Uracil

Uracil
IUPAC name Pyrimidine-2,4(1H,3H)-dione
Other names 2-oxy-4-oxy pyrimidine, 2,4(1H,3H)-pyrimidinedione, 2,4-dihydroxypyrimidine, 2,4-pyrimidinediol
Identifiers
CAS number	66-22-8 Y
UNII	56HH86ZVCT N
ChEMBL	CHEMBL566 N
RTECS number	YQ8650000
Jmol-3D images	Image 1
SMILES O=C1NC=CC(=O)N1
Properties
Molecular formula	C4H4N2O2
Molar mass	112.08676 g/mol
Appearance	Solid
Density	1.32 g/cm³
Melting point	335 °C[1]
Boiling point	N/A - decomposes
Solubility in water	Soluble
Hazards
Main hazards	carcinogen & teratogen with chronic exposure
NFPA 704	1 1 0
Flash point	non flammable
Related compounds
Related compounds	Thymine Cytosine
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Uracil is one of the four nucleobases in the nucleic acid of RNA that are represented by the letters A, G, C and U. The others are adenine, cytosine, and guanine. In RNA, uracil (U) binds to adenine (A) via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine.

Uracil is a common and naturally occurring pyrimidine derivative.^[2] Originally discovered in 1900, it was isolated by hydrolysis of yeast nuclein that was found in bovine thymus and spleen, herring sperm, and wheat germ.^[3] It is a planar, unsaturated compound that has the ability to absorb light.^[4]

Studies reported in 2008, based on ¹²C/¹³C isotopic ratios of organic compounds found in the Murchison meteorite, suggested that uracil, xanthine and related molecules were formed extraterrestrially.^[5][6]

Properties

In RNA, Uracil base-pairs with adenine and replaces thymine during DNA transcription. Methylation of uracil produces thymine.^[7] In DNA, the evolutionary substitution of uracil for thymine may have increased DNA stability and improved the efficiency of DNA replication. Uracil can base-pair with any of the bases, but readily pairs with adenine because the methyl group is repelled into a fixed position.^[7] Uracil pairs with adenine through hydrogen bonding. Uracil is the hydrogen bond acceptor and can form two hydrogen bonds. In RNA, uracil binds with a ribose sugar to form the ribonucleoside uridine. When a phosphate attaches to uridine, uridine 5'-monophosphate is produced.^[4]

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.^[3] 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 tautomers: Amide or lactam structure (left) and imide or lactim structure (right)

Uracil also recycles itself to form nucleotides by undergoing a series of phosphoribosyltransferase reactions.^[2] Degradation of uracil produces the substrates aspartate, carbon dioxide, and ammonia.^[2]

C₄H₄N₂O₂ → H₃NCH₂CH₂COO^- + NH₄⁺ + 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.^[8] The negative charge is placed on the oxygen anion and produces a pK_a of less than or equal to 12. The basic pK_a = -3.4, while the acidic pK_a = 9.38₉. In the gas phase, uracil has 4 sites that are more acidic than water.^[9]

Synthesis

In a scholarly article published in October 2009, NASA scientists reported having reproduced uracil from pyrimidine by exposing it to ultraviolet light under space-like conditions. This suggests that one possible natural original source for Uracil in the RNA world could have been panspermia.^[10]

There are many laboratory syntheses of uracil available. The first reaction is the simplest of the syntheses, by adding water to cytosine to produce uracil and ammonia.^[2] The most common way to synthesize uracil is by the condensation of maleic acid with urea in fuming sulfuric acid^[3] as seen below also. Uracil can also be synthesized by a double decomposition of thiouracil in aqueous chloroacetic acid.^[3]

C₄H₅N₃O + H₂O → C₄H₄N₂O₂ + NH₃

C₄H₄O₄ + CH₄N₂O → C₄H₄N₂O₂ + 2 H₂O + CO

Photodehydrogenation of 5,6-diuracil, which is synthesized by beta-alanine reacting with urea, produces uracil.^[11]

Reactions

Uracil readily undergoes regular reactions including oxidation, nitration, and alkylation. While in the presence of PhOH/NaOCl, uracil can be visualized in the blue region of UV light.^[3] Uracil also has the capability to react with elemental halogens because of the presence of more than one strongly electron donating group.^[3]

Chemical structure of uridine

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 is synthesized in the body and has specific functions.

