Trehalose (from Turkish '' tıgala'' – a sugar derived from insect cocoons + -ose) is a

sugar Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or double ...

consisting of two molecules of

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

. It is also known as mycose or tremalose. Some bacteria, fungi, plants and invertebrate animals synthesize it as a source of energy, and to survive freezing and lack of water. Extracting trehalose was once a difficult and costly process, but around 2000, the Hayashibara company ( Okayama, Japan) discovered an inexpensive extraction technology from starch. Trehalose has high water retention capabilities, and is used in food, cosmetics and as a drug. A procedure developed in 2017 using trehalose allows sperm storage at room temperatures.

Structure

Trehalose is a disaccharide formed by a bond between two α-glucose units. It is found in nature as a

disaccharide A disaccharide (also called a double sugar or ''biose'') 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, lact ...

and also as a monomer in some polymers. Two other isomers exist, α,β-trehalose, otherwise known as neotrehalose, and β,β-trehalose (also referred to as isotrehalose). Neotrehalose has not been isolated from a living organism. Isotrehalose is also yet to be isolated from a living organism, but was found in starch hydroisolates.

Synthesis

At least three biological pathways support trehalose

biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...

. An industrial process can derive trehalose from

corn starch Corn starch, maize starch, or cornflour (British English) is the starch derived from corn (maize) grain. The starch is obtained from the endosperm of the kernel. Corn starch is a common food ingredient, often used to thicken sauces or sou ...

Properties

Chemical

Trehalose is a nonreducing sugar formed from two glucose units joined by a 1–1 alpha bond, giving it the name The bonding makes trehalose very resistant to acid

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

, and therefore is stable in solution at high temperatures, even under acidic conditions. The bonding keeps nonreducing sugars in closed-ring form, such that the

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

end groups do not bind to the

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

residues of proteins (a process called

glycation Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic proces ...

). Trehalose is less soluble than

sucrose Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula . For human consumption, sucrose is extracted and refined ...

, except at high temperatures (>80 °C). Trehalose forms a rhomboid crystal as the dihydrate, and has 90% of the calorific content of sucrose in that form. Anhydrous forms of trehalose readily regain moisture to form the

dihydrate In chemistry, a hydrate is a substance that contains water or its constituent elements. The chemical state of the water varies widely between different classes of hydrates, some of which were so labeled before their chemical structure was understo ...

Anhydrous A substance is anhydrous if it contains no water. Many processes in chemistry can be impeded by the presence of water; therefore, it is important that water-free reagents and techniques are used. In practice, however, it is very difficult to achie ...

forms of trehalose can show interesting physical properties when heat-treated. Trehalose aqueous solutions show a concentration-dependent clustering tendency. Owing to their ability to form

hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

s, they self-associate in water to form clusters of various sizes. All-atom molecular dynamics simulations showed that concentrations of 1.5–2.2 molar allow trehalose molecular clusters to percolate and form large and continuous aggregates. Trehalose directly interacts with nucleic acids, facilitates melting of double stranded DNA and stabilizes single-stranded nucleic acids.

Biological

Organisms ranging from bacteria, yeast, fungi, insects, invertebrates, and lower and higher plants have enzymes that can make trehalose. In nature, trehalose can be found in

plants Plants are predominantly Photosynthesis, photosynthetic eukaryotes of the Kingdom (biology), kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all curr ...

, and

microorganisms A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

. In animals, trehalose is prevalent in shrimp, and also in

insects Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (head, thorax and abdomen), three pairs of j ...

, including grasshoppers, locusts, butterflies, and bees, in which trehalose serves as blood-sugar.

Trehalase The enzyme Trehalase is a glycoside hydrolase, produced by cells in the brush border of the small intestine, which catalyzes the conversion of trehalose to glucose. It is found in most animals. The non-reducing disaccharide trehalose (α-D-glucop ...

