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53-865: CYN was first discovered after an outbreak of a mystery disease on Palm Island , Queensland , Australia . The outbreak was traced back to a bloom of Cylindrospermopsis raciborskii in the local drinking water supply, and the toxin was subsequently identified. Analysis of the toxin led to a proposed chemical structure in 1992, which was revised after synthesis was achieved in 2000. Several analogues of CYN, both toxic and non-toxic, have been isolated or synthesised. C. raciborskii has been observed mainly in tropical areas, however has also recently been discovered in temperate regions of Australia , North , South America , New Zealand and Europe . However, CYN-producing strain of C. raciborskii has not been identified in Europe, several other cyanobacteria species occurring across

106-480: A phosphate attaches to uridine, uridine 5′-monophosphate is produced. Uracil undergoes amide-imidic acid tautomeric shifts because any nuclear instability the molecule may have from the lack of formal aromaticity is compensated by the cyclic-amidic stability. The amide tautomer is referred to as the lactam structure, while the imidic acid tautomer is referred to as the lactim structure. These tautomeric forms are predominant at pH  7. The lactam structure

159-600: A HIV viral capsid inhibitor. Uracil derivatives have antiviral, anti-tubercular and anti-leishmanial activity. Uracil can be used to determine microbial contamination of tomatoes . The presence of uracil indicates lactic acid bacteria contamination of the fruit. Uracil derivatives containing a diazine ring are used in pesticides . Uracil derivatives are more often used as antiphotosynthetic herbicides , destroying weeds in cotton , sugar beet , turnips , soya , peas , sunflower crops, vineyards , berry plantations, and orchards . Uracil derivatives can enhance

212-609: A carbon-rich chemical found in the Universe , may have been formed in red giants or in interstellar dust and gas clouds. Based on C/ C isotopic ratios of organic compounds found in the Murchison meteorite , it is believed that uracil, xanthine , and related molecules can also be formed extraterrestrially. Data from the Cassini mission , orbiting in the Saturn system, suggests that uracil

265-413: A farm in northwest Queensland. A nearby dam containing an algal bloom was tested, and C. raciborskii was identified. Analysis by HPLC / mass spectrometry revealed the presence of CYN in a sample of the biomass . An autopsy of one of the calves reported a swollen liver and gall bladder , along with haemorrhages of the heart and small intestine . Histological examination of the hepatic tissue

318-512: A metabolite) acts on either the spindle or centromeres during cell division , inducing loss of whole chromosomes . The uracil group of CYN has been identified as a pharmacophore of the toxin. In two experiments, the vinylic hydrogen atom on the uracil ring was replaced with a chlorine atom to form 5-chlorocylindrospermopsin, and the uracil group was truncated to a carboxylic acid , to form cylindrospermic acid (Figure 6). Both products were assessed as being non-toxic , even at 50 times

371-510: A non-lethal dose. An initial estimate of the toxicity of CYN in 1985 was that an LD 50 at 24 hours was 64±5 mg of freeze-dried culture/kg of mouse body weight on intraperitoneal injection . A further experiment in 1997 measured the LD 50 as 52 mg/kg at 24 hours and 32 mg/kg at 7 days, however the data suggested that another toxic compound was present in the isolate of sonicated cells used; predictions made by Ohtani et al. about

424-437: A possible natural original source for uracil. In 2014, NASA scientists reported that additional complex DNA and RNA organic compounds of life , including uracil, cytosine and thymine , have been formed in the laboratory under outer space conditions, starting with ice, pyrimidine , ammonia, and methanol, which are compounds found in astrophysical environments. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs),

477-440: A statistical link to the symptoms. All patients recovered within 4 to 26 days, and at the time there was no apparent cause for the outbreak. Initial thoughts on the cause included poor water quality and diet, however none were conclusive, and the illness was coined the “Palm Island Mystery Disease”. At the time, it was noticed that this outbreak coincided with a severe algal bloom in the local drinking water supply, and soon after

530-422: A structure (later proven slightly incorrect) was proposed (Figure 1). This almost-correct molecule possesses a tricyclic guanidine group (rings A, B & C), along with a uracil ring (D). The zwitterionic nature of the molecule makes this highly water-soluble, as the presence of charged areas within the molecule creates a dipole effect, suiting the polar solvent . Sensitivity of key signals in

583-502: Is a weak acid . The first site of ionization of uracil is not known. The negative charge is placed on the oxygen anion and produces a p K a of less than or equal to 12. The basic p K a  = −3.4, while the acidic p K a  = 9.38 9 . In the gas phase, uracil has four sites that are more acidic than water. Uracil is rarely found in DNA, and this may have been an evolutionary change to increase genetic stability. This

