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Trehalose
Trehalose
Trehalose
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Trehalose
Names
IUPAC name
α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside
Systematic IUPAC name
(2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-[(2R,3R,4S,5S,6R)-3,4, 5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-3,4,5-triol
Other names
α,α‐Trehalose, mycose, tremalose
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.002.490 Edit this at Wikidata
UNII
  • InChI=1S/C12H22O11/c13-1-3-5(15)7(17)9(19)11(21-3)23-12-10(20)8(18)6(16)4(2-14)22-12/h3-20H,1-2H2/t3-,4-,5-,6-,7+,8+,9-,10-,11-,12-/m1/s1 checkY
    Key: HDTRYLNUVZCQOY-LIZSDCNHSA-N checkY
  • InChI=1/C12H22O11/c13-1-3-5(15)7(17)9(19)11(21-3)23-12-10(20)8(18)6(16)4(2-14)22-12/h3-20H,1-2H2/t3-,4-,5-,6-,7+,8+,9-,10-,11-,12-/m1/s1
    Key: HDTRYLNUVZCQOY-LIZSDCNHBN
  • OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O1)O[C@@H]2[C@H](O)[C@@H](O)[C@H](O)[C@H](O2)CO
Properties
C12H22O11 (anhydride)
Molar mass 342.296 g/mol (anhydrous)
378.33 g/mol (dihydrate)
Appearance White orthorhombic crystals
Density 1.58 g/cm3 at 24 °C
Melting point 203 °C (397 °F; 476 K) (anhydrous)
97 °C (dihydrate)
68.9 g per 100 g at 20 °C[1]
Solubility Slightly soluble in ethanol, insoluble in diethyl ether and benzene[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Trehalose is a sugar derived from two molecules of glucose. Trehalose is a disaccharide formed by a 1,1-glycosidic bond between two α-glucose units. It is found in nature as a disaccharide and also as a monomer in some polymers.[3] 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 found in starch hydroisolates.[3] Some bacteria, fungi, plants and invertebrate animals synthesize it as a source of energy, and to survive freezing and lack of water.

Synthesis

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At least three biological pathways support trehalose biosynthesis.[3] An industrial process can derive trehalose from corn starch.[4]

Properties

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Chemical

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Trehalose is a nonreducing sugar formed from two glucose units joined by a 1–1 alpha bond, giving it the name α-D-gluco­pyranosyl-(1→1)-α-D-gluco­pyranoside. The bonding makes trehalose very resistant to acid hydrolysis, 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 end groups do not bind to the lysine or arginine residues of proteins (a process called glycation). Trehalose is less soluble than sucrose, 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.[clarification needed]

Trehalose aqueous solutions show a concentration-dependent clustering tendency. Owing to their ability to form hydrogen bonds, 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[clarification needed] and form large and continuous aggregates.[5]

Trehalose directly interacts with nucleic acids, facilitates melting of double stranded DNA and stabilizes single-stranded nucleic acids.[6]

Biological

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Organisms ranging from bacteria, yeast, fungi, insects, invertebrates, and lower and higher plants have enzymes that can make trehalose.[3] In nature, trehalose can be found in plants, and microorganisms. In animals, trehalose is prevalent in shrimp, and also in insects, including grasshoppers, locusts, butterflies, and bees, in which trehalose serves as blood-sugar.[7][8] Trehalase genes are found in tardigrades, the microscopic ecdysozoans found worldwide in diverse extreme environments.[9]

Trehalose is the major carbohydrate energy storage molecule used by insects for flight.[10] 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, for which cleavage of one glycosidic linkage releases only one glucose molecule.[citation needed]

The concentrations of both trehalose and glucose in the insect hemolymph are tightly controlled by multiple enzymes and hormones, including trehalase, insulin-like peptides (ILPs and DILPs), adipokinetic hormone (AKH), leucokinin (LK), octopamine and other mediators, thereby maintaining carbohydrate homeostasis by endocrine and metabolic feedback mechanisms.[11][12][13][14]

