Institute of Biochemistry of Biologically Active Substances, National Academy of Sciences of Belarus, Grodno, 230023, Belarus.
Yanka Kupala's Grodno State University, Grodno, 230023, Belarus.
Biochemistry (Mosc). 2023 Apr;88(4):466-480. doi: 10.1134/S000629792304003X.
The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, key role of pantothenate kinase (PANK) and CoA synthetase (CoASY) in the formation of the priority mitochondrial pool of CoA, with a high metabolic turnover of the coenzyme and limited transport of Pan across the blood-brain barrier are considered. The system of acetyl-CoA, a secondary messenger, which is the main substrate of acetylation processes including formation of N-acetyl aspartate and acetylcholine, post-translational modification of histones, predetermines protection of the neurons against degenerative signals and cholinergic neurotransmission. Biochemical mechanisms of neurodegenerative syndromes in the cases of PANK and CoASY defects, and the possibility of correcting of CoA biosynthesis in the models with knockouts of these enzymes have been described. The data of a post-mortem study of the brains from the patients with Huntington's and Alzheimer's diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in the pathognomonic neurostructures. In the frontal cortex of the patients with Parkinson's disease, combined immunofluorescence of anti-CoA- and anti-tau protein was detected, reflecting CoAlation during dimerization of the tau protein and its redox sensitivity. Redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro with synaptosomal membranes and mitochondria during modeling of aluminum neurotoxicity accompanied by the decrease in the level of CoA in CNS. The ability of CoA biosynthesis precursors to stabilize glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism during exposure to neurotoxins, development of neuroinflammation and neurodegeneration, and justifies the combined use of Pan derivatives (for example, D-panthenol) and glutathione precursors (N-acetylcysteine). Taking into account the discovery of new functions of CoA (redox-dependent processes of CoAlation of proteins, possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology), it seems promising to study bioavailability and biotransformation of Pan derivatives, in particular of D-panthenol, 4'-phospho-pantetheine, its acylated derivatives, and compositions with redox pharmacological compounds, are promising for their potential use as etiopathogenetic agents.
考虑了泛酸（Pan）在 CoA 生物合成和水解中的生物转化过程、泛酰巯基乙胺（CoASH）合成酶（CoASY）和磷酸泛酰巯基乙胺（Pantetheine）激酶（PANK）在形成优先线粒体池 CoA 中的关键作用，辅酶具有高代谢周转率，而 Pan 穿过血脑屏障的转运有限。乙酰辅酶 A 系统作为第二信使，是包括 N-乙酰天冬氨酸和乙酰胆碱形成、组蛋白翻译后修饰在内的乙酰化过程的主要底物，预先决定了神经元对退行性信号和胆碱能神经传递的保护。描述了 PANK 和 CoASY 缺陷的神经退行性综合征的生化机制，以及在这些酶敲除模型中纠正 CoA 生物合成的可能性。提供了亨廷顿病和阿尔茨海默病患者死后大脑研究的数据，证明中枢神经系统中 Pan 缺乏，在神经病变结构中尤为明显。在帕金森病患者的额皮质中，检测到抗 CoA-和抗 tau 蛋白的联合免疫荧光，反映了 tau 蛋白二聚化过程中的 CoAlation 及其氧化还原敏感性。在模拟伴随中枢神经系统 CoA 水平降低的铝神经毒性时，通过突触体膜和线粒体在体外证实了 CoA 生物合成前体的氧化还原活性和抗氧化特性。考虑到 CoA（蛋白质的氧化还原依赖的 CoAlation 过程、神经退行性病变中氧化应激和 Pan（CoA）缺乏的可能关联）的新功能的发现，研究 Pan 衍生物（例如 D-泛醇）和谷胱甘肽前体（N-乙酰半胱氨酸）的生物利用度和生物转化似乎很有前途。
