Ap4A

Diadenosine tetraphosphate or Ap4A is a putative alarmone, ubiquitous in nature being common to everything from bacteria to humans. It is made up of two adenosines joined together by a 5′-5′ linked chain of four phosphates. Adenosine polyphosphates are capable of inducing multiple physiological effects.[1]

Ap4A
Names
IUPAC name
O1,O7-Di(5′-deoxyadenosin-5′-yl) tetrahydrogen tetraphosphate
Systematic IUPAC name
O1,O7-Bis{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl} tetrahydrogen tetraphosphate
Other names
Diadenosine tetraphosphate; 5',5'''-Diadenosine tetraphosphate; AppppA
Identifiers
3D model (JSmol)
  • C1=NC2=C(C(=N1)N)N=CN2[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)OC[C@@H]4[C@H]([C@H]([C@@H](O4)N5C=NC6=C5N=CN=C6N)O)O)O)O
Properties
C20H28N10O19P4
Molar mass 836.390 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Function

In Eukaryotes

Ap4A can be created by a non-canonical activity of the Lysyl-tRNA synthetase (LysRS). This function of LysRS is activated by the phosphorylation of LysRS on serine 207, its subsequent dissociation from the multi-synthetase complex (MSC).[2] The molecule's role as a second messenger has recently been discovered in The LysRS-Ap4A-MITF signaling pathway.[3] Ap4A binds to the MITF-HINT1 inhibitory complex, specifically to the molecule histidine triad nucleotide–binding protein 1(HINT1), releasing the Microphthalmia-associated transcription factor (MITF) and causing an increase in the transcription of its target genes.[4] Ap4A also positively regulates the activity of the transcription factor USF2 through a similar molecular mechanism to that of MITF.[5]

It has also been shown, that Ap4A plays a role in the functionality of dendritic cells (DCs). An increase in the intracellular amount Improves their motility and antigen presenting ability through alterations in small GTPases present in the cells. This was discovered by creating mice deficient in the enzyme NUDT2, which serves as an Ap4A hydrolase and thus controls the levels of Ap4A in the cell.[6] Ap4A, however, has also been shown to cause apoptosis in several cell lines through an unknown mechanism, the degradation of Ap4A was necessary for the process as hydrolysis‐resistant analogues of the molecule showed no apoptotic activity.[7]

In Prokaryotes

In E. Coli, Ap4A has been shown to function as an alarmone, as the intracellular concentration of the molecule increases upon heat stress.[8] Ap4A can also be incorporated into RNA as a 5' Cap along with other dinucleoside polyphosphates. It serves as a substrate for the RNA polymerase and the intracellular levels of these capped RNAs increase upon stress, suggesting that the cap adds a level of stability to the RNA.[9]

Myxococcus xanthus is a type of Gram-negative bacteria, and M. xanthus lysyl-tRNA synthetase (LysS) is an enzyme from the bacteria that synthesizes diadenosine tetraphosphates (Ap4A) when adenosine triphosphate (ATP) is present. Diadenosine pentaphosphate (Ap5A) is synthesized from Ap4A with ATP.[10]