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636-431: Is achieved by the enzyme UMP synthase . In contrast to the purine nucleotides, the pyrimidine ring (orotidylic acid) that leads uracil is synthesized first and then linked to ribose phosphate , forming UMP. There are many laboratory synthesis of uracil available. The first reaction is the simplest of the syntheses, by adding water to cytosine to produce uracil and ammonia : The most common way to synthesize uracil

689-427: Is an anticancer drug ( antimetabolite ) used to masquerade as uracil during the nucleic acid replication process. Because 5-fluorouracil is similar in shape to, but does not undergo the same chemistry as, uracil, the drug inhibits RNA transcription enzymes, thereby blocking RNA synthesis and stopping the growth of cancerous cells. Uracil can also be used in the synthesis of caffeine. Uracil has also shown potential as

742-473: Is because cytosine can deaminate spontaneously to produce uracil through hydrolytic deamination. Therefore, if there were an organism that used uracil in its DNA, the deamination of cytosine (which undergoes base pairing with guanine) would lead to formation of uracil (which would base pair with adenine) during DNA synthesis. Uracil-DNA glycosylase excises uracil bases from double-stranded DNA. This enzyme would therefore recognize and cut out both types of uracil –

795-482: Is by the condensation of malic acid with urea in fuming sulfuric acid : Uracil can also be synthesized by a double decomposition of thiouracil in aqueous chloroacetic acid . Photodehydrogenation of 5,6-diuracil, which is synthesized by beta- alanine reacting with urea , produces uracil. In 2009, NASA scientists reported having produced uracil from pyrimidine and water ice by exposing it to ultraviolet light under space-like conditions. This suggests

848-459: Is cytotoxic within 16–18 hours it has been suggested that other mechanisms are the cause of cell death. Cytochrome P450 has been implicated in the toxicity of CYN, as blocking the action of P450 reduces the toxicity of CYN. It has been proposed that an activated P450-derived metabolite (or metabolites) of CYN is the main cause of toxicity. Shaw et al. . demonstrated that the toxin could be metabolised in vivo , resulting in bound metabolites in

901-422: Is its stability . Although the toxin has been found to degrade rapidly in an algal extract when exposed to sunlight , it is resistant to degradation by changes in pH and temperature , and shows no degradation in either the pure solid form or in pure water. As a result, in turbid and unmoving water the toxin can persist for long periods, and although boiling water will kill the cyanobacteria, it may not remove

954-408: Is not conclusively the method of cytotoxicity of the compound. Froscio et al. . proposed that CYN has at least two separate modes of action: the previously reported protein synthesis inhibition, and an as-yet unclear method of causing cell death. It has been shown that cells can survive for long periods (up to 20 hours) with 90% inhibition of protein synthesis, and still maintain viability. Since CYN

1007-464: Is present in the surface of the moon Titan . In 2023, uracil was observed in a sample from 162173 Ryugu , a near-Earth asteroid , with no exposure to Earth's biosphere, giving further evidence for synthesis in space. Uracil readily undergoes regular reactions including oxidation , nitration , and alkylation . While in the presence of phenol (PhOH) and sodium hypochlorite (NaOCl), uracil can be visualized in ultraviolet light . Uracil also has

1060-753: Is related to alterations in the gut microbiome by artificial sweetners. A study including Aspartame conducted at Cedars-Sinai in Los Angeles by Ruchi Mathur, MD detected CYN in the duodenum at levels four times above baseline in Aspartame users, along with alterations in bacterial species. Pathological changes associated with CYN poisoning were reported to be in four distinct stages: inhibition of protein synthesis , proliferation of membranes , lipid accumulation within cells, and finally cell death . Examination of mice livers removed at autopsy showed that on intraperitoneal injection of CYN, after 16 hours ribosomes from

1113-610: Is shorter-lived than DNA, and any potential uracil-related errors do not lead to lasting damage. Apparently, either there was no evolutionary pressure to replace uracil in RNA with the more complex thymine, or uracil has some chemical property that is useful in RNA, which thymine lacks. Uracil-containing DNA still exists, for example in Organisms synthesize uracil, in the form of uridine monophosphate (UMP), by decarboxylating orotidine 5'-monophosphate (orotidylic acid). In humans this decarboxylation