In plants, trehalose is seen in sunflower seeds, moonwort, Selaginella plants,[15] and sea algae. Within the fungi, it is prevalent in some mushrooms, such as shiitake (Lentinula edodes), oyster, king oyster, and golden needle.[16]

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.[15]

The two prevalent theories as to how trehalose works within the organism in the state of cryptobiosis are the vitrification theory, a state that prevents ice formation, or the water displacement theory, whereby water is replaced by trehalose.[9][17]

In bacterial cell wall, trehalose has a structural role in adaptive responses to stress such as osmotic differences and extreme temperature.[18] Yeast uses trehalose as a carbon source in response to abiotic stresses.[19] In humans, trehalose is thought to act as a neuroprotective by inducing autophagy and thereby clearing protein aggregates.[20][21]

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.[22]

Nutritional and dietary properties

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Trehalose is rapidly broken down into glucose by the enzyme trehalase, which is present in the brush border of the intestinal mucosa of omnivores (including humans) and herbivores.[23]: 135  It causes less of a spike in blood sugar than glucose.[24] 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.[25]: 444 

It is commonly used in prepared frozen foods, like ice cream, because it lowers the freezing point of foods.[24]

Deficiency of trehalase enzyme is unusual in humans, except in the Greenlandic Inuit, where it is present in only 10–15% of the population.[26]: 197 

Metabolism

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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).[27] Second, trehalose synthase (TS) in certain types of bacteria could produce trehalose by using maltose and another disaccharide with two glucose units as substrates.[28] Third, the TreY-TreZ pathway in some bacteria converts starch that contain maltooligosaccharide or glycogen directly into trehalose.[29] Fourth, in primitive bacteria, trehalose glycisyltransferring synthase (TreT) produces trehalose from ADP-glucose and glucose.[30] Fifth, trehalose phosphorylase (TreP) either hydrolyses trehalose into glucose-1-phosphate and glucose or may act reversibly in certain species.[31] Vertebrates do not have the ability to synthesize or store trehalose.[32] 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.[33] 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.[34]

Medical use

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Trehalose is an ingredient, along with hyaluronic acid, in an artificial tears product used to treat dry eye.[35][19] Outbreaks of Clostridioides difficile were initially associated with trehalose,[24][36][37] but this finding was disputed in 2019.[38]

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).[39][40]

History

[edit]

In 1832, H.A.L. Wiggers discovered trehalose in an ergot of rye,[41] and in 1859 Marcellin Berthelot isolated it from Trehala manna, a substance made by weevils and named it trehalose.[42]

Trehalose has long been known as an autophagy inducer that acts independently of mTOR.[43] In 2017, research was published showing that trehalose induces autophagy by activating TFEB,[44] a protein that acts as a master regulator of the autophagy-lysosome pathway.[45]

See also

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References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Trehalose

View on Grokipedia
from Grokipedia
Trehalose is a non-reducing consisting of two D-glucose molecules linked by an α,α-1,1-glycosidic bond, with the molecular formula C₁₂H₂₂O₁₁ and a molecular weight of 342.3 g/mol. It occurs naturally in a wide range of organisms, including , fungi, , , and , but is not synthesized by mammals. In these organisms, trehalose plays a crucial role as a stress protectant, stabilizing proteins, membranes, and cellular structures against , freezing, , and extreme temperatures, enabling survival in harsh environments through mechanisms like anhydrobiosis. Chemically, trehalose is a white, crystalline powder with a of 203°C, low hygroscopicity, and high solubility in water, making it chemically stable and non-reactive under physiological conditions. Biologically, it functions as an energy reserve in some species and a signaling precursor, such as trehalose-6-phosphate, which regulates and stress responses in and microbes. In humans, trehalose is metabolized by the trehalase in the intestinal into two glucose molecules, with about 45% the of but a similar caloric value of approximately 4 kcal/g, slower absorption, and a more gradual impact on blood glucose levels. Trehalose has diverse applications due to its bioprotective properties and safety profile, recognized as generally (GRAS) by regulatory authorities for use in and pharmaceuticals. In the , it serves as a stabilizer for proteins, fats, and flavors in products like baked goods, , and frozen foods, enhancing texture and without excessive sweetness. Medically, it is incorporated into formulations (e.g., monoclonal antibodies like Avastin and Lucentis) for stabilization during storage and delivery, and is under investigation for therapeutic uses in dry eye treatments, neurodegenerative diseases such as Huntington's and Alzheimer's, and as a potential inducer.

