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Uracil

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Last Updated: 02 July 2021

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Uracil

Names
textIUPAC name Pyrimidine-2,4(1 H ,3 H )-dione
text_2Other names 2-oxy-4-oxy pyrimidine, 2,4(1H,3H)-pyrimidinedione, 2,4-dihydroxypyrimidine, 2,4-pyrimidinediol
Identifiers
CAS Number66-22-8 Y
3D model ( JSmol )lactam form: Interactive image, lactim form: Interactive image
3DMetB00026
Beilstein Reference606623
ChEBICHEBI:17568 N
ChEMBLChEMBL566 N
ChemSpider1141 N
DrugBankDB03419
ECHA InfoCard100.000.565
EC Number200-621-9
Gmelin Reference2896
IUPHAR/BPS4560
KEGGC00106
PubChem CID1174
RTECS numberYQ8650000
UNII56HH86ZVCT N
CompTox Dashboard ( EPA )DTXSID4021424
textInChI InChI=1S/C4H4N2O2/c7-3-1-2-5-4(8)6-3/h1-2H,(H2,5,6,7,8) N Key: ISAKRJDGNUQOIC-UHFFFAOYSA-N N, InChI=1/C4H4N2O2/c7-3-1-2-5-4(8)6-3/h1-2H,(H2,5,6,7,8) Key: ISAKRJDGNUQOIC-UHFFFAOYAV
text_2SMILES lactam form: O=C1NC=CC(=O)N1, lactim form: Oc1nccc(O)n1
Properties
Chemical formulaC 4 H 4 N 2 O 2
Molar mass112.08676 g/mol
AppearanceSolid
Density1.32 g/cm 3
Melting point335 C (635 F; 608 K)
Boiling pointN/A - decomposes
Solubility in waterSoluble
Hazards
Main hazardscarcinogen and teratogen with chronic exposure
GHS Signal wordWarning
GHS hazard statementsH315 , H319 , H335 , H361
GHS precautionary statementsP201 , P202 , P261 , P264 , P271 , P280 , P281 , P302+352 , P304+340 , P305+351+338 , P308+313 , P312 , P321 , P332+313 , P337+313 , P362 , P403+233 , P405 , P501
NFPA 704 (fire diamond)1 1
Flash pointNon-flammable
Related compounds
Related compoundsThymine Cytosine
textExcept where otherwise noted, data are given for materials in their standard state (at 25 C , 100 kPa).
text_2Infobox references

Spontaneous hydrolytic deamination of cytosine to uracil generates highly mutagenic DNA base lesion. About 70200 genomic cytosine bases per day are converted to uracils in every human cell. Importantly, rate of cytosine deamination is greatly increased at elevated temperatures and in single - strand DNA. If not repair, uracil will pair with adenine during DNA replication and will inevitably produce CGTA transition mutation. Indeed, CT transitions, likely arising through cytosine damage, are the most frequently occurring base substitutions observed in living organisms. In addition, uracil in DNA occurs from incorporation of dUMP instead of TMP from nucleotide pool; This process results in UA pairs that are not mutagenic but can be lethal for cells when accumulated at high level in genomic DNA. To counteract the genotoxic effects of uracil in DNA, organisms from all major domains of life use base excision repair pathway, which is mediated by DNA glycosylases. Uracil removal in BER is initiated by highly specific and efficient uracil - DNA N - glycosylases that excise uracil from DNA by hydrolyzing glycosidic bond between abnormal base and sugar. Ungs are monofunctional DNA glycosylases that excise uracil and leave the apurinic / apyrimidinic site, which in turn is cloven by AP endonuclease to generate single - strand break flank with 3 - hydroxyl and 5 - deoxyribose phosphate groups. Next, using the 3 - OH terminus, DNA polymerase initiates repair synthesis to incorporate regular nucleotides and to remove the 5 - dRp group. Finally, DNA ligase seals nick to restore DNA duplex integrity. Dna glycosylases acting on genomic uracil are found in all living organisms and belong to the uracil - DNA glycosylase structural superfamily, which consists of five families. Family 1 UNGs, highly conserved in prokaryotes and eukaryotes, are the most efficient enzymes for removal of uracil from DNA. Intriguingly, certain Archaea and pupating insects contain no uracil - DNA glycosylases. Complete genome sequences of several termophilic and mesophilic archaean species do not reveal homology to any of the five UDG families, raising the question of how these organisms deal with uracil threat to genome stability. Using biochemical approach, Fritz and coworkers have identified Mth212 protein, homolog of Escherichia coli AP endonuclease Xth, as DNA uridine endonuclease in Methanothermobacter thermautotrophicus H. It has been shown that Mth212 can cleave 5 to AP sites and deoxyuridines in duplex DNA and also possess efficient 35 exonuclease activity, indicating that this archaeal protein is true AP endonuclease. Furthermore, DNA glycosylase - independent repair of uracil residues was reconstituted using four purified proteins of M. Thermautotrophicus: Mth212, DNA polymerase B, 5 - flap endonuclease, and DNA ligase. Interestingly, Xth family AP endonucleases other than Mth212, including E. Coli Xth, Methanosarcina mazei Mm3148, and human AP endonuclease 1, do not exhibit DNA uridine endonuclease activity under experimental conditions used to measure it.

