2,6-Diaminopurine

2,6-diaminopurine (2,6-DAP, also known as 2-aminoadenine, standard IUPAC symbol n2A[1]: N4.1, N4.4 ) is a compound once used in the treatment of leukemia.[2] It is found instead of adenine (A) in the genetic material of some bacteriophage viruses,[3]

In August 2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting 2,6-diaminopurine and related organic molecules, including the DNA and RNA components adenine and guanine, may have been formed extraterrestrially in outer space.[4][5][6]

## Contents

* 1 Abbreviations
* 2 In viruses
* 3 Biosynthesis
* 4 In cellular life
* 5 Bioengineering
* 6 References

## Abbreviations

In virology it is referred to as the "Z" base.[7] However, "Z" refers instead to 6-amino-5-nitropyridin-2-one in the Artificially Expanded Genetic Information System (AEGIS), so context is required to differentiate.[8] AEGIS refers to this base as "AminoA" instead.[9]

It has also been called the "D" base,[10][11] but the more common interpretation of "D" is dihydrouridine.[12]

## In viruses

DiampurineT DNA base pair

In cyanophage S-2L (Siphoviridae), diaminopurine is used instead of adenine (host evasion).[13] Diaminopurine base (Z) pairs perfectly with thymine (T) as it is identical to adenine (A) but has an amine group at position 2 forming 3 intermolecular hydrogen bonds, eliminating the major difference between the two types of basepairs (weak:A-T and strong:C-G). This improved stability affects protein-binding interactions that rely on those differences.

Four papers published April 2021 further describes the use and production of the Z-base. It is now known that:[14]

* The S-2L phage avoids incorporating A bases in the genome by hydrolyzing dATP (DatZ enzyme);[15]
* The Z base is produced by a pathway involving DUF550 (MazZ) and PurZ in S-2L and Vibrio phage PhiVC8;[7]
* The PrimPol/AEP DNA polymerase responsible for handling the Z base occurs in the same gene cluster as the three aforementioned enzymes;[16]
* The Z base is quite widespread in both Siphoviridae and Podoviridae, based on the occurrence of the said gene cluster.[17]

In August 2021, it was shown that DatZ, MazZ and PurZ are sufficient to replace some occurrence of A by Z in the bacterial genome of E. coli; expression of this system is toxic to the cell. The structures of MazZ (subtype 2) and PurZ are also determined, showing a possible link between PurZ and archaeal versions of PurA.[18]

## Biosynthesis

2-aminoadenine is produced in two steps. The enzyme MazZ (homologous to MazG, EC 3.6.1.8) first performs:[18]

dGTP \+ H2O = dGMP \+ diphosphate

The enzyme PurZ (homologous to PurA, EC 6.3.4.4) then performs:[7]

(d)ATP + dGMP \+ L-aspartate = (d)ADP + phosphate + 2-aminodeoxyadenylosuccinate (dSMP)

The resulting dSMP is processed by host enzymes analogously to adenylosuccinate to produce dZTP.

## In cellular life

This article is missing information about results of the altered H-bond strength in DNA and RNA. Please expand the article to include this information. Further details may exist on the talk page. (October 2021)

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2,6-DAP was used to treat leukemia since as early as 1951.[19] It is known to arrest progression of cell cycle in mouse leukemia cells by 1989.[20] Cancer cells are known to become resistant to DAP by losing their adenine phosphoribosyltransferase (APRT) function,[21] a process shared with E. coli.[22]

DAP derivatives are in vitro antivirals useful against pseudorabies virus, a economically important livestock disease.[23] This base, in its free form, is able to correct UGA nonsense mutations by encouraging translational readthrough, through the inhibition of FTSJ1.[24]

## Bioengineering

In bioengineering, anti-miRNA oligonucleotides (specifically, the serinol nucleic acid [SNA] type) incorporating base Z instead of A show enhanced binding to RNA.[25]

DAP is used similarly to other nuclear acid analogues in the investigation of enzyme structures and mechanisms.[26]

