TY - JOUR
T1 - Extracellular 4′-phosphopantetheine is a source for intracellular coenzyme A synthesis
AU - Srinivasan, Balaji
AU - Baratashvili, Madina
AU - Van Der Zwaag, Marianne
AU - Kanon, Bart
AU - Colombelli, Cristina
AU - Lambrechts, Roald A.
AU - Schaap, Onno
AU - Nollen, Ellen A.
AU - Podgoršek, Ajda
AU - Kosec, Gregor
AU - Petković, Hrvoje
AU - Hayflick, Susan
AU - Tiranti, Valeria
AU - Reijngoud, Dirk Jan
AU - Grzeschik, Nicola A.
AU - Sibon, Ody C.M.
N1 - Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/10/19
Y1 - 2015/10/19
N2 - The metabolic cofactor coenzyme A (CoA) gained renewed attention because of its roles in neurodegeneration, protein acetylation, autophagy and signal transduction. The long-standing dogma is that eukaryotic cells obtain CoA exclusively via the uptake of extracellular precursors, especially vitamin B5, which is intracellularly converted through five conserved enzymatic reactions into CoA. This study demonstrates an alternative mechanism that allows cells and organisms to adjust intracellular CoA levels by using exogenous CoA. Here CoA was hydrolyzed extracellularly by ectonucleotide pyrophosphatases to 4′-phosphopantetheine, a biologically stable molecule able to translocate through membranes via passive diffusion. Inside the cell, 4′-phosphopantetheine was enzymatically converted back to CoA by the bifunctional enzyme CoA synthase. Phenotypes induced by intracellular CoA deprivation were reversed when exogenous CoA was provided. Our findings answer long-standing questions in fundamental cell biology and have major implications for the understanding of CoA-related diseases and therapies.
AB - The metabolic cofactor coenzyme A (CoA) gained renewed attention because of its roles in neurodegeneration, protein acetylation, autophagy and signal transduction. The long-standing dogma is that eukaryotic cells obtain CoA exclusively via the uptake of extracellular precursors, especially vitamin B5, which is intracellularly converted through five conserved enzymatic reactions into CoA. This study demonstrates an alternative mechanism that allows cells and organisms to adjust intracellular CoA levels by using exogenous CoA. Here CoA was hydrolyzed extracellularly by ectonucleotide pyrophosphatases to 4′-phosphopantetheine, a biologically stable molecule able to translocate through membranes via passive diffusion. Inside the cell, 4′-phosphopantetheine was enzymatically converted back to CoA by the bifunctional enzyme CoA synthase. Phenotypes induced by intracellular CoA deprivation were reversed when exogenous CoA was provided. Our findings answer long-standing questions in fundamental cell biology and have major implications for the understanding of CoA-related diseases and therapies.
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U2 - 10.1038/nchembio.1906
DO - 10.1038/nchembio.1906
M3 - Article
C2 - 26322826
AN - SCOPUS:84941874187
SN - 1552-4450
VL - 11
SP - 784
EP - 792
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 10
M1 - 1906
ER -