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Properties

In RNA, uracil base - pairs with adenine and replaces thymine during DNA transcription. Methylation of uracil produces thymine. In DNA, evolutionary substitution of thymine for uracil may have increased DNA stability and improved efficiency of DNA replication. Uracil pairs with adenine through hydrogen bonding. When base is paired with adenine, uracil acts as both hydrogen bond acceptor and hydrogen bond donor. In RNA, uracil binds with ribose sugar to form ribonucleoside Uridine. When phosphate attaches to Uridine, Uridine 5 - monophosphate IS produce. Uracil undergoes Amide - imidic acid tautomeric shifts because any nuclear instability molecule may have from lack of formal aromaticity IS compensated by cyclic - amidic stability. Amide tautomer IS referred to as lactam structure, while imidic acid tautomer IS referred to as lactim structure. These tautomeric forms are predominant at pH 7. Lactam structure IS the most common form of uracil. Uracil tautomers: Amide or lactam structure and imide or lactim structure uracil also recycle itself to form nucleotides by undergoing a series of phosphoribosyltransferase reactions. Degradation of uracil produces substrates aspartate, carbon dioxide, and ammonia. C 4 H 4 N 2 O 2 H 3 NCH 2 CH 2 COO + NH 4 + CO 2 oxidative degradation of uracil produces urea and maleic acid in the presence of H 2 O 2 and Fe 2 + or in the presence of diatomic oxygen and Fe 2 +. Uracil IS weak acid. The first site of ionization of uracil IS not know. Negative charge IS placed on oxygen anion and produces p K of less than or equal to 12. Basic p K = - 3. 4, while acidic p K = 9. 38 9. In the gas phase, uracil has 4 sites that are more acidic than water.

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Synthesis

All canonical nucleobases except cytosine were detected in samples of formamide exposed to LIDB. Irradiation of formamide and DAMN using high - power laser produce adenine, guanine, and uracil, whereas DAMN suspensions produce all of the bases. When formamide was irradiated in the presence of clay, all four bases were detect. The role of clay is to protect adsorbed cytosine against deamination to uracil in further reaction step. To demonstrate this, formamide was irradiated in the presence of olivine chondrite meteorite Northwest Africa 6472. Olivine is a silicate mineral with very low or negligible absorption capacity. Indeed, results of irradiation with and without chondrite meteorite are roughly similar and clearly show that cytosine was not form in the presence of olivine, whereas clay supported the formation of all study bases. Thus, following general model is made for high - energy synthesis of nucleobases from formamide. Synthesis is initiated by reaction of formamide with CN forming several intermediates. This part of the reaction pathway leads to DAMN. Photoisomerization of DAMN produces 2 3 - diaminofumaronitrile, which bind to another CN to readily cyclize into trisubstituted pyrimidinyl radical. This moiety serves as a precursor for cytosine and uracil. Another pathway includes an additional reaction step in which DAFN cyclizes to 4 - amino - 5cyanoimidazole. This synthetic pathway may lead either directly to adenine or precursor of guanine.

