Argininosuccinate synthetase 1 (ASS1) (ASS1)

Argininosuccinate synthetase 1 (ASS1) is a key metabolic enzyme that catalyzes the penultimate step of the urea cycle, converting citrulline and aspartate into argininosuccinate [1, 3]. In many aggressive malignancies, such as melanoma and hepatocellular carcinoma, ASS1 expression is lost due to epigenetic silencing, a phenomenon known as arginine auxotrophy [2, 3]. Because these ASS1-deficient tumor cells cannot synthesize arginine endogenously, they become critically dependent on the uptake of arginine from the extracellular pool for essential processes like protein synthesis and polyamine production [2, 4]. This metabolic dependency creates a therapeutic window for arginine deprivation therapy, which utilizes enzymes like pegylated arginine deiminase (ADI-PEG 20) or recombinant human arginase to deplete systemic arginine levels [2, 5]. Depleting the extracellular arginine pool induces metabolic stress and apoptosis specifically in ASS1-deficient cells while sparing normal tissues that can produce their own arginine [3, 5]. However, clinical challenges include the potential for tumors to develop resistance by upregulating ASS1 expression or utilizing alternative metabolic pathways [2, 6].

Other names

Argininosuccinate synthaseCitrulline--aspartate ligaseASSCTLN1

Arginine deprivation therapy via enzymatic depletion of systemic arginine, leading to metabolic exhaustion and apoptosis in ASS1-deficient cells [2, 5].