Diadenosine tetraphosphate (Ap4A) - anE. colialarmone or a damage metabolite?

Autor:	Alon Savidor, Dan S. Tawfik, Laura Fumagalli, Alexander Brandis, Yishai Levin, Dragana Despotovic
Rok vydání:	2017
Předmět:	Lysine-tRNA Ligase 0301 basic medicine Metabolite Biology medicine.disease_cause Biochemistry 03 medical and health sciences chemistry.chemical_compound Stress Physiological Side product Escherichia coli medicine Homeostasis Molecular Biology 030102 biochemistry & molecular biology Escherichia coli Proteins Gene Expression Regulation Bacterial Cell Biology Metabolism Acid Anhydride Hydrolases Heat stress Zinc Zinc homeostasis 030104 developmental biology chemistry Ap4A Dinucleoside Phosphates Signal Transduction Alarmone
Zdroj:	The FEBS Journal. 284:2194-2215
ISSN:	1742-464X
DOI:	10.1111/febs.14113
Popis:	Under stress, metabolism is changing: specific up- or down-regulation of proteins and metabolites occurs as well as side effects. Distinguishing specific stress-signaling metabolites (alarmones) from side products (damage metabolites) is not trivial. One example is diadenosine tetraphosphate (Ap4A) - a side product of aminoacyl-tRNA synthetases found in all domains of life. The earliest observations suggested that Ap4A serves as an alarmone for heat stress in Escherichia coli. However, despite 50 years of research, the signaling mechanisms associated with Ap4A remain unknown. We defined a set of criteria for distinguishing alarmones from damage metabolites to systematically classify Ap4A. In a nutshell, no indications for a signaling cascade that is triggered by Ap4A were found; rather, we found that Ap4A is efficiently removed in a constitutive, nonregulated manner. Several fold perturbations in Ap4A concentrations have no effect, yet accumulation at very high levels is toxic due to disturbance of zinc homeostasis, and also because Ap4A's structural overlap with ATP can result in spurious binding and inactivation of ATP-binding proteins. Overall, Ap4A met all criteria for a damage metabolite. While we do not exclude any role in signaling, our results indicate that the damage metabolite option should be considered as the null hypothesis when examining Ap4A and other metabolites whose levels change upon stress.
Databáze:	OpenAIRE
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