N4-Acetylcytidine

N4-Acetylcytidine
Names
IUPAC name
N-[1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]acetamide
Other names
  • ac4C
  • N-acetylcytidine
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.021.087
EC Number
  • 223-195-6
KEGG
  • InChI=1S/C11H15N3O6/c1-5(16)12-7-2-3-14(11(19)13-7)10-9(18)8(17)6(4-15)20-10/h2-3,6,8-10,15,17-18H,4H2,1H3,(H,12,13,16,19)/t6-,8-,9-,10-/m1/s1
    Key: NIDVTARKFBZMOT-PEBGCTIMSA-N
  • CC(=O)NC1=NC(=O)N(C=C1)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O
Properties
C11H15N3O6
Molar mass 285.256 g·mol−1
Appearance white amorphous solid, sometimes yellow/brown
Density 1.72 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

N4-Acetylcytidine (ac4C, ac4C) is a post-transcriptional modification found in tRNAs,[1] rRNAs,[1] and mRNAs.[1][2] In this modification, the amino group at the N4 position of the RNA base cytosine is acetylated, resulting in the formation of an amide.[3] In vivo, this modification is considered highly conserved because it is seen in all three domains of life: archaea, bacteria, and eukarya.[3]

Discovery

The first appearances of ac4C in the literature are from 1965 and 1966.[4][5] These early studies refer to the acetylated nucleoside as N6-acetylcytidine and describe the acetylation as occurring on the exocyclic amino group of cytidine.[4][5] After the IUPAC established a globalized nucleic acid notation in 1970,[6] the modern designation for the modified nucleotide became N4-acetyl cytidine. In 1965, M. Anteunis and M. Van Montagu report the in-vitro synthesis of N6-acetyl cytidine through the use of thiolacetic acid or α-acetoxyacrylonitrile and the characterization of the structure with proton magnetic resonance (PMR).[4] In 1966, Zachau and coworkers, reported the ellucidated primary structures of two serine tRNAs from yeast and mention the presence of N6-acetyl cytidine at the C12 position.[3][5]

In vivo

In vivo, the ac4C modification is installed by the enzyme N-acetyltransferase 10 (NAT10), sometimes with assistance from other cofactors such as THUMPD1.[1][3] Across organisms, homologues of human NAT10 have been observed across archaea, bacteria, and eukarya.[1] In tRNA, rRNA, and mRNA, ac4C modifications are associated with contributions to efficiency of protein translation, as well as increased RNA stability.[1]

tRNA

The RNA modification ac4C was first identified in tRNA in 1966, when Zachau and coworkers reported ac4C at position 12 of yeast serine tRNA.[5] In 1972, ac4C was reported at the wobble position of the E. coli elongator methionine tRNA.[7] This modification of the wobble base is thought to improve recognition of the AUG codon.[8] In tRNA for leucine and serine, the ac4C modification has been identified at position 12 in Saccharomyces cerevisiae.[9] Johansson and coworkers showed that ac4C contributes to tRNA stability.[9] Deletion of the TAN1 gene, which is required for ac4C formation, resulted in decreased levels of mature serine tRNA.[9]

rRNA

In 1978, Thomas and coworkers found ac4C on rat 18S rRNA.[1][10] In 1988, Johansen and coworkers observed ac4C in the 3' end helix of Dictyostelium discoideum 18S rRNA.[1][11] In 1993, Bruenger and coworkers found ac4C on C. thermophila 5S rRNA.[1][12] In 2014, Ito and coworkers reported that in HEK293 cells, NAT10 catalyzed the formation of ac4C at position 1842 on 18S rRNA.[1][13] The acetylated rRNA has been associated with increased stability, particularly under thermal stress.[3]

mRNA

In mRNA, the ac4C modification is also reported to be catalyzed by NAT10 and its homologues across species.[2][14] In 2018, Arango and coworkers reported the ac4C modification in mRNA catalyzed by NAT10 in HeLa cells, identified the modification by using mass spectrometry and confirmed it with dot blot analysis.[14] In 2019, Tardu and coworkers quantitatively reported ac4C modifications in Saccharomyces cerevisiae using ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS) methods.[2]

Enzymology (NAT10 and homologues)

In bacteria, TmcA-type RNA acetyltransferases catalyze the acetylation of the wobble base cytidine of initiator methionine tRNA.[3][8][15] An analysis of knockout strains in E. coli indicates that TmcA is nonessential and does not cause growth defects.[3][8][16]

In eukaryotes, the RNA acetyltransferases, human Nat10 and yeast Kre33, function alongside adapter proteins to install ac4C in leucine and serine tRNA and in helices 34 and 45 of 18S rRNA.[3][13][17][18] Cellular studies identified the adapter proteins Thumpd1 for Nat10 and Tan1 for Kre33.[3][9] It was also seen that rRNA acetylation requires an adapter short nucleolar RNA.[3][18] Ito and coworkers found that Nat10 and Kre33 exclusively modified model RNAs containing a 5'-CCG-3' sequence.[3][17]