Structure and Properties

Molecular Structure

Trehalose is a composed of two D-glucose units linked together, with the molecular formula C12_{12}H22_{22}O11_{11}. This structure features both glucose molecules in their form, connected via an α,α-1,1-glycosidic bond between the anomeric carbons (C-1) of each unit, forming α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside. The α,α-1,1-glycosidic linkage renders trehalose a non-reducing , as the bond configuration involves both anomeric carbons, preventing ring opening and subsequent oxidation at either site. In contrast, consists of D-glucose and D-fructose linked by an α-1,2-glycosidic bond (α-D-glucopyranosyl-(1→2)-β-D-fructofuranoside), while features two D-glucose units connected by an α-1,4-glycosidic bond (4-O-α-D-glucopyranosyl-D-glucopyranose), the latter allowing a free anomeric carbon on one unit. The of trehalose specifies α-anomeric configurations at both glucose units, with the hydroxyl groups oriented accordingly in the conformation of the rings. Among its isomeric forms, α,α-trehalose predominates in biological systems, while rarer β,β- and α,β-trehalose isomers occur less frequently.

Physical Properties

Trehalose appears as a white to off-white, odorless crystalline powder in its form, or as a dihydrate with similar characteristics. The form of trehalose has a of 203 °C, at which it decomposes without fully melting, while the dihydrate initially melts at around 97 °C, losing and resolidifying before reaching the . Trehalose exhibits high solubility in water, approximately 68.9 g per 100 g at 20 °C, making it suitable for aqueous solutions; it is slightly soluble in and insoluble in . In contrast to many other disaccharides, trehalose demonstrates low hygroscopicity, attributed to the strong bonding within its lattice, which maintains stable water content (around 9.5% in the dihydrate) up to relative humidities of about 92%. The specific optical rotation of trehalose is [α]D +178° in , reflecting its α,α-1,1-glycosidic linkage. Trehalose has a molecular weight of 342.30 g/mol and a of 1.58 g/cm³ for the form. Trehalose exists in multiple polymorphic forms, including a stable dihydrate and variants (Tα, Tβ), which influence its hygroscopic behavior and stability.

Chemical Properties

Trehalose is classified as a non-reducing because its two glucose moieties are connected via an α,α-1,1-glycosidic bond, eliminating free anomeric hydroxyl groups. This configuration renders it chemically inert toward oxidizing agents, preventing reactions with Benedict's or Fehling's reagents that detect reducing sugars. Unlike , trehalose resists acid-catalyzed due to the stability of its α,α-1,1-glycosidic bond. , trehalose proceeds exclusively through enzymatic by trehalase, yielding two molecules of glucose as follows: \ceC12H22O11+H2O−>[trehalase]2C6H12O6\ce{C_{12}H_{22}O_{11} + H_2O ->[trehalase] 2 C_6H_{12}O_6} This enzymatic specificity underscores trehalose's role in controlled energy release within organisms. Trehalose exhibits superior thermal and compared to many disaccharides, largely attributable to the absence of a reducing end that inhibits participation in the during . Additionally, its molecular structure enables the formation of extensive hydrogen-bonding networks, facilitating the creation of stable, glass-like amorphous phases that enhance its utility in stabilization contexts. Trehalose remains stable across a broad spectrum, from 2 to 10, without significant degradation.

