Cytosine

Not to be confused with cytokine, cytidine, cysteine, cystine, or cytisine.

Cytosine

Names
Preferred IUPAC name 4-Aminopyrimidin-2(1H)-one
Other names 4-Amino-1H-pyrimidine-2-one
Identifiers
CAS Number	71-30-7 Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:16040 Y
ChEMBL	ChEMBL15913 Y
ChemSpider	577 Y
ECHA InfoCard	100.000.681
KEGG	C00380 Y
MeSH	Cytosine
PubChem CID	597
UNII	8J337D1HZY Y
CompTox Dashboard (EPA)	DTXSID4044456
InChI InChI=1S/C4H5N3O/c5-3-1-2-6-4(8)7-3/h1-2H,(H3,5,6,7,8) Y Key: OPTASPLRGRRNAP-UHFFFAOYSA-N Y InChI=1/C4H5N3O/c5-3-1-2-6-4(8)7-3/h1-2H,(H3,5,6,7,8) Key: OPTASPLRGRRNAP-UHFFFAOYAY
SMILES O=C1Nccc(N)n1
Properties
Chemical formula	C4H5N3O
Molar mass	111.10 g/mol
Density	1.55 g/cm3 (calculated)
Melting point	320 to 325 °C (608 to 617 °F; 593 to 598 K) (decomposes)
Acidity (pKa)	4.45 (secondary), 12.2 (primary)
Magnetic susceptibility (χ)	−55.8·10−6 cm3/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

Cytosine (/ˈsaɪtəˌsiːn, -ˌziːn, -ˌsɪn/) (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). Cytosine pairs specifically with guanine through hydrogen bonds. It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an amine group at position 4 and a keto group at position 2). The nucleoside of cytosine is cytidine. In Watson–Crick base pairing, it forms three hydrogen bonds with guanine. Its structural integrity and pairing are vital for the accurate storage and transmission of genetic information.

History

Cytosine was discovered and named by Albrecht Kossel and Albert Neumann in 1894 when it was hydrolyzed from calf thymus tissues. A structure was proposed in 1903, and was synthesized (and thus confirmed) in the laboratory in the same year.

In 1998, cytosine was used in an early demonstration of quantum information processing when Oxford University researchers implemented the Deutsch–Jozsa algorithm on a two qubit nuclear magnetic resonance quantum computer (NMRQC).

In March 2015, NASA scientists reported the formation of cytosine, along with uracil and thymine, from pyrimidine under the space-like laboratory conditions, which is of interest because pyrimidine has been found in meteorites although its origin is unknown.

Chemical reactions

Cytosine

Guanine

Cytosine and guanine with the direction of hydrogen bonding indicated (arrow points positive to negative charge).
Methylation of cytosine occurs on carbon number 5.

Chemically, cytosine is classified as a pyrimidine derivative, characterized by a heterocyclic aromatic ring with nitrogen atoms at positions 1 and 3. Its structure allows it to form three hydrogen bonds with guanine, contributing to the stability of the DNA double helix. Cytosine can be found as part of DNA, as part of RNA, or as a part of a nucleotide. In the context of nucleic acids, cytosine's ability to pair with guanine is crucial for the fidelity of genetic information during DNA replication and RNA transcription. This specific pairing ensures that genetic codes are accurately copied and expressed.

As cytidine triphosphate (CTP), it can act as a co-factor to enzymes, and can transfer a phosphate to convert adenosine diphosphate (ADP) to adenosine triphosphate (ATP).

In DNA and RNA, cytosine is paired with guanine. However, it is inherently unstable, and can change into uracil (spontaneous deamination). This can lead to a point mutation if not repaired by the DNA repair enzymes such as uracil glycosylase, which cleaves a uracil in DNA.

Cytosine residues in DNA can undergo methylation into 5-methylcytosine by an enzyme called DNA methyltransferase or additionally hydroxylated to make 5-hydroxymethylcytosine. This epigenetic modification plays a pivotal role in regulating gene expression, embryonic development, and genomic imprinting. Abnormal methylation patterns have been linked to various diseases, including cancer. The difference in rates of deamination of cytosine and 5-methylcytosine (to uracil and thymine) forms the basis of bisulfite sequencing.

