and Gilg E. Uber das Vorkommen von Trehalose in Selaginella lepidophylla. Ber Deut Pharm Ges 1913;23:326-330
  2. Argüelles J.C. Why can’t vertebrates synthesize trehalose? J Mol Evol 2014;79:111-116. doi:10.1007/s00239-014-9645-9
  3. Blazquez M., Santos E., Flores C., Martinez-Zapater J., Salinas J., Gancedo C. Isolation and molecular characterization of the Arabidopsis TPS1 gene, encoding trehalose-6-phosphate synthase. Plant J 1998;13(5):685-9. doi:10.1046/j.1365-313x.1998.00063.x
  4. Figueroa C.M., Lunn J.E. A tale of two sugars: trehalose 6-phosphate and sucrose. Plant Physiol 2016;172(1):7-27. doi:10.1104/pp.16.00417
  5. Lee H.J., Yoon Y.S., Lee S.J. Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction. Cell Death Dis 2018;9(7):712. doi:10.1038/s41419-018-0749-9
  6. Lunn J.E., Delorge I., Figueroa C.M., Van Dijck P., Stitt M. Trehalose metabolism in plants. Plant J 2014;79(4):544-67. doi:10.1111/tpj.12509
  7. Palva E.T., Li P.H. Plant cold hardiness. Gene regulation and genetic engineering. Springer US, 2012
  8. Vanaporn M. & Titball R.W. Trehalose and bacterial virulence. Virulence 2020;11(1):1192-1202. doi:10.1080/21505594.2020.1809326
  9. Schluepmann H., Pellny T., van Dijken A., Smeekens S. and Paul M. Trehalose 6-phosphate is indispensable for carbohydrate utilization and growth in Arabidopsis thaliana. Proc Natl Acad Sci 2003;100(11):6849-6854. doi:10.1073/pnas.1132018100
  10. Vogel G., Aeschbacher R.A., Muller J., Boller T., Wiemken A. Trehalose-6-phosphate phosphatases from Arabidopsis thaliana: identification by functional complementation of the yeast tps2 mutant. Plant J 1998;13:673-683. doi:10.1046/j.1365-313X.1998.00064.x

Biochemistry, metabolism and nutrition