Biosynthesis and Metabolism

Biosynthesis Pathways

Trehalose is primarily synthesized through the OtsA/OtsB pathway, also known as the trehalose-6-phosphate synthase/phosphatase (TPS/TPP) pathway, which is conserved across , fungi, , and . In this two-step process, trehalose-6-phosphate synthase (OtsA or TPS) catalyzes the condensation of UDP-glucose and glucose-6-phosphate to form trehalose-6-phosphate, followed by of trehalose-6-phosphate by trehalose-6-phosphate (OtsB or TPP) to yield trehalose. In such as , the genes otsA and otsB encode these enzymes, enabling from glycolytic intermediates. Fungi, including , utilize homologous enzymes encoded by TPS1 (synthase) and TPS2 (), often as part of a multi-subunit complex that includes regulatory subunits Tps3 and Tsl1. In like , multiple TPS isoforms (e.g., AtTPS1–4 in class I, which are catalytically active) and TPP genes (e.g., AtTPPA–J) facilitate synthesis, with class II TPS isoforms primarily serving regulatory roles. employ similar OtsA/OtsB homologs, where TPS/TPP activity supports trehalose production essential for development and stress tolerance. Alternative pathways exist in certain and , bypassing the TPS/TPP route. The TreY/TreZ pathway, prominent in organisms like Mycobacterium species and archaea such as Sulfolobus solfataricus, involves maltooligosyltrehalose synthase (TreY), which transfers a maltosyl unit from maltooligosaccharides, , or to form maltooligosyltrehalose, followed by by maltooligosyltrehalose trehalohydrolase (TreZ) to release trehalose. Another route, mediated by trehalose synthase (TreS), directly isomerizes to trehalose in a single reversible transglycosylation step, observed in some and . These - or -derived pathways allow trehalose accumulation under conditions where UDP-glucose is limited, complementing the primary . Biosynthesis is tightly regulated to balance carbon allocation and prevent metabolic imbalances. exerts feedback inhibition on TPS activity, reducing synthesis when intracellular levels are high, as demonstrated in bacterial and fungal systems. In and , trehalose-6-phosphate acts as a key signal, inhibiting hexokinases to modulate glycolytic flux and directing carbon toward storage or growth processes. This regulation integrates trehalose production with overall carbon , ensuring efficient resource use across organisms. The de novo synthesis can be simplified as the conversion of two glucose units into trehalose via activated intermediates: UDP-glucose + glucose-6-phosphate → trehalose-6-phosphate + UDP (catalyzed by TPS), followed by trehalose-6-phosphate + H₂O → trehalose + phosphate (catalyzed by TPP).

Metabolic Breakdown

Trehalose is primarily degraded through by the trehalase, classified as α,α-trehalase with the EC number 3.2.1.28, which cleaves the to yield two molecules of D-glucose. This enzymatic action represents the key catabolic step in trehalose across various organisms, enabling the release of glucose for further utilization. In mammals, which do not synthesize trehalose endogenously, trehalase is primarily a membrane-bound enzyme expressed in the brush border of intestinal enterocytes and renal proximal tubules to hydrolyze dietary trehalose. In microorganisms, such as bacteria and fungi, trehalose serves as an alternative carbon source during nutrient limitation, with trehalase playing a central role in its utilization. Under conditions of carbon starvation or osmotic stress relief, trehalase activity is induced to hydrolyze accumulated trehalose, providing glucose for energy production and supporting survival. For instance, in Escherichia coli, periplasmic trehalase (TreA) facilitates trehalose catabolism, integrating it into central metabolism when external carbon sources are scarce. In yeast like Saccharomyces cerevisiae, cytosolic neutral trehalases (e.g., Nth1) are activated post-stress to mobilize trehalose reserves, highlighting its role in stress recovery. Genetic defects in the TREH gene, which encodes intestinal trehalase, result in trehalase deficiency, a rare autosomal recessive condition leading to trehalose intolerance. Affected individuals experience osmotic , , , and upon consuming trehalose-containing foods, due to undigested trehalose drawing water into the intestinal lumen. This disorder underscores the enzyme's essential role in carbohydrate assimilation, though it is often underdiagnosed owing to the rarity of dietary trehalose exposure. The metabolic breakdown of trehalose ultimately yields energy equivalent to that of two glucose molecules, as the liberated glucoses enter directly, generating ATP through subsequent . This integration supports cellular , particularly in organisms relying on trehalose as a reserve . Trehalose's confers resistance to non-specific , necessitating trehalase for efficient degradation.

