RESUMEN
N6 -isopentenyladenosine (i6 A) is an RNA modification found in cytokinins, which regulate plant growth/differentiation, and a subset of tRNAs, where it improves the efficiency and accuracy of translation. The installation and removal of this modification is mediated by prenyltransferases and cytokinin oxidases, and a chemical approach to selective deprenylation of i6 A has not been developed. We show that a selected group of oxoammonium cations function as artificial deprenylases to promote highly selective deprenylation of i6 A in nucleosides, oligonucleotides, and live cells. Importantly, other epigenetic modifications, amino acid residues, and natural products were not affected. Moreover, a significant phenotype difference in the Arabidopsis thaliana shoot and root development was observed with incubation of the cation. These results establish these small organic molecules as direct chemical regulators/artificial deprenylases of i6 A.
Asunto(s)
Óxidos N-Cíclicos/farmacología , Citocininas/metabolismo , Isopenteniladenosina/metabolismo , Piperidinas/farmacología , Prenilación/efectos de los fármacos , ARN/metabolismo , Arabidopsis/efectos de los fármacos , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/toxicidad , Citocininas/química , Epigénesis Genética/efectos de los fármacos , Humanos , Isopenteniladenosina/química , Células MCF-7 , Oligorribonucleótidos/química , Oligorribonucleótidos/metabolismo , Piperidinas/química , Piperidinas/toxicidad , Reguladores del Crecimiento de las Plantas/química , Reguladores del Crecimiento de las Plantas/metabolismo , Raíces de Plantas/efectos de los fármacos , Brotes de la Planta/efectos de los fármacos , ARN/químicaRESUMEN
N6 -Methyladenosine (m6 A) represents a common and highly dynamic modification in eukaryotic RNA that affects various cellular pathways. Natural dioxygenases such as FTO and ALKBH5 are enzymes that demethylate m6 A residues in mRNA. Herein, the first identification of a small-molecule modulator that functions as an artificial m6 A demethylase is reported. Flavin mononucleotide (FMN), the metabolite produced by riboflavin kinase, mediates substantial photochemical demethylation of m6 A residues of RNA in live cells. This study provides a new perspective to the understanding of demethylation of m6 A residues in mRNA and sheds light on the development of powerful small molecules as RNA demethylases and new probes for use in RNA biology.
Asunto(s)
Adenosina/análogos & derivados , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Mononucleótido de Flavina/metabolismo , Adenosina/química , Adenosina/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/análisis , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/análisis , Mononucleótido de Flavina/análisis , Células HEK293 , Células HeLa , Humanos , Estructura MolecularRESUMEN
We disclose herein a Ru(II)-catalyzed decarboxylative and oxidative coupling of N-substituted indolyl carboxylic acids with broad substrate scope in an aqueous solution. This method provides a sustainable and efficient access to synthesize various indole-fused cyclohexanyl acetic acids under mild conditions.