Names | |
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IUPAC name (22S,25S)-5α-spirosolan-3β-yl β-D-glucopyranosyl-(1→2)-[β-D-xylopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside [1] | |
Other names Tomatine, Tomatin, Lycopersicin | |
Identifiers | |
3D model (JSmol) | |
ChEBI | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard | 100.037.647 |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C50H83NO21 [2] | |
Molar mass | 1034.18816 [3] |
Appearance | crystalline solid |
Melting point | 263-268 °C [4] |
insoluble but soluble in methanol, ethanol, dioxane and propylene glycol [4] | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Tomatine (sometimes called tomatin or lycopersicin) is a glycoalkaloid, found in the stems and leaves of tomato plants, and in the fruits at much lower concentrations. Chemically pure tomatine is a white crystalline solid at standard temperature and pressure. [1] [5]
Tomatine is sometimes confused with the glycoalkaloid solanine. [6]
Tomatoes were brought to Europe in the early 1500s. The English botanist John Gerard was one of the first cultivators of the tomato plant. In his publication Grete Herball , he considered tomatoes poisonous due to their levels of what would later be called tomatine, plus high acid content. Consequently, tomatoes were generally not eaten in Britain until the mid-18th century. [7] [ better source needed ]
In 1837, the first medicinal tomato pills were advertised in the United States because of their positive effects upon the biliary organs. The product “Phelp’s Compound Tomato Pills” was extracted from the tomato plant, and contained tomatine. The pills were made by the medic Guy R. Phelps, who stated that the alkaloid tomatine was one of the most useful discoveries ever made. Tomatine then was said to be an antidote to mercury. [8]
In the mid 20th century, scientists from the US Department of Agriculture were the first to isolate tomatine from the wild tomato species Lycopersicon pimpinellifolium and the cultured species Lycopersicon esculentum. [9] [10]
Alpha-tomatine (α-tomatine) belongs to the compound group steroidal glycoalkaloids. These compounds consist of an aglycon, which is a cholesterol derivative, and a carbohydrate chain, which in the case of α-tomatine consists of two d-glucose units, a d-galactose unit, and a d-xylose unit. [12] In α-tomatine, the tetrasaccharide called lycotetraose is attached to the O-3 of the steroidal aglycone. [13] At first it was thought that the synthesis of steroidal alkaloids only involved multiple steps of hydroxylation, oxidation and amination of cholesterol with arginine as the source of the incorporated nitrogen. Later the glycoalkaloid metabolism genes were discovered. [12] These genes produce the glycoalkaloid metabolism enzymes, which are responsible for the synthesis of steroidal alkaloid aglycones in potato and tomato plants. [12] The reaction these enzymes perform are shown in the figure 1.
Tomatine may play a major role in resistance of the tomato plant against fungal, microbial, insect, and herbivoral attack.[ citation needed ]
The effects of the glycoalkaloids (to which tomatine belongs), can be divided in two main parts: the disruption of cellular membranes and the inhibition of the enzyme acetylcholinesterase. Tomatine is responsible in tomato plants for resistance against for example the Colorado beetle and to snails. [14] It is also a defense against fungi. [15] [16]
The membrane disruptive properties of tomatine are caused by the ability to form 1:1 complexes with cholesterol. A possible mechanism of the membrane disruption by glycoalkaloids is displayed in figure 2. First, the aglycon part of tomatine binds reversibly to sterols in the membrane (figure 2, part 2). When this reaches a certain density, the glycosidic residues of the glycoalkaloids interact with each other by electrostatic interactions. This interaction catalyzes the development of an irreversible matrix of glycoalkaloid-sterol complexes (figure 2, part 4). In this way, the sterols from the external membrane are immobilized and membrane budding will arise. Tubular structures are formed, because of the structure of tomatine (figure 2, part 6). [14] [17] This membrane disruption causes cell death by cell leakage. [14] Also, the disrupted membrane has an influence on sodium transport, by altering the membrane potential and reducing active sodium transport. When tomatine is orally ingested, the brush border of the intestine is damaged by the membrane-disruptive properties of tomatine, so increased uptake of macromolecules occurs. This damage to the epithelial barriers is dose-dependent. [14] [17]
Tomatine is considered to be a fungitoxic compound, as it completely inhibits mycelial growth of the fungi C. orbiculare (MC100=2.0 mM), S. linicola (MC100=0.4 mM), and H. turcicum (MC100=0.13 mM). For the inhibition at a low pH, much more tomatine is required, so the compound is more effectively fungitoxic at a high pH, when the alkaloid is unprotonated. The unprotonated form of tomatine forms complexes with sterols such as cholesterol, which may cause disruption of cell membrane and changes in membrane permeability. [18]
Tomatine is effective against fungi at pH 8 but not at pH 4. A possible explanation for this is that the tomatine only in the deprotonated form binds to cholesterol to form the earlier mentioned complexes. [15] Tomatine disrupts liposome membranes containing 3-β-hydroxy sterol, while liposomes without 3-β-hydroxy sterols are resistant to membrane disruption. [16] Tomatine inhibits also the fungal types Ph. infestans and Py. aphanidermatum, which do not have any sterols in their membranes, so another mechanism of action must be present. [15]