Biological Functions

Natural Occurrence

Trehalose is widely distributed across various taxa, reflecting its ancient evolutionary origins and conserved role in cellular processes. In microorganisms, it accumulates to significant levels, serving as a major storage . In the Saccharomyces cerevisiae, trehalose can reach up to 20% of the cell's dry weight under certain growth conditions, such as nutrient limitation or stress responses. In , concentrations vary; for instance, in Mycobacterium smegmatis, free trehalose constitutes approximately 1.5–3% of the dry cell weight, while some bacterial spores can accumulate up to 25% trehalose by dry weight. This broad presence in prokaryotes and unicellular eukaryotes underscores trehalose's fundamental distribution in microbial life. In plants, trehalose occurs at low levels in most species but is more prominent in certain structures and resurrection plants. It is found in seeds and pollen of various plants, where it contributes to a minor fraction of total sugars; for example, in Arabidopsis thaliana, trehalose concentrations are typically 20–30 nmol per gram fresh weight. In resurrection plants like Selaginella lepidophylla, trehalose levels vary from trace amounts in hydrated states to up to 12% of dry weight during desiccation, highlighting its accumulation in response to environmental extremes. Among animals, trehalose is particularly abundant in , especially arthropods, where it functions as the primary circulating . In , it serves as the main blood in the ; for locusts such as Locusta migratoria, hemolymph trehalose concentrations average around 21 g/L, comprising over 90% of total sugars. This transport role extends across arthropods, maintaining stable energy supply in their open circulatory systems. In fungi and , trehalose is commonly stored in dormant structures like spores and cysts, aiding in during adverse conditions. Fungal spores often contain high trehalose levels, which are mobilized upon , while in , it appears in vegetative cells and reproductive cysts as part of reserves. Overall, trehalose's occurrence spans from to higher eukaryotes, with concentrations ranging from trace levels to over 15% in specialized cases like tissues.

Protective Roles

Trehalose plays a crucial role in enhancing organismal survival under environmental stresses by stabilizing cellular structures and modulating stress responses. In desiccation tolerance, it acts as a replacement agent, forming a glassy matrix that preserves protein and integrity during . This process prevents structural collapse in anhydrobiotic organisms, such as tardigrades, where trehalose synergizes with like CAHS to limit and maintain . Studies in model anhydrobiotes, including and nematodes, demonstrate trehalose's potency in mitigating desiccation-induced damage, with levels rising sharply to counteract loss. In cryoprotection, trehalose inhibits formation during freezing, reducing cellular damage in overwintering . By lowering the freezing point and promoting over , it protects and tissues in species like the alpine grasshopper, where trehalose concentrations peak during cold acclimation alongside other cryoprotectants such as . This mechanism enables freeze-tolerant arthropods to survive subzero temperatures without lethal ice propagation, as observed in Andean where trehalose contributes to . Trehalose also confers protection against by scavenging (ROS) and stabilizing cellular components. In , it reduces ROS-induced damage, such as , during exposure to oxidants like , thereby preserving membrane integrity and cellular function. Furthermore, trehalose enhances anoxia tolerance in organisms like , where elevated levels via trehalose phosphate synthase activity support survival under oxygen deprivation by mitigating associated oxidative bursts upon reoxygenation. As a chemical chaperone, trehalose inhibits protein misfolding and aggregation, particularly in neurodegenerative contexts. It directly suppresses beta-amyloid fibril formation in models, reducing by stabilizing unfolded proteins and promoting proper folding without altering amyloid precursor protein processing. This chaperone activity extends to proteins, where trehalose prevents aggregation in neuronal cells, highlighting its role in maintaining under stress. The protective functions of trehalose exhibit evolutionary conservation across domains of life, from bacteria to eukaryotes, as a universal stress response mechanism. Trehalose biosynthesis genes, such as those encoding trehalose-6-phosphate synthase, are widely distributed and upregulated under osmotic, desiccation, and oxidative stresses in prokaryotes and eukaryotes alike, enabling adaptive survival in diverse environments like saline habitats in crustaceans. This conservation underscores trehalose's fundamental role in stress biology, linking its disaccharide structure to broad cytoprotective effects.

