Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
College of Chemistry and Molecular Engineering, Peking-Tsinghua Center for Life Sciences, Center for Quantitative Biology, Peking University, Beijing, 100871, China.
Nat Commun. 2018 Dec 21;9(1):5442. doi: 10.1038/s41467-018-07868-6.
Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. Paradoxically, PHGDH and serine synthesis are required in the presence of abundant environmental serine even when serine uptake exceeds the requirements for nucleotide synthesis. Here, we establish a mechanism for how PHGDH maintains nucleotide metabolism. We show that inhibition of PHGDH induces alterations in nucleotide metabolism independent of serine utilization. These changes are not attributable to defects in serine-derived nucleotide synthesis and redox maintenance, another key aspect of serine metabolism, but result from disruption of mass balance within central carbon metabolism. Mechanistically, this leads to simultaneous alterations in both the pentose phosphate pathway and the tri-carboxylic acid cycle, as we demonstrate based on a quantitative model. These findings define a mechanism whereby disruption of one metabolic pathway induces toxicity by simultaneously affecting the activity of multiple related pathways.
磷酸甘油酸脱氢酶 (PHGDH) 催化从头合成丝氨酸过程中的关键步骤。矛盾的是，即使环境丝氨酸的摄取量超过核苷酸合成的需求，PHGDH 和丝氨酸合成在丰富的环境丝氨酸存在的情况下也是必需的。在这里，我们建立了一个 PHGDH 维持核苷酸代谢的机制。我们表明，PHGDH 的抑制诱导了核苷酸代谢的改变，而与丝氨酸的利用无关。这些变化不能归因于丝氨酸衍生的核苷酸合成和氧化还原维持的缺陷，这是丝氨酸代谢的另一个关键方面，而是由于中心碳代谢中质量平衡的破坏所致。从机制上讲，这会导致磷酸戊糖途径和三羧酸循环同时发生改变，正如我们基于定量模型所证明的那样。这些发现定义了一种机制，即通过同时影响多个相关途径的活性，破坏一种代谢途径会导致毒性。