The other known action of the compound is the pH-dependent competitive inhibition of the enzyme acetylcholinesterase. [14] [15] The majority of synthetic pesticides used in agriculture work by inhibition of acetylcholinesterase is to kill insects. [19]
Even now, little is known about the bioavailability, pharmacokinetics and metabolism of the glycoalkaloids in humans. [14] One important factor is the poor uptake of tomatine into general blood circulation. When tomatine is orally ingested, much tomatine may form complexes with cholesterol from the other food present in the stomach. The complexes of tomatine and cholesterol are not absorbed in the intestine, but are excreted. [15] For the complexation with cholesterol to occur, the presence of a carbohydrate chain is essential. The aglycon tomatidine, which is tomatine without the sugars, does not form the complexes. [14] [17] The complexation probably occurs in the duodenum, because the acidic conditions in the stomach itself lead to protonation of the tomatine, and the protonated form of tomatine does not bind to cholesterol. [15]
Hydrolysis of tomatine likely takes place, but whether it is acid- or glycosidase-catalyzed is not known. [15] The hydroxylation of tomatine likely leads to the formation of tomatidine, which is the aglycon of tomatine. Tomatidine is a metabolite which may not be completely nontoxic; it could have effects on the human body. [15]
Fungal tomatinase enzymes can transform tomatine to deactivate it. Detoxification can take place by removing one glucose residue. Other fungal species hydrolyze tomatine to the less toxic aglycon tomatidine by removing all the sugar residues. Tomatidine can still inhibit some fungal species, but is less toxic than tomatine. Fungi use diverse pathways for the hydrolysis of tomatine. Also, the level of toxicity depends on the type of fungus. [16] [20] The metabolite tomatidine can be hydrolyzed further by membrane-bound CYP-450 oxygenases. [15]
Tomatine has been used as a reagent in analytical chemistry for precipitating cholesterol from solution. [21] Also, tomatine is known to be an immune adjuvant in connection with certain protein antigens. [22]
The possible risks of tomatine for humans have not been formally studied, so no NOAEL can be deduced. The toxicity of tomatine has only been studied on laboratory animals. The symptoms of acute tomatine poisoning in animals are similar to the symptoms of poisoning by solanine, a potato glycoalkaloid. These symptoms include vomiting, diarrhea, abdominal pain, drowsiness, confusion, weakness, and depression. [23] Generally, tomatine is regarded to cause less toxic effects to mammals than other alkaloids such as solanine. [24]
The human consumption of moderate amounts of tomatine seems to occur without notable toxic effects. This is reinforced by the widespread consumption of “pickled green” and “fried green tomatoes” and the consumption of high-tomatine tomatoes (a variant of L. esculentum var. cerasiforme, better known as the "cherry tomato", indigenous to Peru) with very high tomatine content (in the range of 500–5000 μg/kg of dry weight). [25]
New York Times food science writer Harold McGee found scant evidence for tomato toxicity in the medical and veterinary literature, and observed that dried tomato leaves (which contain higher concentrations of alkaloids than the fruits) are occasionally used as a food flavoring or garnish, without problems. He also reported that an adult human would probably have to eat over half a kilogram of tomato leaves to ingest a toxic (not necessarily lethal) dose. [6]
A steroid is an organic compound with four fused rings arranged in a specific molecular configuration.
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally.
Saponins, also selectively referred to as triterpene glycosides, are bitter-tasting usually toxic plant-derived organic chemicals that have a foamy quality when agitated in water. They are widely distributed but found particularly in soapwort, a flowering plant, the soapbark tree and soybeans. They are used in soaps, medicines, fire extinguishers, speciously as dietary supplements, for synthesis of steroids, and in carbonated beverages. Saponins are both water and fat soluble, which gives them their useful soap properties. Some examples of these chemicals are glycyrrhizin and quillaia, a bark extract used in beverages.
Solanine is a glycoalkaloid poison found in species of the nightshade family within the genus Solanum, such as the potato, the tomato, and the eggplant. It can occur naturally in any part of the plant, including the leaves, fruit, and tubers. Solanine has pesticidal properties, and it is one of the plant's natural defenses. Solanine was first isolated in 1820 from the berries of the European black nightshade, after which it was named. It belongs to the chemical family of saponins.
Sterol is an organic compound with formula C
17H
28O, whose molecule is derived from that of gonane by replacement of a hydrogen atom on C3 position by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the gonane structure, additional functional groups, and/or modified ring systems derived from gonane are called steroids. Therefore, sterols are a subgroup of the steroids. They occur naturally in most eukaryotes, including plants, animals, and fungi, and can also be produced by some bacteria. The most familiar type of animal sterol is cholesterol, which is vital to cell membrane structure, and functions as a precursor to fat-soluble vitamins and steroid hormones.
