Arginine metabolic pathway

The arginine metabolic pathway is a critical biochemical network centered on the semi-essential amino acid L-arginine, which serves as a fundamental precursor for proteins, nitric oxide, polyamines, and creatine (Szakacs et al., 2022). In many malignancies, such as melanoma, hepatocellular carcinoma, and mesothelioma, the enzyme argininosuccinate synthetase 1 (ASS1) is downregulated, rendering these cells "arginine auxotrophic" and entirely dependent on the extracellular L-arginine pool for survival (Delage et al., 2010). Therapeutic strategies targeting this pathway typically involve the administration of pegylated enzymes, such as pegargiminase (ADI-PEG 20) or pegzilarginase, which enzymatically deplete systemic arginine to starve auxotrophic tumor cells, leading to cell cycle arrest and apoptosis (Long et al., 2017). Beyond direct tumor starvation, the availability of arginine in the tumor microenvironment is a major determinant of immune efficacy, as its depletion by arginase-secreting myeloid cells can lead to T-cell dysfunction and immunosuppression (Rodriguez et al., 2004). Consequently, modulating the extracellular arginine pool offers a dual therapeutic approach: metabolic starvation of cancer cells and potential restoration of anti-tumor immunity.

Other names

Extracellular L-arginine poolArginine deprivation therapyL-arginine metabolismArginine auxotrophy pathway

Enzymatic depletion of extracellular L-arginine to induce metabolic starvation, inhibit protein synthesis, and trigger the integrated stress response in arginine-auxotrophic cells (Szakacs et al., 2022).