Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. Despite their importance, the interplay between these pathways remains poorly understood. Using genetic and metabolic analyses in Saccharomyces cerevisiae, we elucidate how cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. We find that deficiencies in the Kennedy pathway limit nucleotide salvage, prompting compensatory activation of de novo nucleotide synthesis and the pentose phosphate pathway. This metabolic shift enhances the production of antioxidants such as NADPH and glutathione. Moreover, we observe that the Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, indicating its role in antioxidative defense as an adaptive mechanism in aged cells. Our findings highlight the critical role of phospholipid synthesis pathway choice in the integrative regulation of nucleotide metabolism, redox balance and membrane properties for cellular defense.

磷脂和核苷酸合成是真核生物的基本代谢过程，它们的失调与各种疾病状态有关。尽管它们很重要，但这些途径之间的相互作用仍然知之甚少。利用酿酒酵母中的遗传和代谢分析，我们阐明了磷脂合成肯尼迪途径中三磷酸胞苷的使用如何影响核苷酸代谢和氧化还原平衡。我们发现 Kennedy 途径中的缺陷限制了核苷酸挽救，促进了从头核苷酸合成和磷酸戊糖途径的代偿性激活。这种代谢转变促进了 NADPH 和谷胱甘肽等抗氧化剂的产生。此外，我们观察到磷脂合成的 Kennedy 通路在复制衰老过程中受到抑制，表明它在衰老细胞中作为适应机制在抗氧化防御中的作用。我们的研究结果强调了磷脂合成途径选择在核苷酸代谢、氧化还原平衡和细胞防御膜特性的综合调节中的关键作用。