一种代谢物胶水预测AICAR与一碳供应的反向偶联
A metabolite glue predicts inverse coupling of AICAR to one-carbon supply
- Nodes & Links Ltd（节点与链接有限公司）
机构由 AI 辅助整理，请以论文原文为准。
AI总结：
本研究通过代谢物胶水模型揭示AICAR与一碳供应呈反向偶联，并预测NUDT5敲除后偶联反转，为嘌呤代谢调控及化疗药物毒性机制提供新见解。
AI中文摘要：
甲酸是线粒体一碳代谢的输出物，驱动增殖细胞中腺嘌呤核苷酸水平从低到高的转换。Oizel等人2020年的动力学模型在从头嘌呤合成受生物合成需求支配的假设下重现了这种转换。此后两项独立研究确定了该假设所代表的物理控制器：ADP-核糖焦磷酸酶NUDT5结合并抑制磷酸核糖焦磷酸酰胺转移酶（PPAT）——嘌呤合成的限速酶，其中AMP作为变构代谢物胶水，底物PRPP竞争性解离该复合物。我们用显式的PRPP池和胶水门控的PPAT步骤取代了需求支配假设，并完全根据已发表的结合数据进行校准。该模型做出了一个尖锐且可证伪的预测：嘌呤前体AICAR与一碳可用性呈反向偶联，当一碳单位稀缺时AICAR升高，当一碳单位丰富时AICAR清除。这种反向偶联是胶水作用的结果：当反馈被移除——即NUDT5敲除的遗传状态——模型反而预测AICAR随一碳可用性升高而升高，符号相反。该预测在不拟合AICAR测量数据的情况下调和了Oizel等人2020年的AICAR测量结果，并且模型独立重现了NUDT5缺失细胞中PRPP池下降的报道。我们提出了区分胶水与组成型节流阀的实验，并讨论了这对AMPK信号传导以及硫嘌呤和抗叶酸化疗药物细胞毒性的影响，这些药物的作用汇聚于同一PPAT–NUDT5节点。
英文摘要：
Formate, an output of mitochondrial one-carbon metabolism, drives a switch from low to high adenine nucleotide levels in proliferating cells. The kinetic model of Oizel et al 2020 reproduced this switch under the assumption that de novo purine synthesis is slaved to biosynthetic demand. Two independent studies have since identified the physical controller that this assumption stands in for: the ADP-ribose pyrophosphatase NUDT5 binds and inhibits phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme of purine synthesis, with AMP acting as an allosteric metabolite glue and the substrate PRPP competing to dissociate the complex. We replace the demand-slaving assumption with an explicit PRPP pool and a glue-gated PPAT step, calibrated entirely against the published binding data. The model makes a sharp, falsifiable prediction: the purine precursor AICAR is coupled inversely to one-carbon availability, rising as one-carbon units become scarce and clearing when they are abundant. This inverse coupling is a consequence of the glue: with the feedback removed -- the genetic state of a NUDT5 knockout -- the model instead predicts AICAR rising with one-carbon availability, opposite in sign. The prediction reconciles the AICAR measurements of Oizel eat al 2020 without having been fitted to them, and the model independently reproduces the fall of the PRPP pool reported in NUDT5-deleted cells. We propose experiments that discriminate the glue from a constitutive throttle, and discuss the consequences for AMPK signalling and for the cytotoxicity of thiopurine and antifolate chemotherapeutics, whose action converges on this same PPAT--NUDT5 node.