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1166-453: Is synthesized in the body and has specific functions. When uracil reacts with anhydrous hydrazine , a first-order kinetic reaction occurs and the uracil ring opens up. If the pH of the reaction increases to > 10.5, the uracil anion forms, making the reaction go much more slowly. The same slowing of the reaction occurs if the pH decreases, because of the protonation of the hydrazine. The reactivity of uracil remains unchanged, even if

1219-407: Is the most common form of uracil. Uracil also recycles itself to form nucleotides by undergoing a series of phosphoribosyltransferase reactions. Degradation of uracil produces the substrates β-alanine , carbon dioxide , and ammonia . Oxidative degradation of uracil produces urea and maleic acid in the presence of H 2 O 2 and Fe or in the presence of diatomic oxygen and Fe . Uracil

1272-729: The hydroxyl group on the uracil bridge can be considered necessary for toxicity. As yet, the relative toxicities of CYN and epiCYN have not been compared. The cylindrospermopsin biosynthetic gene cluster (BGC) was described from Cylindrospermopsis raciborskii AWT205 in 2008. Since the Palm Island outbreak, several other species of cyanobacteria have been identified as producing CYN: Anabaena bergii , Anabaena lapponica , Aphanizomenon ovalisporum , Umezakia natans , Raphidiopsis curvata . and Aphanizomenon issatschenkoi . In Australia, three main toxic cyanobacteria exist: Anabaena circinalis , Microcystis species and C. raciborskii . Of these

1325-418: The rough endoplasmic reticulum (rER) had detached, and at 24 hours, marked proliferation of the membrane systems of the smooth ER and Golgi apparatus had occurred. At 48 hours, small lipid droplets had accumulated in the cell bodies, and at 100 hours, hepatocytes in the hepatic lobules were destroyed beyond function. The process of protein synthesis inhibition has been shown to be irreversible, however

1378-637: The 24‑hour toxicity were considerably higher, and it was proposed that another metabolite was present to account for the relatively low 24‑hour toxicity level measured. Because the most likely human route of uptake of CYN is ingestion, oral toxicity experiments were conducted on mice. The oral LD 50 was found to be 4.4-6.9 mg CYN/kg, and in addition to some ulceration of the oesophageal gastric mucosa , symptoms were consistent with that of intraperitoneal dosing. Stomach contents included culture material, which indicated that these LD 50 figures might be overestimated. Another means of exposure to CYN

1431-422: The LD 50 of CYN. In the previous determination of the structure of deoxycylindrospermopsin, a toxicity assessment of the compound was carried out. Mice injected intraperitoneally with four times the 5-day median lethal dose of CYN showed no toxic effects. As this compound was shown to be relatively abundant, it was concluded that this analogue was comparatively non-toxic. Given that both CYN and epiCYN are toxic,

1484-470: The NMR spectrum to small changes in pH suggested that the uracil ring exists in a keto / enol tautomeric relationship, where a hydrogen transfer results in two distinct structures (Figure 2). It was originally proposed that a hydrogen bond between the uracil and guanidine groups in the enol tautomer would make this the dominant form. A second metabolite of C. raciborskii was identified from extracts of

1537-599: The Wikimedia System Administrators, please include the details below. Request from 172.68.168.133 via cp1102 cp1102, Varnish XID 28609832 Upstream caches: cp1102 int Error: 429, Too Many Requests at Fri, 29 Nov 2024 04:50:50 GMT Uracil Uracil ( / ˈ j ʊər ə s ɪ l / ) ( symbol U or Ura ) is one of the four nucleotide bases in the nucleic acid RNA . The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds . In DNA ,

1590-399: The activity of antimicrobial polysaccharides such as chitosan . In yeast , uracil concentrations are inversely proportional to uracil permease. Mixtures containing uracil are also commonly used to test reversed-phase HPLC columns. As uracil is essentially unretained by the non-polar stationary phase, this can be used to determine the dwell time (and subsequently dwell volume, given

1643-452: The capability to react with elemental halogens because of the presence of more than one strongly electron donating group. Uracil readily undergoes addition to ribose sugars and phosphates to partake in synthesis and further reactions in the body. Uracil becomes uridine , uridine monophosphate (UMP), uridine diphosphate (UDP), uridine triphosphate (UTP), and uridine diphosphate glucose (UDP-glucose). Each one of these molecules