Applications

Nutritional and Dietary Uses

Trehalose occurs naturally in various foods, including mushrooms where it can constitute up to 2% of the fresh weight in certain species, and in trace amounts in (0.1–1.9%). It has been added to foods as a and stabilizer since the , particularly in where it received food additive approval in 1995 and is used without quantity limits in products like rice, noodles, and baked goods. In humans, trehalose is digested in the by the trehalase, which hydrolyzes it into two molecules of glucose for absorption. Approximately 70–90% of ingested trehalose is absorbed this way, with the remainder fermented by . It provides 4 kcal/g, comparable to , but elicits a lower glycemic response with an index of about 45 relative to glucose's 100, making it suitable for blood sugar management in dietary contexts. The U.S. granted trehalose (GRAS) status in 2000 for use in general foods at levels consistent with good manufacturing practices. Safety studies confirm no adverse effects at typical intake levels up to 50 g daily, though rare trehalase deficiency (affecting about 0.4–1% of populations in some regions) can cause , , and osmotic upon consumption. Under FDA labeling rules, added trehalose counts toward the "added sugars" declaration on facts panels, as it is a caloric incorporated during processing. It is incorporated into low-calorie products, such as bars and frozen desserts, to enhance texture and flavor while allowing reductions in higher-glycemic .

Medical and Pharmaceutical Uses

Trehalose has emerged as a promising therapeutic agent in due to its ability to stabilize the tear film and protect ocular surfaces in dry eye disease (DED). In , preservative-free containing 3% trehalose, such as Thealoz®, were approved in the for the of moderate to severe DED, providing lubrication and hydration by forming a protective film on the . Clinical studies have demonstrated that these formulations, often combined with as in Thealoz Duo®, significantly improve patient satisfaction, reduce ocular discomfort, and enhance tear stability compared to hyaluronic acid-only drops, with efficacy observed as early as the first month of use. This protective effect leverages trehalose's role as a molecular chaperone, which helps maintain protein and integrity in the unstable tear film environment. In neurodegenerative disorders, trehalose exhibits neuroprotective potential by inhibiting protein aggregation and promoting autophagy, key mechanisms implicated in diseases like Huntington's and Parkinson's. Animal models of Huntington's disease have shown that oral trehalose administration reduces polyglutamine protein aggregates, attenuates motor deficits, and extends lifespan by enhancing autophagic clearance of toxic inclusions. Similarly, in Parkinson's disease rodent models, trehalose diminishes alpha-synuclein aggregation, lowers neurotoxicity, and preserves dopaminergic neurons, with effects attributed to its autophagy-inducing properties without adverse impacts on metabolic organs at neuroprotective doses. These preclinical findings support trehalose's exploration as a disease-modifying agent, though human translation remains in early stages. The Phase 2/3 STRIDES trial of intravenous trehalose in spinocerebellar ataxia type 3 was terminated in 2023. Trehalose also serves as a stabilizer in pharmaceutical formulations, particularly for mRNA-based , where it enhances storage stability and enables handling. In lipid nanoparticle (LNP)-encapsulated mRNA , including those developed for , trehalose-loaded LNPs form a vitrified matrix during lyophilization, preserving mRNA integrity and LNP structure for up to 12 weeks at or 24 weeks at , thereby addressing cold-chain limitations of conventional formulations. This adjuvant-like role has been integral to advancing thermostable platforms, reducing degradation during transport and storage while maintaining . For trehalase deficiency, a rare causing osmotic and abdominal discomfort upon trehalose ingestion due to impaired , enzyme replacement therapy remains investigational, with no completed clinical trials reported as of 2025; preclinical models suggest potential benefits from targeted trehalase supplementation to restore intestinal function. Trehalose shows anti-diabetic potential through its low (approximately 45) and minimal insulin requirement for absorption, aiding glucose in diabetic models. Studies in streptozotocin-induced diabetic rats indicate that intraperitoneal trehalose reduces fasting blood glucose and improves insulin sensitivity via pathways involving AMPK activation and reduced , without exacerbating . Human trials confirm lower postprandial glycemic and insulinemic responses compared to , supporting its use in managing impaired glucose tolerance. As of 2025, trehalose's clinical development includes ongoing interventional studies for ocular applications, such as evaluating 3% trehalose solutions in moderate to severe DED to assess corneal epithelial healing (NCT06655441), and protocols for , including a multicenter protocol (NCT05597436), focusing on enhancement and symptom progression. These efforts build on Phase I/II safety data confirming tolerability in neurodegenerative patients.

