title: Extracellular 4'-phosphopantetheine is a source for intracellular coenzyme A synthesis.
abstract: 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.
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Balaji
authors: B
authors: Srinivasan
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Madina
authors: M
authors: Baratashvili
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Marianne
authors: M
authors: van der Zwaag
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Bart
authors: B
authors: Kanon
authors: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors: Cristina
authors: C
authors: Colombelli
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Roald A
authors: RA
authors: Lambrechts
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Onno
authors: O
authors: Schaap
authors: European Research Institute for the Biology of Aging, University of Groningen, Groningen, the Netherlands.
authors: Ellen A
authors: EA
authors: Nollen
authors: Acies Bio d.o.o., Ljubljana, Slovenia.
authors: Ajda
authors: A
authors: Podgoršek
authors: Acies Bio d.o.o., Ljubljana, Slovenia.
authors: Gregor
authors: G
authors: Kosec
authors: Acies Bio d.o.o., Ljubljana, Slovenia.
authors: Hrvoje
authors: H
authors: Petković
authors: Departments of Molecular and Medical Genetics, Pediatrics, and Neurology, Oregon Health &Science University, Portland, Oregon, USA.
authors: Susan
authors: S
authors: Hayflick
authors: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors: Valeria
authors: V
authors: Tiranti
authors: Department of Laboratory Medicine, Center for Liver Digestive and Metabolic Diseases, University Medical Center Groningen, Groningen, the Netherlands..
authors: Dirk-Jan
authors: http://orcid.org/0000-0003-1157-4491
authors: DJ
authors: Reijngoud
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Nicola A
authors: NA
authors: Grzeschik
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Ody C M
authors: OC
authors: Sibon
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism*; D002460:Cell Line; D003065:Coenzyme A / Q000096:biosynthesis* / Q000097:blood / Q000494:pharmacology; D003066:Coenzyme A Ligases / Q000378:metabolism; D004330:Drosophila / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008136:Longevity / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D010204:Pantetheine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism
chemical_list: D010204:Pantetheine; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003066:Coenzyme A Ligases; C003129:4'-phosphopantetheine; D003065:Coenzyme A