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

s are found in

tardigrade Tardigrades (), known colloquially as water bears or moss piglets, are a phylum of eight-legged segmented micro-animals. They were first described by the German zoologist Johann August Ephraim Goeze in 1773, who called them Kleiner Wasserbär ...

s, the microscopic

ecdysozoan Ecdysozoa () is a group of protostome animals, including Arthropoda (insects, chelicerata, crustaceans, and myriapods), Nematoda, and several smaller phyla. They were first defined by Aguinaldo ''et al.'' in 1997, based mainly on phylogenetic t ...

s found worldwide in diverse extreme environments. Trehalose is the major carbohydrate energy storage molecule used by insects for flight. One possible reason for this is that the

glycosidic linkage A glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate. A glycosidic bond is formed between the hemiacetal or hemiketal group ...

of trehalose, when acted upon by an insect trehalase, releases two molecules of glucose, which is required for the rapid energy requirements of flight. This is double the efficiency of glucose release from the storage polymer

starch Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diets ...

, for which cleavage of one glycosidic linkage releases only one glucose molecule. In plants, trehalose is seen in sunflower seeds,

moonwort ''Botrychium'' is a genus of ferns, seedless vascular plants in the family Ophioglossaceae. ''Botrychium'' species are known as moonworts. They are small, with fleshy roots, and reproduce by spores shed into the air. One part of the leaf, the ...

, ''

Selaginella ''Selaginella'' is the sole genus of vascular plants in the family Selaginellaceae, the spikemosses or lesser clubmosses. This family is distinguished from Lycopodiaceae (the clubmosses) by having scale-leaves bearing a ligule and by having ...

'' plants, and sea algae. Within the fungi, it is prevalent in some mushrooms, such as

shiitake The shiitake (alternate form shitake) (; ''Lentinula edodes'') is an edible mushroom native to East Asia, which is now cultivated and consumed around the globe. It is considered a Medicinal fungi, medicinal mushroom in some forms of tradition ...

(''Lentinula edodes''),

oyster Oyster is the common name for a number of different families of salt-water bivalve molluscs that live in marine or brackish habitats. In some species, the valves are highly calcified, and many are somewhat irregular in shape. Many, but not al ...

, king oyster, and golden needle. Even within the plant kingdom, ''

'' (sometimes called the resurrection plant), which grows in desert and mountainous areas, may be cracked and dried out, but will turn green again and revive after rain because of the function of trehalose. The two prevalent theories as to how trehalose works within the organism in the state of cryptobiosis are the

vitrification Vitrification (from Latin ''vitreum'', "glass" via French ''vitrifier'') is the full or partial transformation of a substance into a glass, that is to say, a non-crystalline amorphous solid. Glasses differ from liquids structurally and glasses po ...

theory, a state that prevents ice formation, or the water displacement theory, whereby water is replaced by trehalose. In bacterial cell wall, trehalose has a structural role in adaptive responses to stress such as osmotic differences and extreme temperature. Yeast uses trehalose as carbon sources in response to abiotic stresses. In humans, the only known function of trehalose is its ability to activate autophagy inducer. Trehalose has also been reported for anti-bacterial, anti-biofilm, and anti-inflammatory (''in vitro'' and ''in vivo'') activities, upon its esterification with fatty acids of varying chain lengths.

Nutritional and dietary properties

Trehalose is rapidly broken down into glucose by the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

trehalase The enzyme Trehalase is a glycoside hydrolase, produced by cells in the brush border of the small intestine, which catalyzes the conversion of trehalose to glucose. It is found in most animals. The non-reducing disaccharide trehalose (α-D-glucop ...

, which is present in the

brush border A brush border (striated border or brush border membrane) is the microvilli-covered surface of simple cuboidal and simple columnar epithelium found in different parts of the body. Microvilli are approximately 100 nanometers in diameter and the ...

of the

intestinal mucosa The gastrointestinal wall of the gastrointestinal tract is made up of four layers of specialised tissue. From the inner cavity of the gut (the lumen) outwards, these are: # Mucosa # Submucosa # Muscular layer # Serosa or adventitia The mucosa is ...

of omnivores (including humans) and herbivores. It causes less of a spike in

blood sugar Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...

than glucose. Trehalose has about 45% the sweetness of sucrose at concentrations above 22%, but when the concentration is reduced, its sweetness decreases more quickly than that of sucrose, so that a 2.3% solution tastes 6.5 times less sweet as the equivalent sugar solution. It is commonly used in prepared frozen foods, like ice cream, because it lowers the freezing point of foods. The