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Reactions

Uracil readily undergoes regular reactions including oxidation, nitration, and alkylation. While in the presence of Phenol / Sodium hypochlorite, uracil can be visualized in the blue region of UV light. Uracil also has 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 - monophosphate, Uridine - diphosphate, Uridine - triphosphate, and uracil - diphosphate glucose. Each one of these molecules is synthesize in the body and has specific functions. When uracil reactes with anhydrous hydrazine, first order kinetic reaction occurs and a ring of uracil opens up. If pH of reaction increases to > 10. 5, uracil anion forms making reaction go much slower,. The same slowing of reaction occurs if pH decreases because of protonation of hydrazine. Reactivity of uracil IS unchanged even if the temperature changes.

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Uses

Rna acts as a messenger between DNA and protein synthesis complexes know as ribosomes, forms vital portions of ribosomes, and acts as an essential carrier molecule for amino acids to be used in protein synthesis. Rna is very similar to DNA, but differs in a few important structural details: RNA is a single strand, while DNA is a double strand. Also, RNA nucleotides contain ribose sugars while DNA contains deoxyribose and RNA uses predominantly uracil instead of thymine present in DNA. Rna is transcribed from DNA by enzymes called RNA polymerases and further processed by other enzymes. Rna serves as a template for translation of genes into proteins, transferring amino acids to ribosome to form proteins, and also translating transcripts into proteins. Rna is a polymer with a ribose and phosphate backbone and four different bases: adenine, guanine, cytosine, and uracil. The first three are the same as those found in DNA, but in RNA thymine is replaced by uracil as base complementary to adenine. This base is also pyrimidine and is very similar to thymine. Uracil is energetically less expensive to produce than thymine, which may account for its use in RNA. In DNA, however, uracil is readily produced by chemical degradation of cytosine, so having thymine as normal base makes detection and repair of such incipient mutations more efficient. Thus, uracil is appropriate for RNA, where quantity is important but lifespan is not, whereas thymine is appropriate for DNA where maintaining sequence with high fidelity is more critical.

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Results

Model of B - cell lymphoma development in UNG - deficient mice. Pathway illustrates normal development of UNG + / B cells after translocation to secondary lymphoid tissues, leading to antibody - secreting plasma cells and memory cells. Pathway models how cytokine dysregulation and increased accumulation of untargeted mutations in UNG / B cells result in lymphoid hyperplasia and an increased number of cells having mutator phenotype. Eventually, this may lead to development of follicular lymphoma and progression to diffuse large B - cell lymphoma. The Model shows sources for generation of uracil in DNA and repair pathways of lesions in non - replicating chromatin and at replication fork. Uracil excision by UNG2 in single - strand DNA at replication fork will probably result in stalled replication that will initiate recombination or translesion synthesis. Uracil - initiated diversification pathways in activated B cells are highlighted in red, newly replicated DNA is in blue and RNA is in green. U, uracil; HmU, hydroxymethyluracil.

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Background

Uracil is one of five main nucleobases found in nucleic acids DNA and RNA. Others are adenine, cytosine, guanine, and thymine. However, while the other four are found in DNA, Uracil is usually only found in RNA. Uracil, thymine, and cytosine are pyrimidine derivatives, and guanine and adenine are purine derivatives. In DNA, thymine and cytosine form hydrogen bonds with their complementary purine derivatives, adenine and cytosine, respectively. In RNA, Uracil replaces thymine as usual complement of adenine. Thus, thymine is usually seen only in DNA and Uracil only in RNA. Methylation of Uracil produces thymine, providing a mechanism for repair and protection of DNA and improvement of DNA replication. One of the common mutations in DNA involves two adjacent thymines. Uracils are common and naturally occurring. Uracil was originally discovered in 1900 and it was isolated by hydrolysis of yeast nuclein that was found in bovine thymus and spleen, herring sperm, and wheat germ. Uracil is used in cells to carry out synthesis of important enzymes and biosynthesis of polysaccharides. Derivatives of Uracil, developed through human creativity, include compounds that can be used as pharmaceutical drugs with anticancer properties, and those used in agriculture as herbicides and pesticide.Ssss