Analogues in Medicine

Cytosine analogues (chemical) have been instrumental in the development of various therapeutic agents, particularly in oncology and antifungal treatments. These analogues are structurally modified derivatives of cytosine designed to interfere with nucleic acid metabolism, thereby exerting cytostatic or cytotoxic antibiotic effects on target cells.

Anti-fungal agents

Flucytosine (5-fluorocytosine) is a fluorinated cytosine analogue utilized in the treatment of serious fungal infections caused by Candida albicans and Cryptococcus species. Administered orally, flucytosine is absorbed and subsequently deaminated by fungal cytosine deaminase to 5-fluorouracil (5-FU), which disrupts fungal RNA and DNA synthesis. Due to the potential for rapid development of resistance, flucytosine is often used in combination with Amphotericin B to enhance efficacy and reduce resistance emergence. Notably, co-administration with cytarabine, another cytosine analogue, may inactivate flucytosine's antifungal activity through competitive inhibition.

Antineoplastic agents

Cytarabine (cytosine arabinoside or Ara-C) is a chemotherapeutic agent primarily employed in the treatment of acute myeloid leukemia (AML) and other hematologic malignancies. As an analogue of deoxycytidine, cytarabine undergoes phosphorylation to its active triphosphate form, which incorporates into DNA during replication, leading to chain termination and apoptosis of rapidly dividing cells. Its efficacy is attributed to the inhibition of DNA polymerase and subsequent disruption of DNA synthesis.

Mechanisms of action

The therapeutic effects of cytosine analogues are largely due to their ability to mimic natural nucleosides, allowing their incorporation into nucleic acids. Once incorporated, these analogues can inhibit essential enzymes such as DNA polymerase or thymidylate synthase, disrupt nucleic acid synthesis, and induce cell death. For instance, flucytosine's metabolite, 5-FU, interferes with both RNA function and DNA synthesis in fungal cells, while cytarabine's incorporation into DNA leads to replication arrest in malignant cells.

Clinical considerations

While cytosine analogues have proven effective in various therapeutic contexts, their use is associated with potential adverse effects. Flucytosine can cause bone marrow suppression, hepatotoxicity, and gastrointestinal disturbances. Cytarabine is known for side effects such as myelosuppression, cerebellar toxicity, and mucositis. Therefore, careful monitoring and supportive care are essential during treatment with these agents.

In summary, cytosine analogues play a crucial role in medical therapeutics, particularly in antifungal and anticancer applications. Their ability to interfere with nucleic acid metabolism underpins their clinical utility, while also necessitating careful management of associated toxicities.

Biological function

When found third in a codon of RNA, cytosine is synonymous with uracil, as they are interchangeable as the third base. When found as the second base in a codon, the third is always interchangeable. For example, UCU, UCC, UCA and UCG are all serine, regardless of the third base. Spontaneous deanimation of cytosine converts it into uracil, leading to G:C to A:T transition mutations if not corrected. The DNA repair machinery, particularly uracil-DNA glycosylase, identifies and excises uracil to maintain genomic integrity.

Active enzymatic deamination of cytosine or 5-methylcytosine by the APOBEC family of cytosine deaminases could have both beneficial and detrimental implications on various cellular processes as well as on organismal evolution. The implications of deamination on 5-hydroxymethylcytosine, on the other hand, remains less understood.

Theoretical aspects

Until October 2021, Cytosine had not been found in meteorites, which suggested the first strands of RNA and DNA had to look elsewhere to obtain this building block. Cytosine likely formed within some meteorite parent bodies, however did not persist within these bodies due to an effective deamination reaction into uracil.

In October 2021, Cytosine was announced as having been found in meteorites by researchers in a joint Japan/NASA project, that used novel methods of detection which avoided damaging nucleotides as they were extracted from meteorites.

External links and citations

• Cytosine MS Spectrum
• EINECS number 200-749-5
• Shapiro R (1999). "Prebiotic cytosine synthesis: a critical analysis and implications for the origin of life". Proc. Natl. Acad. Sci. U.S.A. 96 (8): 4396–401. Bibcode:1999PNAS...96.4396S. doi:10.1073/pnas.96.8.4396. PMC 16343. PMID 10200273.