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1696-680: The continent are able to synthesize it. In 1979, 138 inhabitants of Palm Island , Queensland , Australia , were admitted to hospital, suffering various symptoms of gastroenteritis . All of these were children; in addition, 10 adults were affected but not hospitalised. Initial symptoms, including abdominal pain and vomiting , resembled those of hepatitis ; later symptoms included kidney failure and bloody diarrhoea . Urine analysis revealed high levels of proteins , ketones and sugar in many patients, along with blood and urobilinogen in lesser numbers. The urine analysis, along with faecal microscopy and poison screening, could not provide

1749-486: The conversion of glucose to galactose in the liver and other tissues in the process of carbohydrate metabolism . Uracil is also involved in the biosynthesis of polysaccharides and the transportation of sugars containing aldehydes . Uracil is important for the detoxification of many carcinogens , for instance those found in tobacco smoke. Uracil is also required to detoxify many drugs such as cannabinoids (THC) and morphine (opioids). It can also slightly increase

1802-651: The cyanobacteria after the observation of a frequently occurring peak accompanying that of CYN during UV and MS experiments. Analysis by MS and NMR methods concluded that this new compound was missing the oxygen adjacent to the uracil ring, and was named deoxycylindrospermopsin (Figure 3). In 1999, an epimer of CYN, named 7-epicyclindrospermopsin (epiCYN), was also identified as a minor metabolite from Aphanizomenon ovalisporum . This occurred whilst isolating CYN from cyanobacteria taken from Lake Kinneret in Israel . The proposed structure of this molecule differed from CYN only in

1855-660: The direct costs incurred totalled more than A$ 1.3 million. Moreover, 2000 site-days of recreation were also lost, and the economic cost was estimated at A$ 10 million, after taking into account indirectly affected industries such as tourism , accommodation and transport . Current methods include liquid chromatography coupled to mass spectrometry ( LC-MS ), mouse bioassay, protein synthesis inhibition assay, and reverse-phase HPLC-PDA (Photo Diode Array) analysis. A cell free protein synthesis assay has been developed which appears to be comparable to HPLC-MS. Palm Island, Queensland Too Many Requests If you report this error to

1908-402: The evolutionary substitution of thymine for uracil may have increased DNA stability and improved the efficiency of DNA replication (discussed below). Uracil pairs with adenine through hydrogen bonding . When base pairing with adenine, uracil acts as both a hydrogen bond acceptor and a hydrogen bond donor. In RNA, uracil binds with a ribose sugar to form the ribonucleoside uridine . When

1961-539: The focus turned to the dam in question. An epidemiological study of this “mystery disease” later confirmed that the Solomon Dam was implicated, as those that became ill had used water from the dam. It became apparent that a recent treatment of the algal bloom with copper sulfate caused lysis of the algal cells, releasing a toxin into the water. A study of the dam revealed that periodic blooms of algae were caused predominantly by three strains of cyanobacteria : two of

2014-459: The genus Anabaena , and Cylindrospermopsis raciborskii , previously unknown in Australian waters. A mouse bioassay of the three demonstrated that although the two Anabaena strains were non-toxic, C. raciborskii was highly toxic. Later isolation of the compound responsible led to the identification of the toxin cylindrospermopsin. A later report alternatively proposed that the excess copper in

2067-459: The latter, which produces CYN, has attracted considerable attention, not only due to the Palm Island outbreak, but also as the species is spreading to more temperate areas. Previously, the algae was classed as only tropical , however it has recently been discovered in temperate regions of Australia, Europe , North and South America , and also New Zealand . In August 1997, three cows and ten calves died from cylindrospermopsin poisoning on

2120-430: The liver and lungs, along with varying epithelial cell necrosis in areas of the kidneys. A more recent mouse bioassay of the effects of cylindrospermopsin revealed an increase in liver weight, with both lethal and non-lethal doses; in addition the livers appeared dark-coloured. Extensive necrosis of hepatocytes was visible in mice administered a lethal dose, and some localised damage was also observed in mice administered

2173-450: The liver tissue, and that damage was more prevalent in rat hepatocytes than other cell types. Due to the structure of CYN, which includes sulfate , guanidine and uracil groups, it has been suggested that CYN acts on DNA or RNA . Shaw et al. . reported covalent binding of CYN or its metabolites to DNA in mice, and DNA strand breakage has also been observed. Humpage et al. also supported this, and in addition postulated that CYN (or

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2226-460: The one incorporated naturally, and the one formed due to cytosine deamination, which would trigger unnecessary and inappropriate repair processes. This problem is believed to have been solved in terms of evolution, that is by "tagging" (methylating) uracil. Methylated uracil is identical to thymine. Hence the hypothesis that, over time, thymine became standard in DNA instead of uracil. So cells continue to use uracil in RNA, and not in DNA, because RNA

