Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
Nat Chem Biol. 2015 Oct;11(10):784-92. doi: 10.1038/nchembio.1906. Epub 2015 Aug 31.
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.
代谢辅助因子辅酶 A（CoA）因其在神经退行性变、蛋白质乙酰化、自噬和信号转导中的作用而重新受到关注。长期以来的观点认为，真核细胞只能通过摄取细胞外前体，特别是维生素 B5，来获得 CoA，维生素 B5 在细胞内通过五个保守的酶促反应转化为 CoA。本研究证明了一种替代机制，允许细胞和生物体通过使用外源性 CoA 来调节细胞内 CoA 水平。在这里，CoA 被细胞外核苷酸焦磷酸酶水解为 4'-磷酸泛酰巯基乙胺，这是一种生物稳定的分子，能够通过被动扩散穿过膜转运。在细胞内，4'-磷酸泛酰巯基乙胺通过双功能酶 CoA 合酶被酶促转化回 CoA。当提供外源性 CoA 时，细胞内 CoA 缺乏引起的表型被逆转。我们的发现回答了基础细胞生物学中长期存在的问题，并对理解与 CoA 相关的疾病和治疗具有重要意义。
