Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
Biomolecules. 2022 Aug 1;12(8):1065. doi: 10.3390/biom12081065.
Coenzyme A (CoA) is ubiquitous and essential for key cellular processes in any living organism. Primary degradation of CoA occurs by enzyme-mediated pyrophosphate hydrolysis intracellularly and extracellularly to form adenosine 3',5'-diphosphate and 4'-phosphopantetheine (PPanSH). The latter can be recycled for intracellular synthesis of CoA. Impairments in the CoA biosynthetic pathway are linked to a severe form of neurodegeneration with brain iron accumulation for which no disease-modifying therapy is available. Currently, exogenous administration of PPanSH is examined as a therapeutic intervention. Here, we describe biosynthetic access to thiophosphate analogs of PPanSH, 3'-dephospho-CoA, and CoA. The stabilizing effect of thiophosphate modifications toward degradation by extracellular and peroxisomal enzymes was studied in vitro. Experiments in a CoA-deficient cell model suggest a biomimetic potential of the PPanSH thiophosphate analog PPanSH (C1). According to our findings, the administration of PPanSH may provide an alternative approach to support intracellular CoA-dependent pathways.
辅酶 A（CoA）在任何生物体的关键细胞过程中都是普遍存在且必不可少的。CoA 的主要降解是通过酶介导的焦磷酸水解在细胞内和细胞外进行的，形成腺苷 3'，5'-二磷酸和 4'-磷酸泛酰巯基乙胺（PPanSH）。后者可被回收用于 CoA 的细胞内合成。CoA 生物合成途径的损伤与一种严重的神经退行性疾病有关，这种疾病伴有脑铁积累，但目前尚无有效的治疗方法。目前，正在研究外源性给予 PPanSH 作为一种治疗干预措施。在这里，我们描述了生物合成硫代磷酸类似物 PPanSH、3'-去磷酸辅酶 A 和辅酶 A 的方法。研究了硫代磷酸修饰对细胞外和过氧化物酶体酶降解的稳定作用。在 CoA 缺乏的细胞模型中的实验表明，PPanSH 的硫代磷酸类似物 PPanSH（C1）具有仿生潜力。根据我们的发现，给予 PPanSH 可能提供一种替代方法来支持细胞内依赖 CoA 的途径。
