Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Department of Medicine, Department of Biological Chemistry and Molecular Pharmacology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Metab. 2024 Jun;6(6):1008-1023. doi: 10.1038/s42255-024-01059-y. Epub 2024 Jun 13.
The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K-AKT signalling regulate the vitamin B transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN).
三羧酸循环、营养物质氧化、组蛋白乙酰化和脂质、聚糖和血红素的合成都需要辅酶 A（CoA）作为辅助因子。尽管 CoA 携带的酰基的来源和调节在这些过程中受到了广泛的研究，但一个关键的基本问题却很少被考虑：CoA 的产生本身是如何被控制的？在这里，我们讨论了 CoA 的许多细胞作用，以及从半胱氨酸、ATP 和必需营养素泛酸（维生素 B）或从哺乳动物中回收的前体调控其生物合成的调节机制。涉及乙酰-CoA、其他酰基辅酶 A、酰基辅酶 A 肉碱、MYC、p53、PPARα、PINK1 以及胰岛素和生长因子刺激的 PI3K-AKT 信号转导的代谢物反馈和信号机制调节维生素 B 转运蛋白 SLC5A6/SMVT 和 CoA 生物合成酶 PANK1、PANK2、PANK3、PANK4 和 COASY。我们还讨论了测量 CoA 相关代谢物的方法、靶向 CoA 生物合成的化合物以及由于途径酶突变引起的疾病，包括白内障、心肌病和神经退行性变（PKAN 和 COPAN）。
