Argininosuccinate synthase 1 (ASS1) (ASS1)

Argininosuccinate synthase 1 (ASS1) is a cytosolic enzyme that catalyzes the conversion of citrulline and aspartate into argininosuccinate, representing the rate-limiting step in the de novo biosynthesis of arginine (UniProt P00966). In many human cancers, such as melanoma, mesothelioma, and hepatocellular carcinoma, the ASS1 gene is epigenetically silenced or deleted, leading to a metabolic phenotype known as arginine auxotrophy (PMID: 21212444). Because these ASS1-deficient cancer cells cannot produce their own arginine, they are entirely dependent on the uptake of extracellular arginine for survival, proliferation, and protein synthesis (PMID: 27103441). This metabolic vulnerability is exploited by arginine-depleting agents, such as pegylated arginine deiminase (ADI-PEG20), which lower systemic arginine levels to starve the tumor cells while sparing normal tissues that can synthesize their own arginine (PMID: 30104600). Clinical challenges include the development of neutralizing antibodies against the therapeutic enzymes and the potential for tumors to develop resistance by re-expressing ASS1 (PMID: 25091762). Current research focuses on combining arginine deprivation with other metabolic inhibitors or chemotherapy to enhance efficacy in ASS1-deficient tumors (PMID: 28611301).

Other names

Argininosuccinate synthetase 1Citrulline--aspartate ligaseASSCTLN1

Systemic depletion of extracellular arginine to induce metabolic starvation, cell cycle arrest, and apoptosis in arginine-auxotrophic (ASS1-deficient) cancer cells.