Industrial and Commercial Uses

Trehalose is produced commercially on an industrial scale through enzymatic conversion of , a method pioneered by Hayashibara Co., Ltd. in . This process involves the use of thermostable enzymes such as maltooligosyl trehalose synthase (MTSase) and maltooligosyl trehalose trehalohydrolase (MTHase), derived from microorganisms like Arthrobacter sp., to convert liquefied into trehalose with high yield and purity exceeding 98% after crystallization. Commercial production began in 1995, enabling cost-effective manufacturing that reduced prices from over $200 per kg to under $3 per kg, with global output reaching approximately 31,000 tons annually by 2007 and continuing to expand to meet demand in various sectors. The global trehalose market, valued at around USD 169 million in 2024, is projected to grow to USD 181 million in 2025, driven by increasing applications in preservation and stabilization. In the , trehalose serves as a stabilizer for dried and processed products, preventing starch retrogradation, protein denaturation, and oxidation during storage and freeze-drying, which extends without altering flavor or texture. It is approved as a ingredient in the since 2001, used under good manufacturing practices in , goods, and frozen foods to maintain under . In , trehalose functions as a and stabilizer, retaining moisture in formulations and protecting liposomes, , and proteins from drying and , thereby enhancing product stability and hydration . As an in , trehalose is widely employed during lyophilization to safeguard biologics such as antibodies and proteins, forming a protective matrix that preserves structural integrity and activity during freeze-drying and long-term storage at ambient temperatures. This application leverages its non-reducing nature and high temperature, which its superior stability over other sugars like in industrial-scale processes. In , trehalose acts as a cryoprotectant for cells, s, and tissues, mitigating damage during freezing and enabling viable recovery post-thaw without concerns associated with penetrating cryoprotectants like DMSO. It is particularly effective in preserving functionality in industrial biocatalysis and supporting the of mammalian cells, including those used in fertilization (IVF) protocols and banking, where it enhances post-thaw viability and proliferation rates when combined with standard media. Additionally, trehalose stabilizes bioinks in and applications, such as -based assays on paper substrates, by maintaining protein activity during deposition and drying.