## References

1. ↑ IUPAC-IUB Commission on Biochemical Nomenclature (1970). "Abbreviations and symbols for nucleic acids, polynucleotides, and their constituents". Biochemistry 9 (20): 4022–4027. doi:10.1021/bi00822a023. https://iupac.qmul.ac.uk/misc/naabb.html#p44.
2. ↑ "George H. Hitchings". nobelprize.org. https://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/hitchings-bio.html.
3. ↑ "Some viruses thwart bacterial defenses with a unique genetic alphabet". 5 May 2021. https://www.sciencenews.org/article/virus-dna-z-bacteriophage-genetic-alphabet-bond-life.
4. ↑ Callahan, M.P.; Smith, K.E.; Cleaves, H.J.; Ruzica, J.; Stern, J.C.; Glavin, D.P.; House, C.H.; Dworkin, J.P. (11 August 2011). "Carbonaceous meteorites contain a wide range of extraterrestrial nucleobases". Proceedings of the National Academy of Sciences (PNAS) 108 (34): 13995–13998. doi:10.1073/pnas.1106493108. PMID 21836052. Bibcode: 2011PNAS..10813995C.
5. ↑ Steigerwald, John (8 August 2011). "NASA Researchers: DNA Building Blocks Can Be Made in Space". NASA. http://www.nasa.gov/topics/solarsystem/features/dna-meteorites.html. Retrieved 2011-08-10.
6. ↑ ScienceDaily Staff (9 August 2011). "DNA Building Blocks Can Be Made in Space, NASA Evidence Suggests". ScienceDaily. https://www.sciencedaily.com/releases/2011/08/110808220659.htm. Retrieved 2011-08-09.
7. ↑ 7.0 7.1 7.2 Sleiman, Dona; Garcia, Pierre Simon; Lagune, Marion; Loc’h, Jerome; Haouz, Ahmed; Taib, Najwa; Röthlisberger, Pascal; Gribaldo, Simonetta et al. (30 April 2021). "A third purine biosynthetic pathway encoded by aminoadenine-based viral DNA genomes". Science 372 (6541): 516–520. doi:10.1126/science.abe6494. PMID 33926955. Bibcode: 2021Sci...372..516S.
8. ↑ Kawabe, Hinako; Thomas, Christopher A.; Hoshika, Shuichi; Kim, Myong-Jung; Kim, Myong-Sang; Miessner, Logan; Kaplan, Nicholas; Craig, Jonathan M. et al. (26 October 2023). "Enzymatic synthesis and nanopore sequencing of 12-letter supernumerary DNA". Nature Communications 14 (1). doi:10.1038/s41467-023-42406-z. PMID 37884513. Bibcode: 2023NatCo..14.6820K.
9. ↑ Benner, SA; Hutter, D; Sismour, AM (1 September 2003). "Synthetic biology with artificially expanded genetic information systems. From personalized medicine to extraterrestrial life.". Nucleic Acids Research. Supplement 3 (3): 125–6. doi:10.1093/nass/3.1.125. PMID 14510412.
10. ↑ Chou, FC; Kladwang, W; Kappel, K; Das, R (26 July 2016). "Blind tests of RNA nearest-neighbor energy prediction.". Proceedings of the National Academy of Sciences of the United States of America 113 (30): 8430–5. doi:10.1073/pnas.1523335113. PMID 27402765. Bibcode: 2016PNAS..113.8430C.
11. ↑ Hopfinger, MC; Kirkpatrick, CC; Znosko, BM (18 September 2020). "Predictions and analyses of RNA nearest neighbor parameters for modified nucleotides.". Nucleic Acids Research 48 (16): 8901–8913. doi:10.1093/nar/gkaa654. PMID 32810273.
12. ↑ IUPAC-IUB Commission on Biochemical Nomenclature (1970). "Abbreviations and symbols for nucleic acids, polynucleotides, and their constituents". Biochemistry 9 (20): 4022–4027. doi:10.1021/bi00822a023.
13. ↑ Kirnos, MD; Khudyakov, IY; Alexandrushkina, NI; Vanyushin, BF (November 1977). "2-aminoadenine is an adenine substituting for a base in S-2L cyanophage DNA". Nature 270 (5635): 369–70. doi:10.1038/270369a0. PMID 413053. Bibcode: 1977Natur.270..369K.
14. ↑ Bowler, Jacinta (4 May 2021). "Some Viruses Have a Completely Different Genome to The Rest of Life on Earth". ScienceAlert. https://www.sciencealert.com/some-bacteriophages-have-a-completely-different-genome-to-the-rest-of-life-on-earth.