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Supplementary

Smug1 is responsible for hmU - excision activity in mouse tissues. Hmu excision activity measures in oligonucleotides containing single hmU: G and hmU: base pair. Heterozygous SMUG1 knockout reduces, whereas homozygous knockout abolishes hmU excision activity. Biochemical assays were evaluated using a Two - tail T - test 95% confidence level. Hm - dU levels increase in DNA from homozygous but not heterozygous SMUG1 knockout organs. Error bars indicate SD of three biological replicates. Hm - dU and hm - dC levels correlate strongly in the SMUG1 - proficient group and very strongly in the SMUG1 - deficient group, whereas hm - dU and oxo - dG levels do not correlate. The effect of SMUG1 and UNG knockout on Genomic lesion levels were assessed using unpaired T - test or analysis of variance. Ung and SMUG1 complement each other in U excision and UNG / SMUG1 double knockout mice accumulate large amounts of Genomic uracil. Uracil excision activity of UNG / and SMUG1 / organ extracts relative to WT in U: G, U:, and single - strand oligonucleotides. Biochemical assays were evaluated using a Two - tail T - test 95% confidence level. There was no significant Genomic dU accumulation in organs from either SMUG1 + / or SMUG1 / mice. Genomic dU increased slightly in UNG / and drastically in UNG / SMUG1 / mouse organs, respectively. The effect of SMUG1 and UNG knockout on Genomic lesion levels were assessed using unpaired T - test or analysis of variance. Error bars indicate SD of three biological replicates. Mutational landscape of UNG / SMUG1 double knockout tumour. Whole Genome sequencing was performed to assess mutational profiles in tumour arising spontaneously in UNG / SMUG1 double knockout mice. Rainfall plots show distribution of mutations in tumours from two different mice along each chromosome. Each dot represents one variant and the distance between mutations is indicate. Types of base pair changes represent fraction of total variants observe. Trinucleotide plots summarising sequences surrounding each variant normalise to Genomic trinucleotide occurrence. The sequence context of all mutations occurring at C: G base pairs is magnified below. Mutational landscape of UNG / SMUG1 / MSH2 triple knockout tumour. Whole Genome sequencing was performed to assess mutational profiles in tumour arising spontaneously in UNG / SMUG1 / MSH2 triple knockout mice. Rainfall plots show distribution of mutations in tumours from two different mice along each chromosome. Types of base pair changes represent fraction of total variants observe. Trinucleotide plots summarising sequences surrounding each variant normalise to Genomic trinucleotide occurrence. Sequence context of all Mutations occurring at C: G base pairs is magnified below. Mutational signatures. The plot shows mutation density along Chromosome 5 for all four tumours together with the density of exons and CpG islands. The 2230 Mbp region with the highest number of mutations is shown below. Mutational signatures identify UNG / SMUG1 and UNG / SMUG1 / MSH2 tumours. Different mutational signatures present in each tumour give the number of mutations contributing to each signature.

