article published yes Mingyue Li author 01f96916-0235-11eb-9379-a323192643b7 Monika Chodasiewicz author Malavika Muraleedharan author Israel M. Lopez author Michal Gorka author Olga Kerber author Saqer S. Alotaibi author Andrew D.L. Nelson author Rene Lenobel author Jaroslava Friedecká author Aleksandra Skirycz author Jiří Friml author 4159519E-F248-11E8-B48F-1D18A9856A870000-0002-8302-7596 JiFr department Cyclic nucleotides as second messengers in plants project Guanylate cyclase activity of TIR1/AFBs auxin receptors project Cyclic adenosine monophosphate (cAMP) is a fundamental second messenger involved in diverse signaling pathways across both animals and plants. While the role of 3′,5′-cAMP has been extensively characterized, the biological significance of its structural isomer, 2′,3′-cAMP, remains largely unexplored, particularly in plants. Here, we show that 2′,3′-cAMP and 3′,5′-cAMP represent parallel signaling systems in Arabidopsis thaliana, with different enzymatic origins and largely distinct downstream effects. In vitro enzymatic assays show that plant adenylate cyclases (ACs), including AFB5 and HpAC1, produce specifically 3′,5′-cAMP from ATP, whereas the TIR domain of protein L7 also catalyzes the formation of 2′,3′-cAMP from RNA. Comprehensive multiomics analyses reveal that two isomers elicit distinct yet partially overlapping metabolic, proteomic, and transcriptional response: 2′,3′-cAMP activates broad, stress-adaptive gene expression reprogramming, while 3′,5′-cAMP fine-tunes responses related to nutrient status and cellular homeostasis. Our findings establish the existence of dual cAMP signaling systems in plants, each with specialized functions and provide insights into the complex regulatory networks governing plant physiology. https://research-explorer.ista.ac.at/download/21914/21941/2026_ScienceAdv_Li2.pdf application/pdfno AAAS2026 eng 2375-2548 4210218710.1126/sciadv.aea7828 1219 Li M, Chodasiewicz M, Muraleedharan M, Lopez IM, Gorka M, Kerber O, Alotaibi SS, Nelson ADL, Lenobel R, Friedecká J, Skirycz A, Friml J. 2026. Biogenesis and downstream effects of 3’,5’ and 2’,3’ cAMP isomers in plants. Science Advances. 12(19), aea7828. Li, Mingyue, et al. “Biogenesis and Downstream Effects of 3’,5’ and 2’,3’ CAMP Isomers in Plants.” <i>Science Advances</i>, vol. 12, no. 19, aea7828, AAAS, 2026, doi:<a href="https://doi.org/10.1126/sciadv.aea7828">10.1126/sciadv.aea7828</a>. M. Li <i>et al.</i>, “Biogenesis and downstream effects of 3’,5’ and 2’,3’ cAMP isomers in plants,” <i>Science Advances</i>, vol. 12, no. 19. AAAS, 2026. Li, Mingyue, Monika Chodasiewicz, Malavika Muraleedharan, Israel M. Lopez, Michal Gorka, Olga Kerber, Saqer S. Alotaibi, et al. “Biogenesis and Downstream Effects of 3’,5’ and 2’,3’ CAMP Isomers in Plants.” <i>Science Advances</i>. AAAS, 2026. <a href="https://doi.org/10.1126/sciadv.aea7828">https://doi.org/10.1126/sciadv.aea7828</a>. Li M, Chodasiewicz M, Muraleedharan M, et al. Biogenesis and downstream effects of 3’,5’ and 2’,3’ cAMP isomers in plants. <i>Science Advances</i>. 2026;12(19). doi:<a href="https://doi.org/10.1126/sciadv.aea7828">10.1126/sciadv.aea7828</a> M. Li, M. Chodasiewicz, M. Muraleedharan, I.M. Lopez, M. Gorka, O. Kerber, S.S. Alotaibi, A.D.L. Nelson, R. Lenobel, J. Friedecká, A. Skirycz, J. Friml, Science Advances 12 (2026). Li, M., Chodasiewicz, M., Muraleedharan, M., Lopez, I. M., Gorka, M., Kerber, O., … Friml, J. (2026). Biogenesis and downstream effects of 3’,5’ and 2’,3’ cAMP isomers in plants. <i>Science Advances</i>. AAAS. <a href="https://doi.org/10.1126/sciadv.aea7828">https://doi.org/10.1126/sciadv.aea7828</a> 219142026-05-24T22:01:31Z2026-06-02T14:36:41Z