In vitro

Synthesis

Obtaining the modified nucleoside can be done in vitro, often with a one-pot synthesis.[4][19][20] In 1965, M. Anteunis and M. Van Montagu report the in-vitro synthesis of N6-acetyl cytidine through the use of thiolacetic acid or α-acetoxyacrylonitrile and the characterization of the structure with proton magnetic resonance (PMR).[4] In 1968, Montagu and coworkers also report success in obtaining the acetylated nucleoside using thioacetic acid.[19] However, they go on to say that with the nucleotide diphosphate or triphosphates, using thioacetic acid resulted in many side reactions.[19] In 1989, Bhat and coworkers reported success acetylating the nucleoside by dissolving it in dimethylformamide (DMF) and adding acetic anhydride as the acetylating agent.[20]


References

  1. ^ a b c d e f g h i j Jin, Gehui; Xu, Mingqing; Zou, Mengsha; Duan, Shiwei (June 2020). "The Processing, Gene Regulation, Biological Functions, and Clinical Relevance of N4-Acetylcytidine on RNA: A Systematic Review". Molecular Therapy - Nucleic Acids. 20: 13–24. doi:10.1016/j.omtn.2020.01.037. PMC 7068197. PMID 32171170.
  2. ^ a b c Tardu, Mehmet; Jones, Joshua D.; Kennedy, Robert T.; Lin, Qishan; Koutmou, Kristin S. (19 July 2019). "Identification and Quantification of Modified Nucleosides in Saccharomyces cerevisiae mRNAs". ACS Chemical Biology. 14 (7): 1403–1409. doi:10.1021/acschembio.9b00369. PMC 7254066. PMID 31243956.
  3. ^ a b c d e f g h i j k Gamage, Supuni Thalalla; Manage, Shereen A. Howpay; Chu, T. Thu; Meier, Jordan L. (6 February 2024). "Cytidine Acetylation Across the Tree of Life". Accounts of Chemical Research. 57 (3): 338–348. doi:10.1021/acs.accounts.3c00673. PMC 11578069. PMID 38226431.
  4. ^ a b c d e Anteunis, M.; van Montagu, M. (January 1965). "Locked acetyl group in N (6) -acetylcytidine". Bulletin des Sociétés Chimiques Belges. 74 (11–12): 481–487. doi:10.1002/bscb.19650741102.
  5. ^ a b c d Zachau, Hans Georg; Dütting, Bieter; Feldmann, Horst (January 1966). "The Structures of Two Serine Transfer Ribonucleic Acids". Hoppe-Seyler's Zeitschrift für physiologische Chemie. 347 (4): 212–235. doi:10.1515/bchm2.1966.347.1.212. PMID 5991670.
  6. ^ Iupac-Iub Comm. On Biochem. Nomenclature (Cbn) (29 September 1970). "Abbreviations and symbols for nucleic acids, polynucleotides, and their constituents". Biochemistry. 9 (20): 4022–4027. doi:10.1021/bi00822a023.
  7. ^ Ohashi, Z.; Murao, K.; Yahagi, T.; Von Minden, D.L.; McCloskey, James A.; Nishimura, S. (March 1972). "Characterization of C+ located in the first position of the anticodon of Escherichia coli tRNAMet as N-". Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis. 262 (2): 209–213. doi:10.1016/0005-2787(72)90234-1.
  8. ^ a b c Ikeuchi, Yoshiho; Kitahara, Kei; Suzuki, Tsutomu (20 August 2008). "The RNA acetyltransferase driven by ATP hydrolysis synthesizes N4-acetylcytidine of tRNA anticodon". The EMBO Journal. 27 (16): 2194–2203. doi:10.1038/emboj.2008.154. PMC 2500205. PMID 18668122.
  9. ^ a b c d Johansson, Marcus J.O.; Byström, Anders S. (April 2004). "The Saccharomyces cerevisiae TAN1 gene is required for N 4 -acetylcytidine formation in tRNA". RNA. 10 (4): 712–719. doi:10.1261/rna.5198204. PMC 1370561. PMID 15037780.
  10. ^ Thomas, G.; Gordon, J.; Rogg, H. (February 1978). "N4-Acetylcytidine. A previously unidentified labile component of the small subunit of eukaryotic ribosomes". Journal of Biological Chemistry. 253 (4): 1101–1105. doi:10.1016/S0021-9258(17)38117-6. PMID 624721.
