Uracil that was formed extraterrestrially has been detected in the Murchison meteorite,[7] in a near-Earth asteroid,[8] and possibly on the surface of the moon Titan.[9] It has been synthesized under cold laboratory conditions similar to outer space, from pyrimidine embedded in water ice and exposed to ultraviolet light.[10]
Properties
In RNA, uracil base-pairs with adenine and replaces thymine during DNA transcription. Methylation of uracil produces thymine.[11] In DNA, 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 ribonucleosideuridine. When a phosphate attaches to uridine, uridine 5′-monophosphate is produced.[6]
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.[5] 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 is the most common form of uracil.
Uracil also recycles itself to form nucleotides by undergoing a series of phosphoribosyltransferase reactions.[2] Degradation of uracil produces the substrates β-alanine, carbon dioxide, and ammonia.[2]
C4H4N2O2→ H3NCH2CH2COO− + NH+4 + CO2
Oxidative degradation of uracil produces urea and maleic acid in the presence of H2O2 and Fe2+ or in the presence of diatomic oxygen and Fe2+.
Uracil is a weak acid. The first site of ionization of uracil is not known.[12] The negative charge is placed on the oxygen anion and produces a pKa of less than or equal to 12. The basic pKa = −3.4, while the acidic pKa = 9.389. In the gas phase, uracil has four sites that are more acidic than water.[13]
In DNA
Uracil is rarely found in DNA, and this may have been an evolutionary change to increase genetic stability. This 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 – the one incorporated naturally, and the one formed due to cytosine deamination, which would trigger unnecessary and inappropriate repair processes.[14]
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 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 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.[16]
Laboratory
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:[2]
In 2009, NASA scientists reported having produced uracil from pyrimidine and water ice by exposing it to ultraviolet light under space-like conditions.[10] This suggests a possible natural original source for uracil.[18] In 2014, NASA scientists reported that additional complex DNA and RNAorganic 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.[19] Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), a carbon-rich chemical found in the Universe, may have been formed in red giants or in interstellar dust and gas clouds.[20]
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.[5] Uracil also has the capability to react with elemental halogens because of the presence of more than one strongly electron donating group.[5]
When uracil reacts with anhydrous hydrazine, a first-order kinetic reaction occurs and the uracil ring opens up.[21] 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.[21] The reactivity of uracil remains unchanged, even if the temperature changes.[21]
Uses
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.[2] Uracil serves as allosteric regulator and coenzyme for reactions in animals and in plants.[22] 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 the conversion of glucose to galactose in the liver and other tissues in the process of carbohydrate metabolism.[22] Uracil is also involved in the biosynthesis of polysaccharides and the transportation of sugars containing aldehydes.[22] Uracil is important for the detoxification of many carcinogens, for instance those found in tobacco smoke.[23] Uracil is also required to detoxify many drugs such as cannabinoids (THC)[24] and morphine (opioids).[25] It can also slightly increase the risk for cancer in unusual cases in which the body is extremely deficient in folate.[26] 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.[26]
Uracil can be used for drug delivery and as a pharmaceutical. When elemental fluorine reacts with uracil, they produce 5-fluorouracil. 5-Fluorouracil is an anticancer drug (antimetabolite) used to masquerade as uracil during the nucleic acid replication process.[2] 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.[2] Uracil can also be used in the synthesis of caffeine.[27] Uracil has also shown potential as a HIV viral capsid inhibitor.[28] Uracil derivatives have antiviral, anti-tubercular and anti-leishmanial activity.[29][30][31]
In yeast, uracil concentrations are inversely proportional to uracil permease.[35]
Mixtures containing uracil are also commonly used to test reversed-phaseHPLC 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 a known flow rate) of the system.
^ abcdefgGarrett RH, Grisham CM (1997). Principles of Biochemistry with a Human Focus. United States: Brooks/Cole Thomson Learning.
^Behrend R (1885). "Versuche zur Synthese von Körpern der Harnsäurereihe" [Experiments on the synthesis of substances in the uric acid series]. Annalen der Chemie. 229 (1–2): 1–44. doi:10.1002/jlac.18852290102. Dasselbe stellt sich sonach als Methylderivat der Verbindung: welche ich willkürlich mit dem Namen Uracil belege, dar. [The same compound is therefore represented as the methyl derivative of the compound, which I will arbitrarily endow with the name ‘uracil’.]
^ abcdefBrown DJ, Evans RF, Cowden WB, Fenn MD (1994). Taylor EC (ed.). The Pyrimidines. Heterocyclic Compounds. Vol. 52. New York, NY: Wiley. ISBN9780471506560. Archived from the original on 12 May 2018.
^ abHorton HR, Moran LA, Ochs RS, Rawn DJ, Scrimgeour KG (2002). Principles of Biochemistry (3rd ed.). Upper Saddle River, NJ: Prentice Hall. ISBN9780130266729.
^ abClark RN, Pearson N, Brown RH, Cruikshank DP, Barnes J, Jaumann R, et al. (2012). "The Surface Composition of Titan". American Astronomical Society. 44: 201.02. Bibcode:2012DPS....4420102C.
^ abNuevo, Michel; Milam, Stefanie N.; Sandford, Scott A.; Elsila, Jamie E.; Dworkin, Jason P. (2009). "Formation of Uracil from the Ultraviolet Photo-Irradiation of Pyrimidine in Pure H2O Ices". Astrobiology. 9 (7): 683–695. Bibcode:2009AsBio...9..683N. doi:10.1089/ast.2008.0324. ISSN1531-1074. PMID19778279.
^Zorbach WW, Tipson RS (1973). Synthetic Procedures in Nucleic Acid Chemistry: Physical and physicochemical aids in determination of structure. Vol. 2. New York, NY: Wiley-Interscience. ISBN9780471984184.
^ abMashiyama ST, Courtemanche C, Elson-Schwab I, Crott J, Lee BL, Ong CN, et al. (July 2004). "Uracil in DNA, determined by an improved assay, is increased when deoxynucleosides are added to folate-deficient cultured human lymphocytes". Analytical Biochemistry. 330 (1): 58–69. doi:10.1016/j.ab.2004.03.065. PMID15183762.
^Zajac MA, Zakrzewski AG, Kowal MG, Narayan S (2003). "A novel method of caffeine synthesis from uracil". Synthetic Communications. 33 (19): 3291–3297. doi:10.1081/SCC-120023986. S2CID43220488.
^Ramesh D, Sarkar D, Joji A, Singh M, Mohanty AK, G Vijayakumar B, et al. (April 2022). "First-in-class pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones against leishmaniasis and tuberculosis: Rationale, in vitro, ex vivo studies and mechanistic insights". Archiv der Pharmazie. 355 (4): e2100440. doi:10.1002/ardp.202100440. PMID35106845. S2CID246474821.
^Hidalgo A, Pompei C, Galli A, Cazzola S (January 2005). "Uracil as an index of lactic acid bacteria contamination of tomato products". Journal of Agricultural and Food Chemistry. 53 (2): 349–355. doi:10.1021/jf0486489. PMID15656671.
^ abPozharskii AF, Soldatenkov AT, Katritzky AR (1997). Heterocycles in Life and Society: An introduction to heterocyclic chemistry and biochemistry and the role of heterocycles in science, technology, medicine, and agriculture. New York, NY: John Wiley and Sons. ISBN9780471960348.