Cargill Cargill, Incorporated, is a privately held American global food corporation based in Minnetonka, Minnesota, and incorporated in Wilmington, Delaware. Founded in 1865, it is the largest privately held corporation in the United States in ter ...

corporation promotes the use of its brand of trehalose, "Treha", as a substance that "enhances and intensifies certain flavors to bring out the best in your products." Deficiency of trehalase

is unusual in humans, except in the

Greenlandic Inuit Greenlanders ( kl, Kalaallit / Tunumiit / Inughuit; da, Grønlændere) are people identified with Greenland or the indigenous people, the Greenlandic Inuit (''Grønlansk Inuit''; Kalaallit, Inughuit, and Tunumiit). This connection may be r ...

, where it occurs in 10–15% of the population.

Metabolism

Five biosynthesis pathways have been reported for trehalose. The most common pathway is TPS/TPP pathway which is used by organisms that synthesize trehalose using the enzyme trehalose-6-phosphate (T6P) synthase (TPS). Second, trehalose synthase (TS) in certain types of bacteria could produce trehalose by using maltose and another disaccharide with two glucose units as substrates. Third, the TreY-TreZ pathway in some bacteria converts starch that contain maltooligosaccharide or glycogen directly into trehalose. Fourth, in primitive bacteria, trehalose glycisyltransferring synthase (TreT) produces trehalose from ADP-glucose and glucose. Fifth, trehalose phosphorylase (TreP) either hydrolyses trehalose into glucose-1-phosphate and glucose or may act reversibly in certain species. Vertebrates do not have the ability to synthesize or store trehalose. Trehalase in humans is found only in specific location such as the intestinal mucosa, renal brush-border, liver and blood. Expression of this enzyme in vertebrates is initially found during the gestation period that is the highest after weaning. Then, the level of trehalase remained constant in the intestine throughout life. Meanwhile, diets consisting of plants and fungi contain trehalose. Moderate amount of trehalose in diet is essential and having low amount of trehalose could result in diarrhea, or other intestinal symptoms.

Medical use

Trehalose is an ingredient, along with

hyaluronic acid Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans ...

, in an

artificial tears Artificial tears are lubricating eye drops used to relieve dryness and irritation of the ocular surface. Dry eye syndrome ( keratoconjunctivitis sicca) is a common ocular surface disorder and is characterized by disruption of the tear film and i ...

product used to treat

dry eye Dry or dryness most often refers to: * Lack of rainfall, which may refer to **Arid regions **Drought * Dry or dry area, relating to legal prohibition of selling, serving, or imbibing alcoholic beverages * Dry humor, deadpan * Dryness (medical) * ...

. Outbreaks of '' Clostridium difficile'' were initially associated with trehalose, although this finding was disputed in 2019.

History

In 1832, H.A.L. Wiggers discovered trehalose in an

ergot Ergot ( ) or ergot fungi refers to a group of fungi of the genus ''Claviceps''. The most prominent member of this group is ''Claviceps purpurea'' ("rye ergot fungus"). This fungus grows on rye and related plants, and produces alkaloids that ca ...

of rye, and in 1859

Marcellin Berthelot Pierre Eugène Marcellin Berthelot (; 25 October 1827 – 18 March 1907) was a French chemist and Republican politician noted for the ThomsenBerthelot principle of thermochemistry. He synthesized many organic compounds from inorganic substance ...

isolated it from ''Trehala manna'', a substance made by

weevil Weevils are beetles belonging to the Taxonomic rank, superfamily Curculionoidea, known for their elongated snouts. They are usually small, less than in length, and Herbivore, herbivorous. Approximately 97,000 species of weevils are known. They b ...

s and named it trehalose. Trehalose has long been known as an

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

inducer that acts independently of

mTOR The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MT ...

. In 2017 research was published showing that trehalose induces autophagy by activating

TFEB Transcription factor EB is a protein that in humans is encoded by the ''TFEB'' gene. Function TFEB is a master gene for lysosomal biogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane prote ...

, a protein that acts as a master regulator of the autophagy-

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...

pathway.

References

External links

*
Trehalose in sperm preservation
{{Carbohydrates Carbohydrates Disaccharides Sugar substitutes Orphan drugs