References
  1. Luo, Jiankai; Jankowski, Vera; GüNgär, Nihayrt; Neumann, Joachim; Schmitz, Wilhelm; Zidek, Walter; SchlüTer, Hartmut; Jankowski, Joachim (2004). "Endogenous diadenosine tetraphosphate, diadenosine pentaphosphate, and diadenosine hexaphosphate in human myocardial tissue". Hypertension. 43 (5): 1055–9. doi:10.1161/01.hyp.0000126110.46402.dd. PMID 15066958.
  2. Ofir-Birin, Yifat; Fang, Pengfei; Bennett, Steven P.; Zhang, Hui-Min; Wang, Jing; Rachmin, Inbal; Shapiro, Ryan; Song, Jing; Dagan, Arie; Pozo, Jorge; Kim, Sunghoon; Marshall, Alan G.; Schimmel, Paul; Yang, Xiang-Lei; Nechushtan, Hovav; Razin, Ehud; Guo, Min (2013-01-10). "Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription". Molecular Cell. 49 (1): 30–42. doi:10.1016/j.molcel.2012.10.010. ISSN 1097-2765. PMC 3766370. PMID 23159739.
    • Lee, Yu-Nee; Nechushtan, Hovav; Figov, Navah; Razin, Ehud (April 2004). "The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of MITF activity in FcepsilonRI-activated mast cells". Immunity. 20 (2): 145–51. doi:10.1016/S1074-7613(04)00020-2. PMID 14975237.
  4. Yu, Jing; Liu, Zaizhou; Liang, Yuanyuan; Luo, Feng; Zhang, Jie; Tian, Cuiping; Motzik, Alex; Zheng, Mengmeng; Kang, Jingwu; Zhong, Guisheng; Liu, Cong (2019-10-11). "Second messenger Ap4A polymerizes target protein HINT1 to transduce signals in FcεRI-activated mast cells". Nature Communications. 10 (1): 4664. doi:10.1038/s41467-019-12710-8. ISSN 2041-1723. PMC 6789022. PMID 31604935.
  5. Lee, Yu-Nee; Razin, Ehud (2005-10-15). "Nonconventional Involvement of LysRS in the Molecular Mechanism of USF2 Transcriptional Activity in FcεRI-Activated Mast Cells". Molecular and Cellular Biology. 25 (20): 8904–8912. doi:10.1128/MCB.25.20.8904-8912.2005. ISSN 0270-7306. PMC 1265770. PMID 16199869.
  6. Shu, Shin La; Paruchuru, Lakshmi Bhargavi; Tay, Neil Quanwei; Chua, Yen Leong; Foo, Adeline Shen Yun; Yang, Chris Maolin; Liong, Ka Hang; Koh, Esther Geok Liang; Lee, Angeline; Nechushtan, Hovav; Razin, Ehud; Kemeny, David Michael (2019-06-28). "Ap4A Regulates Directional Mobility and Antigen Presentation in Dendritic Cells". iScience. 16: 524–534. doi:10.1016/j.isci.2019.05.045. ISSN 2589-0042. PMC 6595237. PMID 31254530.
  7. Vartanian, Amalia; Alexandrov, Ivan; Prudowski, Igor; McLennan, Alexander; Kisselev, Lev (1999). "Ap4A induces apoptosis in human cultured cells". FEBS Letters. 456 (1): 175–180. doi:10.1016/S0014-5793(99)00956-4. ISSN 1873-3468. PMID 10452553.
  8. Despotović, Dragana; Brandis, Alexander; Savidor, Alon; Levin, Yishai; Fumagalli, Laura; Tawfik, Dan S. (2017). "Diadenosine tetraphosphate (Ap4A) – an E. coli alarmone or a damage metabolite?". The FEBS Journal. 284 (14): 2194–2215. doi:10.1111/febs.14113. ISSN 1742-4658. PMID 28516732.
  9. Hudeček, Oldřich; Benoni, Roberto; Reyes-Gutierrez, Paul E.; Culka, Martin; Šanderová, Hana; Hubálek, Martin; Rulíšek, Lubomír; Cvačka, Josef; Krásný, Libor; Cahová, Hana (2020-02-26). "Dinucleoside polyphosphates act as 5′-RNA caps in bacteria". Nature Communications. 11 (1): 1052. Bibcode:2020NatCo..11.1052H. doi:10.1038/s41467-020-14896-8. ISSN 2041-1723. PMC 7044304. PMID 32103016.
  10. Kimura, Yoshio; Tanaka, Chihiro; Oka, Manami (July 2018). "Identification of Major Enzymes Involved in the Synthesis of Diadenosine Tetraphosphate and/or Adenosine Tetraphosphate in Myxococcus xanthus". Current Microbiology. 75 (7): 811–817. doi:10.1007/s00284-018-1452-x. ISSN 1432-0991. PMID 29468302. S2CID 3402370.
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