Trehalose
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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 Glucose is a sugar with the Chemical formula#Molecular formula, molecul ...
consisting of two molecules of
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
. 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. Trehalose has high water retention capabilities, and is used in food, cosmetics and as a drug.


Structure

Trehalose is 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, ...
formed by a bond between two α-
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
units. It is found in nature as a disaccharide and also as a monomer in some polymers. Two other stereoisomers exist: α,β-trehalose, also called ''neotrehalose'', and β,β-trehalose, also called ''isotrehalose''. Neither of these alternate isomers has been isolated from living organisms, but isotrehalose has been was found in starch hydroisolates.


Synthesis

At least three biological pathways support trehalose
biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
. An industrial process can derive trehalose from
corn starch Cornflour, cornstarch, maize starch, or corn starch (American English) is the starch derived from corn (maize) grain. The starch is obtained from the endosperm of the seed, kernel. Corn starch is a common food ingredient, often used to thick ...
.


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 or
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
end groups do not bind to the lysine or
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
residues of proteins (a process called
glycation Glycation (non-enzymatic glycosylation) is the covalent bond, covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is th ...
). 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. Anhydrous 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 (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
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 the eukaryotes that form the kingdom Plantae; they are predominantly photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with cyanobacteria to produce sugars f ...
, and
microorganisms A microorganism, or microbe, is an organism of microscopic size, which may exist in its single-celled form or as a colony of cells. The possible existence of unseen microbial life was suspected from antiquity, with an early attestation in ...
. In animals, trehalose is prevalent in shrimp, and also in
insects Insects (from Latin ') are 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 jointed ...
, including grasshoppers, locusts, butterflies, and bees, in which trehalose serves as blood-sugar. Trehalase
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s are found in tardigrades, the microscopic ecdysozoans 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 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 diet ...
, for which cleavage of one glycosidic linkage releases only one glucose molecule. The concentrations of both trehalose and glucose in the insect hemolymph are tightly controlled by multiple enzymes and hormones, including trehalase,
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
-like peptides (ILPs and DILPs), adipokinetic hormone (AKH), leucokinin (LK), octopamine and other mediators, thereby maintaining carbohydrate
homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
by endocrine and metabolic
feedback Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause and effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handle ...
mechanisms. In plants, trehalose is seen in sunflower seeds, moonwort, '' Selaginella'' plants, and sea algae. Within the fungi, it is prevalent in some mushrooms, such as
shiitake The shiitake (; ''Chinese/black mushroom'' or ''Lentinula edodes'') is a macrofungus native to East Asia, which is cultivated and consumed around the globe. Taxonomy The fungus was first described scientifically as '' Agaricus edodes'' by ...
(''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 no ...
, king oyster, and golden needle. Even within the plant kingdom, '' Selaginella'' (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 (, via French ') is the full or partial transformation of a substance into a glass, that is to say, a non- crystalline or amorphous solid. Glasses differ from liquids structurally and glasses possess a higher degree of connectivity ...
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 a carbon source in response to abiotic stresses. In humans, trehalose is thought to act as a neuroprotective by inducing
autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
and thereby clearing protein aggregates. 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 An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
trehalase, which is present in the brush border of the intestinal mucosa of omnivores (including humans) and herbivores. It causes less of a spike in
blood sugar The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly regulates blood glucose levels as a part of metabolic homeostasis. For a 70 kg (1 ...
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. Deficiency of trehalase
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
is unusual in humans, except in the Greenlandic Inuit, where it is present in only 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, in an artificial tears product used to treat dry eye. Outbreaks of '' Clostridioides difficile'' were initially associated with trehalose, but this finding was disputed in 2019. In 2021, the FDA accepted an Investigational New Drug (IND) application and granted fast track status for an injectable form of trehalose (SLS-005) as a potential treatment for spinocerebellar ataxia type 3 (SCA3).


History

In 1832, H.A.L. Wiggers discovered trehalose in an ergot of rye, and in 1859 Marcellin Berthelot isolated it from ''Trehala manna'', a substance made by weevils and named it trehalose. Trehalose has long been known as an
autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
inducer that acts independently of mTOR. In 2017, research was published showing that trehalose induces autophagy by activating TFEB, a protein that acts as a master regulator of the autophagy-
lysosome A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
pathway.


See also

* Biostasis * Cryoprotectant * Cryptobiosis * Freeze drying * Lentztrehalose * Trehalosamine * IMCTA-C14


References


External links

*
Trehalose in sperm preservation
{{Carbohydrates Carbohydrates Disaccharides Types of sugar Orphan drugs