2279-418: The orientation of the hydroxyl group adjacent to the uracil ring (Figure 4). Synthetic approaches to CYN started with the piperidine ring (A), and progressed to annulation of rings B and C. The first total synthesis of CYN was reported in 2000 through a 20-step process. Improvements to synthetic methods led to a revision of the stereochemistry of CYN in 2001. A synthetic process controlling each of

2332-456: The risk for cancer in unusual cases in which the body is extremely deficient in folate . The deficiency in folate leads to increased ratio of deoxyuridine monophosphates (dUMP)/ deoxythymidine monophosphates (dTMP) and uracil misincorporation into DNA and eventually low production of DNA. Uracil can be used for drug delivery and as a pharmaceutical . When elemental fluorine reacts with uracil, they produce 5-fluorouracil . 5-Fluorouracil

2385-408: The six stereogenic centres of epiCYN established that the original assignments of both CYN and epiCYN were in fact a reversal of the correct structures. An alternative approach by White and Hansen supported these absolute configurations (Figure 5). At the time of this correct assignment, it was suggested that the enol form was not dominant. One of the key factors associated with the toxicity of CYN

2438-464: The temperature changes. Uracil's use in the body is to help carry out the synthesis of many enzymes necessary for cell function through bonding with riboses and phosphates. Uracil serves as allosteric regulator and coenzyme for reactions in animals and in plants. UMP controls the activity of carbamoyl phosphate synthetase and aspartate transcarbamoylase in plants, while UDP and UTP regulate CPSase II activity in animals . UDP-glucose regulates

2491-525: The tissues. Such bioaccumulation , particularly in the aquaculture industry, was of concern, especially when humans were the end users of the product. The impact of cyanobacterial blooms has been assessed in economic terms. In December 1991, the world's largest algal bloom occurred in Australia, where 1000 km of the Darling - Barwon River was affected. One million people-days of drinking water were lost, and

2544-486: The toxin. Hawkins et al. . demonstrated the toxic effects of CYN by mouse bioassay, using an extract of the original Palm Island strain. Acutely poisoned mice displayed anorexia , diarrhoea and gasping respiration . Autopsy results revealed haemorrhages in the lungs , livers , kidneys , small intestines and adrenal glands . Histopathology revealed dose-related necrosis of hepatocytes , lipid accumulation, and fibrin thrombi formation in blood vessels of

2597-465: The uracil nucleobase is replaced by thymine (T). Uracil is a demethylated form of thymine . Uracil is a common and naturally occurring pyrimidine derivative. The name "uracil" was coined in 1885 by the German chemist Robert Behrend , who was attempting to synthesize derivatives of uric acid . Originally discovered in 1900 by Alberto Ascoli , it was isolated by hydrolysis of yeast nuclein ; it

2650-415: The water contained both extracellular and intracellular CYN, and that the crayfish had accumulated this primarily in the liver but also in the muscle tissue. Examination of the gut contents revealed cyanobacterial cells , indicating that the crayfish had ingested intracellular toxin. An experiment using an extract of the bloom showed that it was also possible to uptake extracellular toxin directly into

2703-466: The water was the cause of the disease. The excessive dosing was following the use of least-cost contractors to control the algae, who were unqualified in the field. Isolation of the toxin using cyanobacteria cultured from the original Palm Island strain was achieved by gel filtration of an aqueous extract, followed by reverse-phase HPLC . Structure elucidation was achieved via mass spectrometry (MS) and nuclear magnetic resonance (NMR) experiments, and

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2756-632: Was also found in bovine thymus and spleen , herring sperm , and wheat germ . It is a planar, unsaturated compound that has the ability to absorb light. Uracil that was formed extraterrestrially has been detected in the Murchison meteorite , in a near-Earth asteroid , and possibly on the surface of the moon Titan . It has been synthesized under cold laboratory conditions similar to outer space, from pyrimidine embedded in water ice and exposed to ultraviolet light. In RNA, uracil base-pairs with adenine and replaces thymine during DNA transcription. Methylation of uracil produces thymine. In DNA,

2809-518: Was consistent with that reported in CYN-affected mice. This was the first report of C. raciborskii causing mortality in animals in Australia. The effect of a bloom of C. raciborskii on an aquaculture pond in Townsville , Australia was assessed in 1997. The pond contained Redclaw crayfish , along with a population of Lake Eacham Rainbowfish to control the excess food. Analysis revealed that

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