在二十种蛋白质氨基酸中，谷氨酰胺和天冬酰胺代表了侧链中含有末端酰胺的独特群体，并且具有直接的代谢关系，谷氨酰胺通过 ATP 依赖性天冬酰胺合成酶 (ASNS) 反应生成天冬酰胺。循环中的谷氨酰胺水平以及通过细胞和组织的代谢通量大大超过了天冬酰胺，癌症中的“谷氨酰胺成瘾”同样受到了相当大的关注。然而，历史和最近的证据共同表明，尽管天冬酰胺的存在量不大，但它在细胞功能中发挥着巨大的调节作用。在这里，我们提出了一个统一的基于证据的假设，即酰胺构成了一个调节信号回路，以谷氨酰胺作为驱动剂，以天冬酰胺作为第二信使，以变构方式调节关键的生化和生理功能，特别是细胞生长和存活。具体来说，有人提出 ASNS 作为增殖细胞进入 S 期和进展的底物充足度的传感器。 ASNS 产生的天冬酰胺作为随后的第二信使，调节关键调节蛋白的活性并促进细胞在面临压力时的生存，并作为细胞生长 S 期进展的前馈驱动因素。我们建议将此信号通路命名为酰胺信号通路 (ASC)，以向 SLC1A5 编码的 ASCT2 致敬，ASCT2 以双向方式转运谷氨酰胺和天冬酰胺，并与多种人类癌症的发病机制有关。最近的发现为 ASC 模型提供了支持，即在代谢应激期间，初级纤毛通过 ASNS 感知谷氨酰胺。

Among the twenty proteinogenic amino acids, glutamine and asparagine represent a unique cohort in containing a terminal amide in their side chain, and share a direct metabolic relationship, with glutamine generating asparagine through the ATP-dependent asparagine synthetase (ASNS) reaction. Circulating glutamine levels and metabolic flux through cells and tissues greatly exceed those for asparagine, and "glutamine addiction" in cancer has likewise received considerable attention. However, historic and recent evidence collectively suggest that in spite of its modest presence, asparagine plays an outsized regulatory role in cellular function. Here, we present a unifying evidence-based hypothesis that the amides constitute a regulatory signaling circuit, with glutamine as a driver and asparagine as a second messenger that allosterically regulates key biochemical and physiological functions, particularly cell growth and survival. Specifically, it is proposed that ASNS serves as a sensor of substrate sufficiency for S-phase entry and progression in proliferating cells. ASNS-generated asparagine serves as a subsequent second messenger that modulates the activity of key regulatory proteins and promotes survival in the face of cellular stress, and serves as a feed-forward driver of S-phase progression in cell growth. We propose that this signaling pathway be termed the Amide Signaling Circuit (ASC) in homage to the SLC1A5-encoded ASCT2 that transports both glutamine and asparagine in a bidirectional manner, and has been implicated in the pathogenesis of a broad spectrum of human cancers. Support for the ASC model is provided by the recent discovery that glutamine is sensed in primary cilia via ASNS during metabolic stress.