Phytosterols are phytosteroids, similar to cholesterol, that serve as structural components of biological membranes of plants. They encompass plant sterols and stanols. More than 250 sterols and related compounds have been identified. Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols.
Glycoalkaloids are a family of chemical compounds derived from alkaloids to which sugar groups are appended. Several are potentially toxic, most notably the poisons commonly found in the plant species Solanum dulcamara and other plants in the genus Solanum, including potato.
Digitonin is a steroidal saponin (saraponin) obtained from the foxglove plant Digitalis purpurea. Its aglycone is digitogenin, a spirostan steroid. It has been investigated as a detergent, as it effectively water-solubilizes lipids. As such, it has several potential membrane-related applications in biochemistry, including solubilizing membrane proteins, precipitating cholesterol, and permeabilizing cell membranes.
Stigmasterol – a plant sterol (phytosterol) – is among the most abundant of plant sterols, having a major function to maintain the structure and physiology of cell membranes. In the European Union, it is a food additive listed with E number E499, and may be used in food manufacturing to increase the phytosterol content, potentially lowering the levels of LDL cholesterol.
Phytotoxins are substances that are poisonous or toxic to the growth of plants. Phytotoxic substances may result from human activity, as with herbicides, or they may be produced by plants, by microorganisms, or by naturally occurring chemical reactions.
Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.
A cardenolide is a type of steroid. Many plants contain derivatives, collectively known as cardenolides, including many in the form of cardenolide glycosides (cardenolides that contain structural groups derived from sugars). Cardenolide glycosides are often toxic; specifically, they are heart-arresting. Cardenolides are toxic to animals through inhibition of the enzyme Na+/K+‐ATPase, which is responsible for maintaining the sodium and potassium ion gradients across the cell membranes.
In enzymology, a sterol 14-demethylase (EC 1.14.13.70) is an enzyme of the Cytochrome P450 (CYP) superfamily. It is any member of the CYP51 family. It catalyzes a chemical reaction such as:
Solamargine is a cytotoxic chemical compound that occurs in plants of the family Solanaceae, such as potatoes, tomatoes, and eggplants. It has been also isolated from Solanum nigrum fungal endophyte Aspergillus flavus. It is a glycoalkaloid derived from the steroidal alkaloid solasodine.
α-Chaconine is a steroidal glycoalkaloid that occurs in plants of the family Solanaceae. It is a natural toxicant produced in green potatoes and gives the potato a bitter taste. Tubers produce this glycoalkaloid in response to stress, providing the plant with insecticidal and fungicidal properties. It belongs to the chemical family of saponins. Since it causes physiological effects on individual organism, chaconine is considered to be defensive allelochemical. Solanine is a related substance that has similar properties.
Solanidine is a poisonous steroidal alkaloid chemical compound that occurs in plants of the family Solanaceae, such as potato and Solanum americanum. Human ingestion of solanidine also occurs via the consumption of the glycoalkaloids, α-solanine and α-chaconine, present in potatoes. The sugar portion of these glycoalkaloids hydrolyses in the body, leaving the solanidine portion. Solanidine occurs in the blood serum of normal healthy people who eat potato, and serum solanidine levels fall markedly once potato consumption ceases. Solanidine from food is also stored in the human body for prolonged periods of time, and it has been suggested that it could be released during times of metabolic stress with the potential for deleterious consequences. Solanidine is responsible for neuromuscular syndromes via cholinesterase inhibition.
Steroidal alkaloids have the basic steroidal skeleton with nitrogen-based functional groups attached to the skeleton. More specifically, they are distinguished by their tetracyclic cyclopentanoperhydrophenanthrene skeleton that marks their close relationship with sterols. They fall in two major categories: Solanum alkaloids and Veratrum alkaloids. A Steroidal alkaloid has also been found in Chonemorpha fragrans, 'chonemorphine' was used to treat intestinal infections in Wistar rats..
C-5 sterol desaturase is an enzyme that is highly conserved among eukaryotes and catalyzes the dehydrogenation of a C-5(6) bond in a sterol intermediate compound as a step in the biosynthesis of major sterols. The precise structure of the enzyme's substrate varies by species. For example, the human C-5 sterol desaturase oxidizes lathosterol, while its ortholog ERG3 in the yeast Saccharomyces cerevisiae oxidizes episterol.
Oxidosqualene cyclases (OSC) are enzymes involved in cyclization reactions of 2,3-oxidosqualene to form sterols or triterpenes.
Cyclobuxine is an alkaloid, which can be found in Buxus sempervirens better known as common boxwood, and is derived from the cholesterol skeleton. Alkaloids can be found in the whole plant, but the largest amounts of alkaloids including cyclobuxine can be found in the leaves and bark.