  11. ^ Johansen, Terje; Johansen, Steinar; Haugh, Finn B. (September 1988). "Nucleotide sequence of the Physarum polycephalum small subunit ribosomal RNA as inferred from the gene sequence: secondary structure and evolutionary implications". Current Genetics. 14 (3): 265–273. doi:10.1007/BF00376747. PMID 3197135.
  12. ^ Bruenger, E; Kowalak, J A; Kuchino, Y; McCloskey, J A; Mizushima, H; Stetter, K O; Crain, P F (January 1993). "5S rRNA modification in the hyperthermophilic archaea Sulfolobus solfataricus and Pyrodictium occultum". The FASEB Journal. 7 (1): 196–200. doi:10.1096/fasebj.7.1.8422966. PMID 8422966.
  13. ^ a b Ito, Satoshi; Horikawa, Sayuri; Suzuki, Tateki; Kawauchi, Hiroki; Tanaka, Yoshikazu; Suzuki, Takeo; Suzuki, Tsutomu (December 2014). "Human NAT10 Is an ATP-dependent RNA Acetyltransferase Responsible for N4-Acetylcytidine Formation in 18 S Ribosomal RNA (rRNA)". Journal of Biological Chemistry. 289 (52): 35724–35730. doi:10.1074/jbc.C114.602698. PMC 4276842. PMID 25411247.
  14. ^ a b Arango, Daniel; Sturgill, David; Alhusaini, Najwa; Dillman, Allissa A.; Sweet, Thomas J.; Hanson, Gavin; Hosogane, Masaki; Sinclair, Wilson R.; Nanan, Kyster K.; Mandler, Mariana D.; Fox, Stephen D.; Zengeya, Thomas T.; Andresson, Thorkell; Meier, Jordan L.; Coller, Jeffery; Oberdoerffer, Shalini (December 2018). "Acetylation of Cytidine in mRNA Promotes Translation Efficiency". Cell. 175 (7): 1872–1886.e24. doi:10.1016/j.cell.2018.10.030. PMC 6295233. PMID 30449621.
  15. ^ Chimnaronk, Sarin; Suzuki, Tateki; Manita, Tetsuhiro; Ikeuchi, Yoshiho; Yao, Min; Suzuki, Tsutomu; Tanaka, Isao (6 May 2009). "RNA helicase module in an acetyltransferase that modifies a specific tRNA anticodon". The EMBO Journal. 28 (9): 1362–1373. doi:10.1038/emboj.2009.69. PMC 2683049. PMID 19322199.
  16. ^ Yacoubi, Basma El; Phillips, Gabriela; Blaby, Ian K.; Haas, Crysten E.; Cruz, Yulien; Greenberg, Jamie; de Crécy-Lagard, Valérie (January 2009). "A Gateway platform for functional genomics in Haloferax volcanii: deletion of three tRNA modification genes". Archaea. 2 (4): 211–219. doi:10.1155/2009/428489. PMC 2686393. PMID 19478918.
  17. ^ a b Ito, Satoshi; Akamatsu, Yu; Noma, Akiko; Kimura, Satoshi; Miyauchi, Kenjyo; Ikeuchi, Yoshiho; Suzuki, Takeo; Suzuki, Tsutomu (September 2014). "A Single Acetylation of 18 S rRNA Is Essential for Biogenesis of the Small Ribosomal Subunit in Saccharomyces cerevisiae". Journal of Biological Chemistry. 289 (38): 26201–26212. doi:10.1074/jbc.M114.593996. PMC 4176211. PMID 25086048.
  18. ^ a b Sharma, Sunny; Langhendries, Jean-Louis; Watzinger, Peter; Kötter, Peter; Entian, Karl-Dieter; Lafontaine, Denis L.J. (27 February 2015). "Yeast Kre33 and human NAT10 are conserved 18S rRNA cytosine acetyltransferases that modify tRNAs assisted by the adaptor Tan1/THUMPD1". Nucleic Acids Research. 43 (4): 2242–2258. doi:10.1093/nar/gkv075. PMC 4344512. PMID 25653167.
  19. ^ a b c Montagu, M.; Molemans, F.; Stockx, J. (January 1968). "Preparation of Cytidine, Cytidylic Acids and Ribonucleic Acid Specifically Acetylated in the Exocyclic Amino Group of Cytosine". Bulletin des Sociétés Chimiques Belges. 77 (3–4): 171–179. doi:10.1002/bscb.19680770307.
  20. ^ a b Bhat, V.; Ugarkar, B. G.; Sayeed, V. A.; Grimm, K.; Kosora, N.; Domenico, P. A.; Stocker, E. (January 1989). "A Simple and Convenient Method for the Selective N-Acylations of Cytosine Nucleosides". Nucleosides and Nucleotides. 8 (2): 179–183. doi:10.1080/07328318908054166.
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