15. ↑ Czernecki, Dariusz; Legrand, Pierre; Tekpinar, Mustafa; Rosario, Sandrine; Kaminski, Pierre-Alexandre; Delarue, Marc (2021-04-23). "How cyanophage S-2L rejects adenine and incorporates 2-aminoadenine to saturate hydrogen bonding in its DNA" (in en). Nature Communications 12 (1): 2420. doi:10.1038/s41467-021-22626-x. ISSN 2041-1723. PMID 33893297. Bibcode: 2021NatCo..12.2420C.
16. ↑ Pezo, Valerie; Jaziri, Faten; Bourguignon, Pierre-Yves; Louis, Dominique; Jacobs-Sera, Deborah; Rozenski, Jef; Pochet, Sylvie; Herdewijn, Piet et al. (30 April 2021). "Noncanonical DNA polymerization by aminoadenine-based siphoviruses". Science 372 (6541): 520–524. doi:10.1126/science.abe6542. PMID 33926956. Bibcode: 2021Sci...372..520P.
17. ↑ Zhou, Yan; Su, Xuexia; Wei, Yifeng; Cheng, Yu; Guo, Yu; Khudyakov, Ivan; Liu, Fuli; He, Ping et al. (30 April 2021). "A widespread pathway for substitution of adenine by diaminopurine in phage genomes". Science 372 (6541): 512–516. doi:10.1126/science.abe4882. PMID 33926954. Bibcode: 2021Sci...372..512Z. https://www.researchgate.net/publication/351214584.
18. ↑ 18.0 18.1 Czernecki, Dariusz; Bonhomme, Frédéric; Kaminski, Pierre-Alexandre; Delarue, Marc (2021-08-05). "Characterization of a triad of genes in cyanophage S-2L sufficient to replace adenine by 2-aminoadenine in bacterial DNA" (in en). Nature Communications 12 (1): 4710. doi:10.1038/s41467-021-25064-x. ISSN 2041-1723. PMID 34354070. Bibcode: 2021NatCo..12.4710C.
19. ↑ Burchenal, JH; Karnofsky, DA; Kingsley-Pillers, EM; Southam, CM; Myers, WP; Escher, GC; Craver, LF; Dargeon, HW et al. (May 1951). "The effects of the folic acid antagonists and 2,6-diaminopurine on neoplastic disease, with special reference to acute leukemia". Cancer 4 (3): 549–69. doi:10.1002/1097-0142(195105)4:3<549::aid-cncr2820040308>3.0.co;2-j. PMID 14839611.
20. ↑ Weckbecker, G; Cory, JG (1989). "Metabolic activation of 2,6-diaminopurine and 2,6-diaminopurine-2'-deoxyriboside to antitumor agents.". Advances in Enzyme Regulation 28: 125–44. doi:10.1016/0065-2571(89)90068-x. PMID 2624171.
21. ↑ Shao, C; Deng, L; Henegariu, O; Liang, L; Stambrook, PJ; Tischfield, JA (20 June 2000). "Chromosome instability contributes to loss of heterozygosity in mice lacking p53.". Proceedings of the National Academy of Sciences of the United States of America 97 (13): 7405–10. doi:10.1073/pnas.97.13.7405. PMID 10861008. Bibcode: 2000PNAS...97.7405S.
22. ↑ Kocharian, ShM; Chukanova, TI; Sukhodolets, VV (1977). "[Mutations of resistance to 2,6-diaminopurine and 6-methylpurine that affect adenine phosphoribosyltransferase in Escherichia coli K-12].". Genetika 13 (10): 1821–30. PMID 348574.
23. ↑ Zouharova, D; Lipenska, I; Fojtikova, M; Kulich, P; Neca, J; Slany, M; Kovarcik, K; Turanek-Knotigova, P et al. (29 February 2016). "Antiviral activities of 2,6-diaminopurine-based acyclic nucleoside phosphonates against herpesviruses: In vitro study results with pseudorabies virus (PrV, SuHV-1).". Veterinary Microbiology 184: 84–93. doi:10.1016/j.vetmic.2016.01.010. PMID 26854349.
24. ↑ Trzaska, C; Amand, S; Bailly, C; Leroy, C; Marchand, V; Duvernois-Berthet, E; Saliou, JM; Benhabiles, H et al. (20 March 2020). "2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations.". Nature Communications 11 (1): 1509. doi:10.1038/s41467-020-15140-z. PMID 32198346. Bibcode: 2020NatCo..11.1509T.
25. ↑ Kamiya, Y; Donoshita, Y; Kamimoto, H; Murayama, K; Ariyoshi, J; Asanuma, H (5 October 2017). "Introduction of 2,6-Diaminopurines into Serinol Nucleic Acid Improves Anti-miRNA Performance.". ChemBioChem 18 (19): 1917–1922. doi:10.1002/cbic.201700272. PMID 28748559.
26. ↑ Bailly, C (1 October 1998). "The use of diaminopurine to investigate structural properties of nucleic acids and molecular recognition between ligands and DNA". Nucleic Acids Research 26 (19): 4309–4314. doi:10.1093/nar/26.19.4309. PMID 9742229.

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