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Introduction

The most common mutation in human cells is CT transitions and this type of mutation is also found very frequently in human tumours. A major fraction of these transitions occur in the CpG context and they have therefore been suggested to result from deamination of 5 - methylcytosine to thymine, or cytosine to uracil. Dna replication would then be inserted in place of G. However, CT transitions are common in other sequences as well. Mismatches caused by deamination are generally repaired by base excision Repair pathway. Ber pathway probably Repair largest fraction of DNA damage, but its significance to human health remains unclear. The present review will focus on repair of one of the most common lesions in DNA, uracil. However, since several known uracil - DNA glycosylases are not strictly uracil - specific, repair of some uracil analogues, namely 5 - hydroxymethyluracil, 3, N 4 - ethenocytosine and 5 - fluorouracil will also be discuss. In addition, repair of T: G mismatches by DNA glycosylases will be address. It has become clear in recent years that BER for removal of uracil from DNA involves several DNA glycosylases, which may have different functional roles. Steps downstream of initial glycosylase step may also differ, depending on the origin and localisation of uracil, specific DNA glycosylase involve, and timing of cell cycle. In this review, emphasis will be on enzymes that initiate the repair process, DNA glycosylases. Uracil in DNA results from deamination of cytosine to uracil, creating premutagenic U: G mispair, or from misincorporation of dUMP instead of dTMP during replication, creating U: pair. Inappropriate uracil is recognise by UDG activity, which cleaves N - glycosidic bond and leaves abasic site in DNA. The first UDG was discovered in Escherichia coli in 1974 in search for activities that would repair uracil in DNA. This also represents the discovery of the BER pathway. An activity that was discovered releases uracil as a free base, leaving intact basic site in DNA. Ung from UNG - gene later proved to be representative of highly conserved family of UDGs present in most living organisms examine. However, mammalian cells contain at least three additional human glycosylases, that have the capacity to remove uracil from DNA. Ung and SMUG1 prefer single - stranded DNA as substrate, but also remove U from double - strand DNA. In contrast, TDG and MBD4 are strictly specific for double - strand DNA, and have very low turnover numbers. Functional roles of different enzymes are only starting to become understood. It seems clear that UNG has a central function in removal of U from misincorporated dUMP - residues. Smug1 has tentatively been proposed to have a specific role in removal of deaminated cytosine residues, but this role needs more experimental confirmation. Roles of TDG and MBD4 may be limited to repair of mismatched uracil, thymine and some damaged pyrimidines in double - strand DNA, particularly in CpG and 5 - methylCpG contexts.


What is Uracil?

Their uracil exchange constitutes one of the major chemical differences between DNA and RNA. However, these two bases are equivalent for both information storage and transmission as they form the same H - bond base paired with adenine. The 5 - methyl group, that is, difference between two bases, has no effect on interaction with adenine. In fact, DNA synthesize in a thymine - less environment has the same coding function, 1 and bacteriophage PBS 1 / 2 relies completely on thymine - less DNA that contains uracil instead of thymine. 2 De novo biosynthesis of thymine is an intricate and energetically expensive process that requires dUMP as starting material and a complex array of two enzymes and cofactors. It is therefore straightforward to ask: is there any specific reason that justifies this costly and seemingly equivalent replacement of uracil by thymine in DNA? It is generally accepted that negative discrimination against uracil in DNA is caused by chemical instability of cytosine. 3 Deamination of cytosine, rather frequent process that readily occurs under physiological circumstances, gives rise to uracil. Unless correct, this mutagenic transition will result in C: G into U: base - pair change, that is, stable point mutation. To deal with this problem, highly efficient repair process has evolved that starts with uracilDNA glycosylase. The importance of this repair process is well reflected in two observations. One, cytosine deamination is one of the most frequent spontaneous mutations in DNA. 5 6 Two, UDG activity resides in at least four families of enzymes: 7 8 redundancy may be required for specific circumstances. Udg - initiated repair deals with cytosine instability; however, it also inherently defines all uracils as mistakes to be remove. Although mismatch - oriented glycosylases do exist, most efficient, UNG protein, excises all uracils, and Nature therefore had to derive yet another addition to this system: label correct uracils with methyl group to distinguish them from deaminate cytosines. Once the methyl label was introduce, its van der Waals characteristics could also be exploited in interactions with DNA - binding proteins. For short - term storage of genetic information, as in modern RNAs, cytosine deamination rates do not pose a serious problem; therefore, uracil does not need to be discriminated against.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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