When uracil reactes with anhydrous hydrazine, a first-order kinetic reaction occurs and the ring of uracil opens up.^[12] If the pH of the reaction increases to >10.5, the uracil anion forms, making the reaction go much slower. The same slowing of the reaction occurs if the pH decreases because of the protonation of the hydrazine.^[12] The reactivity of uracil is unchanged even if the temperature changes.^[12]

Uses

Uracil can be used for drug delivery and as a pharmaceutical. When elemental fluorine is reacted with uracil, 5-fluorouracil is produced. 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 perform the same chemistry as, uracil, the drug inhibits RNA replication enzymes, thereby eliminating RNA synthesis and stopping the growth of cancerous cells.^[2]

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 the human body and in plants.^[13] UMP controls the activity of carbamoyl phosphate synthetase and aspartate transcarbamoylase in plants, while UDP and UTP requlate 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.^[13] Uracil is also involved in the biosynthesis of polysaccharides and the transportation of sugars containing aldehydes.^[13]

It can also increase the risk for cancer in cases in which the body is extremely deficient in folate.^[14] The deficiency in folate leads to increased ratio of deoxyuracilmonophosphates (dUMP)/deoxythyminemonophosphates (dTMP) and uracil misincorporation into DNA and eventually low production of DNA.^[14]

Uracil can be used to determine microbial contamination of tomatoes. The presence of uracil is an indication of lactic acid bacteria contamination in the fruit.^[15] Uracil derivatives containing a diazine ring are used in pesticides.^[16] 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.^[16]

In yeast, uracil concentrations are inversely proportional to uracil permease.^[17]

References

1. ^ Richard L. Myers, Rusty L. Myers: The 100 most important chemical compounds, 92-93 link
2. ^ ^{a b c d e f g} Garrett, Reginald H.; Grisham, Charles M. Principals of Biochemistry with a Human Focus. United States: Brooks/Cole Thomson Learning, 1997.
3. ^ ^{a b c d e f} Brown, D.J. Heterocyclic Compounds: Thy Pyrimidines. Vol 52. New York: Interscience, 1994.
4. ^ ^{a b} Horton, Robert H.; et al.Principles of Biochemistry. 3rd ed. Upper Saddle River, NJ: Prentice Hall, 2002.
5. ^ Martins, Zita; Botta, Oliver; Fogel, Marilyn L.; Sephton, Mark A.; Glavin, Daniel P.; Watson, Jonathan S.; Dworkin, Jason P.; Schwartz, Alan W. et al. (15 June 2008). "Extraterrestrial nucleobases in the Murchison meteorite". Earth and Planetary Science Letters 270 (1-2): 130–136. Bibcode 2008E&PSL.270..130M. doi:10.1016/j.epsl.2008.03.026. 
6. ^ AFP Staff (20 August 2009). "We may all be space aliens: study". AFP. http://afp.google.com/article/ALeqM5j_QHxWNRNdiW35Qr00L8CkwcXyvw. Retrieved 2011-08-14. 
7. ^ ^{a b} www.madsci.org
8. ^ Zorbach, W.W. Synthetic Procedures in Nucleic Acid Chemistry: Physical and Physicochemical Aids in Determination of Structure. Vol 2. New York: Wiley-Interscience, 1973.
9. ^ Lee, J.K.; Kurinovich, Ma. J Am Soc Mass Spectrom.13(8), 2005, 985-95.
10. ^ [1].
11. ^ Chittenden, G.J.F.; Schwartz, Alan W. Nature.263,(5575), 350-1.
12. ^ ^{a b c} Kochetkov, N.K. and Budovskii, E.I. Organic Chemistry of Nucleic Acids Part B. New York: Plenum Press, 1972.
13. ^ ^{a b c} Brown, E.G. Ring Nitrogen and Key Biomolecules: The Biochemistry of N-Heterocycles. Boston: Lluwer Academic Publishers, 1998.
14. ^ ^{a b} Mashiyama, S.T; et al.'Anal Biochem. 330(1),2004, 58-69.
15. ^ Hildalgo, A; et al.'J Agric Food Chem.53(2),2005, 349-55.
16. ^ ^{a b} Pozharskii, A.F.; et al.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: John Wiley and Sons, 1997.
17. ^ http://jb.asm.org/cgi/content/full/181/6/1793