History and Developments

Discovery and Early Research

Trehalose was first isolated in 1832 by the German chemist H.A.L. Wiggers from of , a caused by , where it appeared as a crystalline substance among the sclerotia. This discovery marked the initial recognition of trehalose as a distinct , though its chemical nature remained unclear at the time. In 1859, French chemist Marcellin Berthelot independently isolated the sugar from trehala manna, a cocoon-like secretion produced by the larvae of the weevil Larinus maculatus on plants in the Middle East, and named it trehalose after its source. Berthelot characterized it as a non-reducing disaccharide composed of two glucose units, distinguishing it from common sugars like sucrose. During the late 19th century, German chemist Emil Fischer advanced its structural elucidation in the 1890s, confirming trehalose as α-D-glucopyranosyl α-D-glucopyranoside through enzymatic hydrolysis studies and synthesis attempts, including the identification of trehalase, an enzyme that specifically cleaves the α,1→1 glycosidic bond. Fischer's work laid the foundation for understanding its unique linkage, setting it apart from other disaccharides. Early investigations linked trehalose to biological systems beyond its initial sources. In the , it was detected in fungal metabolites, with studies by researchers like Carl Wehmer highlighting its presence in molds such as species during metabolic analyses. Its occurrence in insect tissues was noted around the same period through examinations of and secretions, though detailed characterization awaited later enzymatic methods. By the early , trehalose was recognized in and extracts, reinforcing its role as a widespread fungal reserve . Analytical advancements in the mid-20th century facilitated more precise detection and quantification. In the and 1940s, emerged as a key technique for separating sugars, with specifically applied to trehalose in the 1950s for isolating it from biological samples like insect hemolymph. These methods, pioneered by Archer Martin and colleagues, allowed resolution of trehalose from glucose and other monosaccharides, enabling studies of its distribution in . Prior to the 1960s, research remained focused on isolation from natural sources such as fungi, , and , with no large-scale commercial production; trehalose was primarily a subject of academic chemistry.

Recent Advances

In the early 1990s, Hayashibara Co. Ltd. developed an enzymatic synthesis method for trehalose production using maltooligosyl trehalose synthase and trehalose-releasing enzyme to convert starch into trehalose. This approach enabled large-scale industrial production starting in 1995, marking a shift from extraction-based methods to cost-effective biotechnology. In 2000, the U.S. Food and Drug Administration granted trehalose Generally Recognized as Safe (GRAS) status for use in foods, facilitating its broader commercialization as a stabilizer and sweetener. Research in the and elucidated the role of trehalose-6-phosphate (T6P) as a key signaling in , regulating carbon partitioning, synthesis, and growth responses to environmental cues. For instance, T6P activates ADP-glucose pyrophosphorylase to enhance accumulation in leaves within 30 minutes of trehalose application. Building on this, efforts in the 2010s produced marker-free transgenic lines overexpressing trehalose biosynthetic genes, which accumulated higher trehalose levels and exhibited improved grain yield under , sodicity, and drought stress without compromising growth or seed production. In the 2000s, trehalose emerged in ophthalmic formulations as a stabilizer for dry eye treatments, with early products like Thealoz eye drops incorporating it to protect corneal epithelial cells from desiccation and oxidative stress. Clinical studies confirmed its efficacy in multi-ingredient drops combining trehalose with hyaluronic acid, reducing symptoms in moderate to severe dry eye disease by preserving tear film stability. More recently in the 2020s, following the COVID-19 pandemic, trehalose has been integrated into lipid nanoparticle (LNP) formulations to enhance mRNA vaccine stability; for example, trehalose-loaded LNPs maintained mRNA integrity during lyophilization and reduced oxidative stress in cells, bridging in vitro and in vivo efficacy gaps. Industrial applications expanded in the 2020s with trehalose's incorporation into bioinks to improve cell viability and structural integrity post-printing. Cryo-bioinks containing trehalose, alongside PEG and , protected red blood cells during freezing and thawing in extrusion-based bioprinting, enabling viable tissue constructs. In microbial-based living materials, trehalose supplementation in gel-sand bioinks supported bacterial mineralization pathways, enhancing mechanical strength for applications in sustainable construction. Additionally, trehalose has advanced for , with trehalose-based nucleolipids serving as inducers in nanocarriers to treat conditions like by promoting lipid efflux. As of 2025, ongoing studies explore trehalose's modulation of the gut , with oral supplementation in synucleinopathy mouse models restoring microbial diversity, promoting beneficial bacteria associated with protection, and enhancing the microbiota-gut-brain axis. In anti-aging research, trehalose induces to counteract age-related declines; topical application restored autophagic flux in aged , mitigating mitochondrial dysfunction and across species. Similarly, systemic trehalose enhanced myelin debris clearance in models by activating TFEB-mediated in macrophages, reducing foamy cell formation.

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